The annual Revision of Psychology

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Volume 50(1999) the 1999 pp 599-624 Annual

THE ALONE-GENE INFLUENCES IN THE BRAIN AND BEHAVIOR

[The revision]
Wahlsten, D.,
The department of Psychology, the University of Alberta, Edmonton, Alberta, Canada T6G
2E9; the electronic mail: wahlsten@psych.ualberta.ca.

The contour
· Abstract
THE INTRODUCTION DE ·
THE · GENE DISCOVERY
· The Compleat Genome
The · Targeted Mutations
The Union of · and Cartography of the Chromosome
· the Places of the Quantitative Feature
· the Allele Association Studies
The Databases of · of Genetic Information
THE · GENE FUNCTION
· Natural Polymorphisms
· the Genetic Dissection
The Systems of · of Genes
· THE BEHAVIORAL CONFIRMATION
The Interactions of · with the Situation of the Test and Atmosphere
· the Growing Necessity for the Standardization of the Test
The Validity of · of Animal Models
THE CONCLUSIONS DE ·
THE RECOGNITIONS DE ·
THE REFERENCES DE ·

The graphics
· Table 1
· Figures 1
· Figures 2
· Table 2
· Figures 3
· Figures 4

The the abstract thing

As the analysis of the traditional behavioral genetics it unites with the neurogenetics, the
field of genetic of the neurobehavioral, focusing in the alone-gene makes, he/she enters in
being. The New one
biotechnology has hurried largely regarding the discovery of the gene and the study of
function of the gene the brain and behavior. More than 7,000 genes in the mice and 10,000
in the humans has been documented now, and the extensive information on the genetics of
several species is quickly available in the Web. Based on the knowledge of the succession
of DNA of a gene, a mutation of the targeted with the capacity to disable it can be created.
These null calls are knockout-also used in the study of a wide range of phenotypes, even
the learning and memory, the appetite and obesity, and rhythms of the circadian. The era of
effects of the examining alone-gene of a perspective of the reductionistic is decreasing, and
he/she investigates with the crisscross series of genes in the several environmental contexts
it is demonstrating a necessity for the system-guided theory.

THE WORDS OF THE KEY: Genome human Project, the place of the quantitative feature,
the reductionism, the Web, the mutation of the targeted,
THE INTRODUCTION
Contrary to the revisions of the previous behavioral genetics in this series that divided the
field for the species (human and nonhuman) (Wimer & Wimer 1985, Rose 1995), [106,81]
this revision divides the field according to the alone-gene and methodologies of the
biometrical. It focuses in the remarkable progress and perspectives in the discovery and
understanding of specific gene makes in several species, even the humans. Many
neurological mutations that exhibit the big effects have had their deciphered successions of
DNA and their products of the protein identified, and much has been wise on how the
expression of the gene is regulated by the atmosphere. The investigators of the behavioral
genetics have advanced to a new phase, and he/she has begun to examine crisscross couples
of genes and to identify viable genetic variants that exercise the subtlest effects now in the
behavior. As the field of genetic of the neurobehavioral arises, the genetic tools are
becoming power stations to investigate in the physiologic psychology.
Typically, the biometrical or the quantitative genetic approach is applied when many
unknown genes are believed, each one with the effect presumably small, to be involved.
Instead of identifying the specific genes, this methodology looks for to divide the variation
among attributable several components to the genetic and environmental variation. There
has been a tension among the two approaches from the early days of genetic, as reflected in
Johannsen (1911:138) [48] the opinion of the methods of the correlational used by Francis
Galton and Karl Pearson: "They have to make at all with anything genetics-or the general
biology! Their premises are inadequate for the vision in the inheritance nature." This
tension continues. Although the mathematical models of biometrics have become more
sophisticated undoubtedly and they have been applying to nervous system and the
behavioral analysis (Rijsdijk & Boomsma 1997), [78] the fundamental disagreements are
plentiful about the basic formulation and assumptions of the quantitative models (the et of
Devlin at the 1997, Schonemann 1997, Wahlsten 1990, 1994), [31,87,101,102] and many
practitioners are being attracted of genetic quantitative to the study of effects of the alone-
gene (the et of Boomsma at the 1997, et of McClearn at the 1991). [11,67] In the view of
Plomin and partners (1994), [76] the quantitative genetic studies are no longer needed
"additional to document the influence importance" genetics (that is to say the one
biotechnology has hurried largely regarding the discovery of the gene and the study of
function of the gene the brain and behavior. More than 7,000 genes in the mice and 10,000
in the humans has been documented now, and the extensive information on the genetics of
several species is quickly available in the Web. Based on the knowledge of the succession
of DNA of a gene, a mutation of the targeted with the capacity to disable it can be created.
These null calls are knockout-also used in the study of a wide range of phenotypes, even
the learning and memory, the appetite and obesity, and rhythms of the circadian. The era of
effects of the examining alone-gene of a perspective of the reductionistic is decreasing, and
he/she investigates with the crisscross series of genes in the several environmental contexts
it is demonstrating a necessity for the system-guided theory.

THE WORDS OF THE KEY: Genome human Project, the place of the quantitative feature,
the reductionism, the Web, the mutation of the targeted,
THE INTRODUCTION
Contrary to the revisions of the previous behavioral genetics in this series that divided the
field for the species (human and nonhuman) (Wimer & Wimer 1985, Rose 1995), [106,81]
this revision divides the field according to the alone-gene and methodologies of the
biometrical. It focuses in the remarkable progress and perspectives in the discovery and
understanding of specific gene makes in several species, even the humans. Many
neurological mutations that exhibit the big effects have had their deciphered successions of
DNA and their products of the protein identified, and much has been wise on how the
expression of the gene is regulated by the atmosphere. The investigators of the behavioral
genetics have advanced to a new phase, and he/she has begun to examine crisscross couples
of genes and to identify viable genetic variants that exercise the subtlest effects now in the
behavior. As the field of genetic of the neurobehavioral arises, the genetic tools are
becoming power stations to investigate in the physiologic psychology.
Typically, the biometrical or the quantitative genetic approach is applied when many
unknown genes are believed, each one with the effect presumably small, to be involved.
Instead of identifying the specific genes, this methodology looks for to divide the variation
among attributable several components to the genetic and environmental variation. There
has been a tension among the two approaches from the early days of genetic, as reflected in
Johannsen (1911:138) [48] the opinion of the methods of the correlational used by Francis
Galton and Karl Pearson: "They have to make at all with anything genetics-or the general
biology! Their premises are inadequate for the vision in the inheritance nature." This
tension continues. Although the mathematical models of biometrics have become more
sophisticated undoubtedly and they have been applying to nervous system and the
behavioral analysis (Rijsdijk & Boomsma 1997), [78] the fundamental disagreements are
plentiful about the basic formulation and assumptions of the quantitative models (the et of
Devlin at the 1997, Schonemann 1997, Wahlsten 1990, 1994), [31,87,101,102] and many
practitioners are being attracted of genetic quantitative to the study of effects of the alone-
gene (the et of Boomsma at the 1997, et of McClearn at the 1991). [11,67] In the view of
Plomin and partners (1994), [76] the quantitative genetic studies are no longer needed
"additional to document the influence importance" genetics (that is to say the one
esheritability) in intelligence, and investigators should try to identify the specific genes on
the other hand.
THE DISCOVERY OF THE GENE
The last goal of genetic behavioral and neural it is an understanding understanding of the
identities, functions, and the pertinent multiple relationships of genes to the behavior of
organisms. In this it considers, it is important to know how many different genes a species
possesses, it has already been identified how many of these, and it is probable that how
many it is important for the behavior.
The Compleat Genome
The Project of Genome Human search to determine the whole succession of the nucleotide
bases (A, C, G, T, or adenine, the cytosine, the guanine, the thymine) in the DNA of the
chromosomes of several species. The global size of the genome regarding millions of bases
(Mb) it is listed for several species in Table 1. once the whole succession of DNA is the
well-known, molecular biologists they can identify each only gene noticing the developing
signatures of low successions that indicate where to begin and to stop the transcription of
DNA in messenger RNA (the mRNA). Each molecule of the mRNA is translated in a
molecule of the protein. If one knows the succession of DNA of a gene, the structure of
their corresponding protein it can be deduced quickly from the genetic code. This has been
completed in several organisms of the unicellular, even a yeast with 6297 genes.

[The help with image that you go]

Table 1. the Size of the genome regarding the number of genes, proteins, and neurons in
several species that are studied intensively in the behavior geneticsa

The sequencing task is vastly more tedious in the vertebrates because the segments of DNA
(the exons) that is transcribed in the mRNA and he/she translated in the protein it is spread
by the numerous and big segments (the introns) that doesn't code for the protein. He/she is
considered that in the humans and mice the informative exons understands a vile 2% of the
total DNA; a fabulously the expensive effort to date has completed the sequencing it only
stops the human's 2% and 0.2% of the genomes of the mouse (the et of Rowen at the 1997).
[83] once the numbers of genes in DNA that has already been the sequenced are known, the
total number can be considered (Table 1). The process of identification of the gene in the
vertebrates can accelerate studying the mRNA expressed in a variety of fabrics of the group
different etario largely. This mRNA can march behind-transcribirse in complementary
DNA (the cDNA) that consists completely of exons that can be analyzed to surrender the
succession expressed label (ESTs). This has been completed in a big scale for the human
genome, and ESTs they exist for one or more exons of some 40,000 of the prospective total
of 70,000 human genes (the et of Rowen at the 1997). [83] the Progress toward a relatively
complete accounting of expressed genes can be evaluated by the number of structures of the
protein known in a species (Table 1).
Sequencing the genome of convenient, the species of the nonhuman has the biggest benefits
for the discovery of the gene in the humans because many genes and proteins are the owing
homologous to the descent of a common but remote ancestor. For example, at least 1914 of
the 6297 proteins of the yeast the cerevisiae of S. has the homologs in the mammals (the et
of Botstein at the 1997), [13] and the homology is substancialmente mayor en más
estrechamente especies relacionadas como los ratones y humanos (vea
www.informatics.jax.org/reports.html para una lista extensa de homologías).
Las Mutaciones de Targeted
¿Del tens de miles de genes en un mamífero, cuántos podría ser pertinente para entender
desarrollo del sistema nervioso y conducta? Esta pregunta puede aproximarse directamente.
Una vez la sucesión de ADN de un exon de un gen es conocida, una sonda de ADN
personalizada puede construirse y entonces puede insertarse en ese gen específico (Joyner
1993). [50] Este procedimiento crea una mutación del targeted que normalmente previene
síntesis de la proteína correspondiente (llamó un knockout, o la mutación nula), pero
también es posible cambiar sólo un aminoácido específico en una proteína (el et de Giese al
1998). [39] El ratón es el asunto preferido para esta técnica, y la 129 tensión innata
normalmente es la fuente de células que son genéticamente alteradas. Porque un substrain
comúnes (129/SvJ) se ha contaminado genéticamente (el et de Simpson al 1997, et de
Threadgill al 1997) [89,95] y la 129 tensión, como todo las tensiones innatas, tiene varios
anormalidades neurales y conductuales, la interpretación de resultados a veces se nubla (el
et de Crawley al 1997, Gerlai 1996, Wahlsten & Chispea 1995, et de Wolfer al 1997).
[24,38,103,108] No obstante, la técnica del knockout es inestimable y puede refinarse para
dirigirse las limitaciones más tempranas. Ciento de tipos de ratones se ha creado que falta
una proteína específica (como el receptor del estrógeno del gen de Estra), y el numeroso
ratón planea de enfermedades genéticas humanas se ha creado alterando el gen pertinente
(por ejemplo el Fmr1 knockout modelo de X Frágil el retraso mental). La mutación nula es
un instrumento relativamente embotado, pero en muchos investigadores de los casos
obtener animales viables que experimentaron sólo efectos perjudiciales menores o no
mostraron los efectos perceptibles en absoluto se han sorprendido. Por ejemplo, ratones con
un dopamine inválido beta-hydroxylase el gen (Dbh) es incapaz sintetizar el norepinephrine
y tener las dificultades de motor, pero puede por otra parte aprender bastante bien (Thomas
& Palmiter 1997). [94] Porque el uso de tamaños de la muestra pequeños es común en el
trabajo con los ratones del knockout, más más de los tales experimentos falte el poder
estadístico para descubrir los efectos pequeños o moderados y hacerlo arriesgado proclamar
el génesis de un ratón completamente normal. Además, investigadores normalmente
enfocan en un phenotype y genes del blanco de interés particular, mientras implicando que
la muestra existente de mutaciones es nada representativa del genome del ratón. Un
funcional examine del genome entero golpeando fuera un gen en un momento es ahora
factible para la levadura; en el futuro cercano el examine también puede ser aplicable a los
gusanos del nematodo, pero no a los animales más complejos.
Otro acercamiento es crear las mutaciones aleatorias (muchos de los cuales ocurrirá en los
genes desconocidos) y registro cuántos de éstos daña desarrollo de un órgano entonces.
Aunque un número preciso no puede determinarse en la actualidad, los datos disponibles
sugieren que los miles de gen-quizás tantos como 70% de todos se requiere para el
desarrollo normal de un órgano complejo como el ojo (Miklos & Rubin 1996). [69]
La unión y Cartografía del Cromosoma
La tecnología ADN-basado puede revelar todos los genes, si o no ellos tienen los
formularios alternados (el alleles) eso crean el polymorphism de la proteína, o diferencias
individuales en la conducta en una población. Por consiguiente, mucha de esta información
genética es de menos interés a psicólogos para quien los relativamente pocos genes
pertinente a los desórdenes conductuales proporcione la información más pertinente. El
acercamiento clásico a las genéticas empieza con una diferencia notable en el phenotype
ysubstantially bigger in more closely related species as the mice and human (he/she sees
www.informatics.jax.org/reports.html for an extensive list of homologies).
The Mutations of Targeted
Of the tens of thousands of genes in a mammal, how many could it be pertinent to
understand development of the nervous system and behavior? This question can approach
directly. Once the succession of DNA of an exon of a gene is known, a personalized probe
of DNA can be built and then it can be inserted in that specific gene (Joyner 1993). [50]
This procedure believes a mutation of the targeted that usually prevents synthesis of the
corresponding protein (he/she called a knockout, or the null mutation), but it is also
possible to only change a specific amino acid in a protein (the et of Giese at the 1998). [39]
The mouse is the favorite matter for this technique, and the 129 innate tension is usually the
source of cells that you/they are genetically altered. Because a common substrain (129/SvJ)
it has been contaminated genetically (the et of Simpson at the 1997, et of Threadgill at the
1997) [89,95] and the 129 tension, as all the innate tensions, he/she has several neural and
behavioral abnormalities, the interpretation of having been sometimes clouds over (the et of
Crawley at the 1997, Gerlai 1996, Wahlsten & it Sparks 1995, et of Wolfer at the 1997).
[24,38,103,108] nevertheless, the technique of the knockout is invaluable and it can be
refined to go the earliest limitations. Hundred of types of mice have been created that it
lacks a specific protein (as the receiver of the estrogen of the gene of Estra), and the
numerous mouse drifts of human genetic illnesses it has been created altering the pertinent
gene (for example the Fmr1 model knockout of Fragile X the mental delay). The null
mutation is a relatively blunt instrument, but in many investigators of the cases to obtain
viable animals that only experienced smaller harmful effects or they didn't show the
perceptible effects at all they have been surprised. For example, mice with an invalid
dopamine beta-hydroxylase the gene (Dbh) it is unable to synthesize the norepinephrine
and to have the motor difficulties, but on the other hand he/she can learn quite well
(Thomas & Palmiter 1997). [94] Because the use of sizes of the small sample is common in
the work with the mice of the knockout, more more than the such experiments it lacks
statistical power to discover the small or moderate effects and to make it chancy to
proclaim the genesis of a totally normal mouse. Also, investigators usually focus in a
phenotype and genes of the target of particular interest, while implying that the existent
sample of mutations is anything representative of the genome of the mouse. A functional
one examines of the whole genome hitting a gene outside in a moment it is now feasible for
the yeast; in the near future the one examines it can also be applicable to the worms of the
nematode, but not to the most complex animals.
Another approach is to create the random mutations (many of which it will happen in the
unknown genes) and I register how many of these it damages development of an organ
then. Although a precise number cannot be determined at the present time, the available
data suggest that the thousands of gene-maybe so many as 70% of all is required for the
normal development of a complex organ as the eye (Miklos & Rubin 1996). [69]
The union and Cartography of the Chromosome
The DNA-based technology can reveal all the genes, if or not they have the alternate forms
(the alleles) that believes the polymorphism of the protein, or differences singular in the
behavior in a population. Consequently, much of this genetic information is from less
interest to psychologists for who the pertinent relatively few genes to the behavioral
disorders provide the most pertinent information. The classic approach to the genetics
begins with a remarkable difference in the phenotype and entonces pregunta si la herencia
sigue que Mendelian gobierna y si el gen hipotético se une a un marcador a una situación
conocida en un cromosoma. La búsqueda para la unión se ha facilitado grandemente por el
descubrimiento de miles de neutral del phenotypically y favorablemente el polymorphic los
marcadores de ADN esparcieron ampliamente por el genome de mamíferos (el et de
Dietrich al 1995). [32] Si una mutación en un gen desconocido con los efectos del
comandante en el cerebro o la conducta ocurre, es ahora posible descubrirlo rápidamente y
localizarlo con precisión en un mapa del cromosoma.
Un ejemplo bueno se proporciona en los ratones por el barrelless (el brl) mutación que
borra el normal barril-formó modelo de asambleas de la neurona en la corteza del
somatosensory. La primera descripción del phenotype fue publicada recientemente (el et de
Welker al 1996), [104] y menos que 2 años después se trazó a una zona estrecha en
cromosoma 11 (el et de Abdel-Majid al 1998) [1] eso ya fue conocido para contener seis
otros genes. Estos seis se hicieron los candidatos creíbles para el brl, y la búsqueda estrechó
para enfocar en el gen rápidamente Adcy1 que codifican para el cyclase de adenylyl de
enzima teclean yo, una parte importante de un intracellular que señala senda que involucra
el AMPERIO cíclico (el campamento) en las neuronas. Como él resultó, esa enzima había
reducido la actividad en los ratones mutante, y una tensión de knockout de unrelated que
faltó un gen de Adcy1 funcional se encontró a

falte los barriles del cerebro. Los ratones mutante también sufrieron los déficites de
memoria. También se clarificaron las causas de las estructuras barril. Este modelo distinto
se impresiona en la corteza cerebral por la entrada neural del vibrissae en el hocico del
animal, y la alteración de la senda del campamento por una mutación previene la impresión
anatómica de experiencia sensoria. Ahora que el gen se entiende bien, está propiamente
llamado el cyclase del adenylyl teclee yo el gen, y la mutación se vuelve la pérdida de
allelle de la función Adcy1brl.
La cartografía genética con los marcadores neutros también trabaja bien en los asuntos
humanos y se ha usado para descubrir los genes pertinente a muchos desórdenes
neurológicos raros recientemente. La mayoría de los casos de inequívocamente cartografía
exitosa de genes de la enfermedad ha involucrado phenotypes del dichotomous que difiere
distintamente entre el normal y los individuos anormales, y donde la mutación tiene un
efecto grande. Se han hecho los tremendos esfuerzos descubrir la unión con genes
hipotéticos que pertenecen a algunos de los desórdenes psiquiátricos más comúnes que
otoño en las categorías de diagnóstico bastante arbitrarias, como la depresión maníaca y
esquizofrenia. Algunos publicaron las demandas de unión han demostrado ser los positivo
falsos, y la más reciente evidencia para la unión de esquizofrenia con los marcadores en los
cromosomas 6 y 8 restos sólo débil sugestivo (Kidd 1997, Moldin 1997, Moldin &
Gottesman 1997). [54,70,71] Dado el muchos estudios hechos en este tema, es razonable
concluir que ningún solo gen contribuye de una manera mayor al etiology de esquizofrenia.
Cualquier influencia genética involucra la interacción del nonlinear" de múltiplo el más
probablemente los factores" genéticos y medioambientales (Cloninger 1997), [21] y estos
efectos serán muy difíciles de identificar con análisis de la unión convencional que asume
todo los efectos para ser independientes (Kidd 1997). [54]
Los Sitios del Rasgo cuantitativos
Más variación conductual es continua y la mayoría de los efectos genéticos probablemente
no es muy grande en el rango normal de variación. Un tamaño de efecto moderado de un
sitio del rasgo cuantitativo (QTL) puede descubrirse por su unión con los marcadores
dethen question if the inheritance continues that Mendelian governs and if the hypothetical
gene unites to a marker to a well-known situation in a chromosome. The search for the
union has been facilitated largely by the discovery of neutral's of the phenotypically
thousands and favorably the polymorphic the markers of DNA spread thoroughly for the
genome of mammals (the et of Dietrich at the 1995). [32] If a mutation in an unknown gene
with the commandant's effects in the brain or the behavior happens, it is now possible to
discover it quickly and to locate him accurately in a map of the chromosome.
A good example is provided in the mice by the barrelless (the brl) mutation that erases the
normal one model of assemblies of the neuron barrel-formed in the bark of the
somatosensory. The first description of the phenotype was published recently (the et of
Welker at the 1996), [104] and less than 2 years later it was traced to a narrow area in
chromosome 11 (the et of Abdel-Majid at the 1998) [1] that was already known to contain
six other genes. These six were made the believable candidates for the brl, and the search
narrowed to focus quickly in the gene Adcy1 that code for the cyclase of enzyme adenylyl
they type me, an important part of an intracellular that points out path that involves the
recurrent AMPERE (the camp) in the neurons. As him it was, that enzyme had reduced the
activity in the mice mutant, and a tension of unrelated knockout that it lacked a gene of
functional Adcy1 it was to

lack the barrels of the brain. The mice mutant also suffered by heart the deficits. The causes
of the structures barrel were also clarified. This different model is impressed in the cerebral
bark by the neural entrance of the vibrissae in the muzzle of the animal, and the alteration
of the path of the camp for a mutation you/he/she prevents the anatomical impression of
sensory experience. Now that the gene understands each other well, it is properly call the
cyclase of the adenylyl I type the gene, and the mutation becomes the loss of allelle of the
function Adcy1brl.
The genetic cartography with the neuter markers also works well in the human matters and
it has been used to discover the pertinent genes recently to many strange neurological
disorders. Most of the cases of unequivocally successful cartography of genes of the illness
has involved phenotypes of the dichotomous that differs distinctly between the normal one
and the abnormal individuals, and where the mutation has a big effect. The tremendous
efforts have been made discover the union with hypothetical genes that belong to some of
the most common psychiatric disorders that autumn in the categories of diagnostic quite
arbitrary, as the maniac depression and schizophrenia. Some published the demands of
union they have demonstrated to be the positive one false, and the most recent evidence for
the schizophrenia union with the markers in the chromosomes 6 and 8 remains only weak
suggestive (Kidd 1997, Moldin 1997, Moldin & Gottesman 1997). [54,70,71] Given the
many studies made in this topic, it is reasonable to conclude that no single gene contributes
from a bigger way to the schizophrenia etiology. Any genetic influence involves the
interaction of the nonlinear" of multiple the more ones probably the factors" genetic and
environmental (Cloninger 1997), [21] and these effects will be very difficult of identifying
with analysis of the conventional union that assumes the whole effects to be independent
(Kidd 1997). [54]
The Places of the quantitative Feature
More behavioral variation is continuous and most of the genetic effects are not probably
very big in the normal range of variation. A size of moderate effect of a place of the
quantitative feature (QTL) it can be discovered for their union with the markers of ADN
neutros (el et de Belknap al 1997, Lander & Schork 1994, el et de McClearn al 1991).
[6,57,67] Los resultados se interpretan el más prontamente cuando el experimento empieza
con dos tensiones innatas porque puede haber sólo dos alleles, y los alleles del marcador se
conocerán en ambas tensiones. En un F2 la cruz híbrida, las frecuencias del genotipo
tendrán las proporciones de Mendelian al marcador. El más íntimo el sitio del marcador es
al gen supuesto, el más bajo será su probabilidad de recombinación. Así, si el QTL tiene un
efecto apreciable en la conducta, debe haber un estadísticamente la diferencia significante
en las cuentas de la prueba conductuales malas de individuos con los genotipos del
marcador diferentes. Examinando varios marcadores en el mismo cromosoma y usando el
programa de computadora de CARTÓGRAFO, el QTL puede localizarse dentro de un
intervalo de confianza.
Dos dificultades mayores desafían a las usuarias de metodología de QTL. (un) UN examine
típicamente del genome entero involucra varios marcadores en cada uno de 20 cromosomas
independientes en los ratones, y en los humanos, 23. Hay un riesgo apreciable de una
asociación positiva falsa así, cuando el Tipo convencional yo el alfa de probabilidad de
error = se usan 0.05 para cada prueba, así que la mayoría de la cosecha de QTL
probablemente será espurio. El Lander & Krugylak (1995) [56] defendió persuasivamente
que investigadores deben usar el alfa = 0.0001 para cada prueba guardar el Tipo yo el error
a 5% para el estudio de la unión entero. (b) aun cuando la evidencia para la existencia de un
QTL está compeliendo, la anchura del intervalo de confianza a lo largo del cromosoma
todavía puede ser demasiado grande para permitir identificación del gen rápida y
sequencing. Una 1% frecuencia de recombinación corresponde a una distancia a lo largo
del cromosoma de aproximadamente 1 centiMorgan (el centímetro), que en los ratones
aproximadamente 2 Mb de ADN y aproximadamente 65 genes contiene. Una revisión de 22
QTLs creyó para ser importante para el alcohol y sensibilidad de droga (el et de Crabbe al
1998) [23] encuentre que el intervalo en más casos estaba más de 15 cm. que Si el QTL
sólo puede localizarse dentro de un 15 intervalo del centímetro, podría ser cualquier uno de
aproximadamente 1000 genes (el et de Belknap al 1997). [6]
Se han publicado muchas demandas de QTLs asignadas para trazar las situaciones ahora en
la literatura de las genéticas conductual, y en algunos casos se han propuesto los símbolos
del gen provisionales. En muchos casos, la validez de estas demandas es sospechosa y el
campo beneficiaría de la circunspección mayor y rigor. Crusio (1998) [26] los comentarios
eso "en el examen más íntimo, como todavía la promesa del método de QTL no se ha
cumplido en absoluto." Hace el buen sentido para reducir el Tipo II errores lanzando un
precio neto ancho en la primera fase de un estudio, pero parece imprudente para exigir algo
se ha trazado o provisionalmente trazó meramente porque hay evidencia significante de
unión estadísticamente. Más allá los confirmatory probar deben ser obligatorios escoger los
positivo falsos y substancialmente estrechar el intervalo de confianza (Darvasi 1998). [28]
el éxito Real no debe reconocerse en las listas largas de QTLs probado débil pero en un o
dos descubrimientos conclusivos de variantes genéticas con los efectos moderados.
Varias estrategias fructíferas por confirmar QTLs hipotético están disponibles (vea el et de
Crabbe al 1998, Darvasi 1998) [23,28]. el Ciervo y coworkers (1997) [14] estudió
severidad de síntomas de retiro de alcohol en ratones derivados de las tensiones C57BL/6J
y DBA/2J. Una granza inicial contra 1522 marcadores genéticos en 21 recombinant
producidos (RI) las tensiones rindieron siete regiones cromosomáticas designadas como
mostrar la unión" "potencial con un QTL" "putativo apropiadamente. En una muestra de
451 F2 los ratones híbridos evaluaron sólo a regiones implicadas en la primera fase,
seNeuter DNA (the et of Belknap at the 1997, Lander & Schork 1994, the et of McClearn at
the 1991). [6,57,67] The results the more ones are interpreted quickly when the experiment
begins with two innate tensions because it can have two alleles, and the alleles of the
marker they will only be known in both tensions. In a F2 the hybrid cross, the frequencies
of the genotype will have the proportions from Mendelian to the marker. The most intimate
the place of the marker is to the supposed gene, the lowest will be its probability of
recombination. This way, if the QTL has an appreciable effect in the behavior, it should
have a statistically the significant difference in the bills of the bad behavioral test of
individuals with the genotypes of the different marker. Examining several markers in the
same chromosome and using the program of computer of CARTOGRAPHER, the QTL can
be located inside an interval of trust.
Bigger two difficulties challenge the users of methodology of QTL. (a) A he/she examines
typically of the whole genome it involves several markers in each one of 20 independent
chromosomes in the mice, and in the humans, 23. There is this way an appreciable risk of a
false positive association, when the conventional Type me the alpha of error probability =
0.05 are used for each test, so most of the crop of QTL will probably be spurious. The
Lander & Krugylak (1995) [56] it defended persuasively that investigators should use the
alpha = 0.0001 for each test to keep the Type me the error to 5% for the study of the union
entirely. (b) even when the evidence for the existence of a QTL is compelling, the width of
the interval of trust along the chromosome can still be too big to allow identification of the
quick gene and sequencing. 1% frequency of recombination corresponds at a distance along
the chromosome of approximately 1 centiMorgan (the centimeter) that in the mice
approximately 2 Mb of DNA and approximately 65 genes contain. A revision of 22 QTLs
believed to be important for the alcohol and drug sensibility (the et of Crabbe at the 1998)
[23] he/she finds that the interval in more cases was more than 15 cm. that If the QTL can
only be located inside a 15 interval of the centimeter, it could be any one of approximately
1000 genes (the et of Belknap at the 1997). [6]
Many demands of QTLs have been published assigned to trace the situations now in the
literature of the behavioral genetics, and in some cases they have intended the symbols of
the provisional gene. In many cases, the validity of these demands is suspicious and the
field would benefit of the biggest circumspection and rigor. Crusio (1998) [26] the
comments that "in the most intimate exam, I eat the promise of the method of QTL it has
not still been completed at all." He/she makes the good sense to reduce the Type II errors
throwing a wide net price in the first phase of a study, but it seems imprudent to demand
something it has been traced or it provisionally traced merely because there is significant
evidence of union statistically. Further on the confirmatory to prove should be obligatory to
choose the positive one false and substantially to narrow the interval of trust (Darvasi
1998). [28] the Real success should not be recognized in the long lists of weak proven
QTLs but in an or two conclusive discoveries of genetic variants with the moderate effects.
Several fruitful strategies to confirm hypothetical QTLs are available (he/she sees the et
from Crabbe to the 1998, Darvasi 1998) [23,28]. the Deer and coworkers (1997) [14]
he/she studied severity of symptoms of retirement of alcohol in derived mice of the tensions
C57BL/6J and DBA/2J. An initial screening against 1522 genetic markers in 21 produced
recombinant (RI) the tensions surrendered seven chromosomal regions designated as
showing the union" "potential with a QTL" "putative appropriately. In a sample of 451 F2
the hybrid mice only evaluated to regions implied in the first phase, you apoyaron tres de
éstos claramente y otro débil apoyó (vea el et de Belknap al 1996) [7]. Los investigadores
engendraron dos líneas de ratones entonces selectivamente para la severidad del retiro alta
y baja, y las frecuencias del allele a tres sitios del marcador divergidos rápidamente y
significativamente, mientras confirmando la existencia de tres QTLs por eso con la
evidencia independiente en la dirección. Aunque las situaciones del mapa hicieron pensar
en a la candidata creíble gen-incluso varios GABA receptor subunits en el cromosoma que
11-95% intervalos de confianza estaban extensamente más de 10 centímetro.
Un acercamiento similar se ha empleado para estudiar la contestación aguda (la pérdida de
corregir el reflejo) a una dosis alta de etanol. Cuando se probaron 124 marcadores en 27
tensiones de RI derivadas del sueño largo (LS) y el sueño corto (SS) las líneas, 11 QTLs"
"provisionales se localizaron con un muy indulgente (el alfa = 0.05) el criterio (el et de
Markel al 1996). [63] UN estudio de los ratones con las cuentas más extremas en una
muestra de 1072 hybrids de F2 apoyó sólo dos de estos QTLs que se localizaron
tentativamente dentro de los intervalos de aproximadamente 16 centímetro (el et de Markel
al 1997). [62] Como una prueba extensa, F2 los ratones híbridos de conocido

el genotipo a los sitios del marcador que flanquean el QTL hipotético fue dado jaque mate a
entonces y su descendencia probó por el dormir etanol-inducido (el et de Bennett al 1997).
[9] Aunque los tamaños de la muestra eran demasiado pequeños para rendir los resultados
conclusivos, esta aplicación de selección marcador-ayudada (Ruane & Colleau 1995) [84]
los sostenimientos la gran promesa por confirmar la presencia de un QTL, localizándolo a
un intervalo del narrower, y estudiar las interacciones del interlocus.
Una vez la presencia de un QTL ha sido adecuadamente inveterada, su identidad precisa
debe demostrarse. Esto sólo es ya probablemente factible para un gen documentado al nivel
bioquímico. De un mapa del cromosoma, investigadores pueden localizar los genes del
candidato creíbles en el intervalo de confianza para su QTL. Por ejemplo, Ciervo y colegas
(1997) [14] notó que un QTL en cromosoma 11 estaba cerca de los genes para tres subunits
del receptor de GABA (Gabra1, Gabra6, Gabrg2). Las sucesiones de ADN llenas del exons
de un gen en las dos tensiones podrían revelar un polymorphism que da lugar a los
formularios diferentes de la proteína. Si único de varios genes del candidato difiere entre
las tensiones, se volverá el objeto de intenso escrutinio, considerando que la presencia de
varios genes del polymorphic en el intervalo confundirá el progreso. La evidencia extensa
podría obtenerse golpeando fuera el gen en cuestión, pero esta evidencia también podría
estar desencaminando. El propio QTL podría involucrar una diferencia bastante menor en
el alleles viable, considerando que un knockout total de otro poderío del gen cercano tiene
muy bien los efectos del pleiotropic mayores en esa conducta. Así, el knockout podría
implicar un gen sin demostrar a ese gen ser la fuente del QTL.
La tarea de identificar genes de efecto moderado beneficiará de un esfuerzo comprensivo
en una variedad ancha de ratón común fatiga para determinar la sucesión de ADN de exons
para los genes conocido para codificar para muchas proteínas del sistema nerviosas. Genes
ya demostrados con el método del knockout para ser pertinente para desarrollo del cerebro
o conducta proporcionarían un lugar de arranque bueno. Fechar, el método del knockout
nos ha enseñado mucho sobre el desarrollo pero no sobre las diferencias individuales. La
era clásica de ratón las genéticas conductuales documentaron las variaciones grandes entre
las tensiones innatas comúnes para una gama amplia de phenotypes conductual. Nosotros
necesitamos saber si los targeted de los genes por los biólogos moleculares son de hecho
los genes que dieron lugar a estas diferencias de tensión ubicuas. Si investigadores
evaluaran la posible relevancia para la conducta de polymorphisms de la proteína definido
en lugar de la búsqueda para la aguja proverbial en la niara que usa el método de QTL, las
respuestas vendrían más fácilmente y serían menos prono al error.
Los Allele Asociación Estudios
El acercamiento de asociación de allele está usándose para evaluar la relevancia de
proteínas del sistema nerviosas muy conocidas a la variación conductual en los humanos.
En el primer paso, se identifican varios alleles de un gen que lleva a los formularios
alterados de una proteína. Por ejemplo, una sucesión del 48-base que codifica para un
cordón de 16 aminoácidos en el dopamine teclea 4 receptor (el gen de DRD4) se repite a
menudo, y un estudio ancho mundial identificó 9 alleles con 2 a 10 repite (el et de Chang al
1996). [17] Muchos el alleles relativamente común en el dopamine el receptor de D2
(DRD2) el gen también se documenta bien (el et de Kidd al 1996). [55] De importancia
crítica la observación que las frecuencias del allele generalmente difieren notablemente de
una población geográfica a otro es (Kidd 1996). [53]
El segundo paso es establecer una correlación entre los alleles específicos y las diferencias
conductuales. Las demandas han sido hecho-pero han dudado persistir-ese el allele de A1
del gen de DRD2 lleva al riesgo más alto de alcoholismo. Si la muestra del estudio es
étnicamente diversa, un allele que es más común en un grupo que tiene una proporción más
alta de alcoholismo podría producir una correlación espuria. El recurso mejor es examinar
las asociaciones del allele dentro de una población más homogénea. En tres poblaciones en
el Taiwán, hay ninguna asociación de alcoholismo por ejemplo, con el alleles en el DRD2 o
gen de DRD4 (el et de Chang al 1997, et de Lu al 1996). [18,59] inspeccionando la
literatura, Kidd (1996) [53] concluyó que "los estudios bien diseñados han sido
consistentemente negativos en la asociación" con el alcoholismo.
Los polymorphisms genéticos también hablan al crónicamente el problema molesto de raza
en las genéticas conductuales. Una valoración comprensiva de frecuencias del allele
alrededor del mundo por Cavalli-Sforza y colegas (1994) [16] encuentre el apoyo pequeño
por las categorías raciales. Los más recientes datos incitaron Kidd (1996) [53] para
comentar: "Es mi creencia que que las clasificaciones raciales de humanos son
científicamente indefendibles que desde que hay ningún límite de diferencia genética
cualitativa y la inmensa mayoría de variación genética esencialmente muestra un modelo
continuo alrededor del mundo."
Se ha dado la publicidad considerable a dos estudios publicados en 1996 eso exigió una
asociación entre el rasgo de personalidad de novedad que busca y el largo 7 repiten allele
del gen de DRD4. Como revelado en Figura 1, ocho estudios subsecuentes de varios países
han obtenido los resultados mixtos. Un meta-análisis de estos datos sugiere que anota en la
novedad que busca la encuesta tiene una desviación normal aproximadamente d = 0.06
superior en las personas con más largo repita el alleles (95% intervalo de confianza de -0.03
a 0.16). Porque hay heterogeneidad significante entre las muestras (Q = 32.9, df = 9, P =
0.0001), es posible que la interacción del epistatic con el fondo genético o interacción con
situaciones de la prueba o los ambientes locales pudiera rendir una asociación significante
en ciertas poblaciones pero no otros.

[La ayuda con imagen que ve] they supported three of these clearly and another weak one
supported (he/she sees the et from Belknap to the 1996) [7]. The investigators engendered
two lines of mice then selectively for the severity of the retirement discharge and low, and
the frequencies of the allele to three places of the marker diverged quickly and
significantly, while confirming the existence of three QTLs for that reason with the
independent evidence in the address. Although the situations of the map made think in to
the believable candidate gene-even several GABA receiving subunits in the chromosome
that 11-95% intervals of trust was widely more than 10 centimeter.
A similar approach has been used to study the sharp answer (the loss of correcting the
reflection) to a high dose of ethanol. When 124 markers were proven in 27 tensions of
derived RI of the long dream (LS) and the short dream (SS) the lines, 11 QTLs"
"provisional they were located with a very indulgent one (the alpha = 0.05) the approach
(the et of Markel at the 1996). [63] A study of the mice with the most extreme bills in a
sample of 1072 hybrids of F2 only supported two of these QTLs that were located
tentatively inside the intervals of approximately 16 centimeter (the et of Markel at the
1997). [62] Like an extensive test, F2 the hybrid mice of well-known

the genotype to the places of the marker that the hypothetical QTL flanks checkmate was
given to then and its descendant proved for sleeping ethanol-induced (the et of Bennett at
the 1997). [9] Although the sizes of the sample were too small to surrender the conclusive
results, this application of marker-helped selection (Ruane & Colleau 1995) [84] the
maintenances the great promise to confirm the presence of a QTL, locating him to an
interval of the narrower, and to study the interactions of the interlocus.
Once the presence of a QTL has been appropriately inveterate, its precise identity should be
demonstrated. This is only already probably feasible for a gene documented at the
biochemical level. Of a map of the chromosome, investigators can locate the believable
candidate's genes in the interval of trust for their QTL. For example, Deer and colleagues
(1997) [14] he/she noticed that a QTL in chromosome 11 were near the genes for three
subunits of the receiver of GABA (Gabra1, Gabra6, Gabrg2). The successions of DNA full
with the exons of a gene in the two tensions could reveal a polymorphism that gives place
to the forms different from the protein. If only of the candidate's several genes it differs
among the tensions, he/she will become the object of intense scrutiny, considering that the
presence of several genes of the polymorphic in the interval will confuse the progress. The
extensive evidence could be obtained hitting the gene outside in question, but this evidence
could also be misleading. The own QTL could involve a quite smaller difference in the
viable alleles, considering that a total knockout of another might of the near gene has the
effects of the biggest pleiotropic very well in that behavior. This way, the knockout could
imply a gene without demonstrating to that gene to be the source of the QTL.
The task of identifying genes of moderate effect will benefit of an understanding effort in a
wide variety of mouse common fatigue to determine the succession of exons DNA for the
genes known to code for many proteins of the nervous system. Genes already demonstrated
with the method of the knockout to be pertinent for development of the brain or behavior
they would provide a place of good outburst. To date, the method of the knockout has
become trained a lot of envelope the development but don't have more than enough
individual differences. The classic era of mouse the behavioral genetics documented the big
variations among the common innate tensions for a wide range of behavioral phenotypes.
We need to know if the targeted of the genes for the molecular biologists is in fact the
genes that gave place to these ubiquitous differences of tension. If investigators evaluated
the possible relevance for the behavior of polymorphisms of the protein defined instead of
the search for the proverbial needle in the haystack that uses the method of QTL, the
answers they would come more easily and they would be less prone to the error.
The Allele Association Studies
The approach of allele association is using he/she stops to evaluate the relevance of proteins
from the very well-known nervous system to the behavioral variation in the humans. In the
first step, several alleles of a gene is identified that takes to the altered forms of a protein.
For example, a succession of the 48-base that codes for a cord of 16 amino acids in the
dopamine types 4 receiver (the gene of DRD4) he/she often repeats, and a world wide study
identified 9 alleles with 2 at 10 he/she repeats (the et of Chang at the 1996). [17] Many the
relatively common alleles in the dopamine the receiver of D2 (DRD2) the gene is also
documented well (the et of Kidd at the 1996). [55] Of critical importance the observation
that the frequencies of the allele generally differ notably from a geographical population to
another is (Kidd 1996). [53]
The second step is to establish a correlation between the specific alleles and the behavioral
differences. The demands have been fact-but they have doubted persist-that the allele of A1
of the gene of DRD2 it takes to the highest risk in alcoholism. If the sample of the study is
ethnically diverse, an allele that is more common in a group than he/she has a higher
proportion of alcoholism it could produce a spurious correlation. The best resource is to
examine the associations of the allele inside a more homogeneous population. In three
populations in the Taiwan, there is any association of alcoholism for example, with the
alleles in the DRD2 or gene of DRD4 (the et of Chang at the 1997, et of Lu at the 1996).
[18,59] inspecting the literature, Kidd (1996) [53] it concluded that "the well designed
studies have been consistently negative in the association" with the alcoholism.
The genetic polymorphisms also speaks chronically to the the annoying problem of race in
the behavioral genetics. An understanding valuation of frequencies of the allele around the
world for Cavalli-Sforza and colleagues (1994) [16] he/she finds the small support for the
racial categories. The most recent data incited Kidd (1996) [53] to comment: "It is my
belief that that the racial classifications of humans are scientifically indefensible that since
there are any limit of difference qualitative genetics and the immense majority of genetic
variation essentially sample a continuous model around the world."
The considerable publicity has been given to two studies published in 1996 that it
demanded an association among the feature of personality of novelty that looks for and the
long one 7 repeat allele of the gene of DRD4. As having revealed in Figure 1, eight
subsequent studies of several countries have obtained the mixed results. A goal-analysis of
these data suggests that he/she scores in the novelty that looks for the survey he/she has a
normal deviation approximately d = 0.06 superior in people with longer repeats the alleles
(95% interval of trust of -0.03 at 0.16). Because there is significant heterogeneity among
the samples (Q = 32.9, df = 9, P = 0.0001), it is possible that the interaction of the epistatic
with the genetic bottom or interaction with situations of the test or the local atmospheres
could surrender a significant association in certain populations but not others.

[The help with image that you go]

Figure 1. el Meta-análisis de 10 estudios de novedad que busca en las personas con el

alleles diferente del dopamine teclea 4 receptor (DRD4) el gen. El número del estudio se
traza a la estimación del punto de tamaño de efecto (d). (los Anaqueles) El 95% intervalo
de confianza para el verdadero tamaño de efecto; (los números blancos en los círculos
negros) un efecto significante al alfa = 0.05 con una prueba dos- detrás de. Los estudios
difirieron un poco en la prueba de personalidad empleada, y en la definición de un allele
largo. En estudios que involucraron más de una muestra, una estimación combinada se
derivó. El meta-análisis se hizo como perfilado por el Bishop & Wahlsten (1997). [10] las
Fuentes de números del estudio: 1, Ebstein et al (1996); [34] 2, Benjamín el al del et
(1996); [8] 3, Malhotra et al (1996); [61] 4, Jonsson et al (1997); [49] 5, Vandenbergh et al
(1997); [99] 6, al de et de Lijadora (1997); [85] 7, Ono et al (1997); [73] 8, Ebstein et al
(1997); [33] 9, Gelernter et al (1997); [37] 10, Sullivan et al (1998). [92]

This exercise with meta-analysis and the history of false positive linkage results for
schizophrenia teach important lessons. When a new claim is made of weak allele
association or linkage with some other measure (such as IQ), experience should
caution us against premature enthusiasm until the result is replicated adequately and
survives meta-analysis. Otherwise, there arises a serious risk that false claims will
mislead public discourse, as allegations of sex-based differences in the human brain
(Bishop & Wahlsten 1997) [10] and an alleged relation between serotonin
metabolism and impulsive violence (Balaban et al 1996) [4] have already done.

Presuming the allele association method does eventually point to a genetic variant
with reliable behavioral correlates, proof that the connection is causal does not
follow automatically. The one gene might be linked to another locus that is actually
responsible for the observed difference, and hence it would be wise to assess several
nearby genes rather than to restrict the scope of the search too early on. The
knockout method will not, of course, be available for confirmatory studies in
humans, but highly specific DNA-based drugs might be used to substantiate an
effect on behavior for the locus in question.

Linkage and allele association methods are entirely adequate for detecting genes
with large phenotypic effects, but these kinds of genetic variants tend to be
uncommon in the human population. Nevertheless, the work can be justified
because of the potential benefit new knowledge may provide for the prevention or
alleviation of suffering. Meanwhile, the hunt for ubiquitous polygenes pursues an
elusive quarry. Detecting small effects requires extraordinarily large samples, even
if the best available research designs are employed (Risch & Merikangas 1996). [79]
There is a profound conflict inherent in this enterprise. In terms of a social calculus
of the cost-benefit ratio, the smaller the potential good that might result from a new
discovery, the more expensive the purchase of that knowledge will be.

Databases of Genetic Information

Despite my reservations about research on genes of small effect, impressive

progress has been made in the detection of genes affecting the nervous system and
behavior; and even a cursory account of the present state of knowledge exceeds the
scope of this review. Fortunately, a vast reservoir of current genetic information is
now readily available on the World Wide Web at species-specific sites (Table 1).
Investigators can search these databases for long lists of genes residing on a specific
chromosome, detailed information about a specific gene, or lists of genes with
possible relevance to a specified phenotype or syndrome. A formal course on skills
 for the Web would be a very useful addition to the neurobehavioral genetics
curriculum.

The Mouse Genome Database (MGD) can be reached via the Jackson Laboratory
(jax) site. In February of 1998, a search for the phenotype "obesity" yielded 13
relevant genes. The gene symbol Lep, or its name, leptin (formerly obese), yielded
the precise map location on chromosome 6, a lengthy abstract, a current
bibliography, and other useful information. It also provided links to the homologous
gene LEP in humans and the DNA sequence of several ESTs. If one does not know
the official gene symbol, it is best to start with a search for a closely related
keyword. For example, the calmodulin kinase II alpha subunit gene symbol is
Camk2a. If the protein symbol CaMKII(often cited in the neuroscience literature) is
entered in a search of the MGD, nothing is found, whereas a search using the
keyword "calmodulin" successfully calls up information on the gene in question and
several others. The MGD currently lists 20,080 genetic markers that have been
placed on the mouse chromosome map and 8911 genes, of which 6171 have been
mapped and 6396 have at least partial DNA sequences available. One must exercise
caution when searching for genes affecting phenotypes, because many in the
database are poorly validated and may be ancient apparitions. One such is the gene
absent corpus callosum (ac), originally reported by Keeler (1933) [51] but not seen
by anyone in the past 60 years. Once a gene is listed in the catalog-no matter how
flimsy the case for its existence-it tends to remain there. Any mouse gene for which
an accurate map position is lacking should not be taken seriously.

After completing a brief registration procedure on the BioMedNet Web site, one can
access the Mouse Knockout Database, which provides extensive data on targeted
mutations. A search detected over 300 articles on over 100 single-gene knockouts
that yield viable animals with alterations in the nervous system and/or behavior.

The Weizmann Institute of Science Gene Cards facility is especially recommended for
accessing human genetics information. It allows searches for gene symbols or keywords
involving phenotypes, yields chromosome map locations, protein characteristics, and
homologies with mice, and offers convenient connections to the Genome Database (GDB)
or Medline literature search. The GDB is presently the most authoritative source on human
genetics, but it may soon cease operations because funding by the US Department of
Energy is being discontinued (Letovsky 1998). [58] Online Mendelian Inheritance in Man
(OMIM) provides a lengthy abstract and bibliography for each gene and can also be
accessed by entering phenotypic keywords. Searching OMIM for "dyslexia" in February
1998 yielded three gene symbols (DYX1, DYX2, THRB). The GDB listing for DYX1
isFigure 1. the Goal-analysis of 10 studies of novelty that looks for in people with the
alleles different from the dopamine types 4 receiver (DRD4) the gene. The number of the
study is traced to the estimate of the point of effect size (d). (the Shelves) 95% interval of
trust for the true effect size; (the white numbers in the black circles) a significant effect to
the alpha = 0.05 with a test two - behind. The studies differed a little in the test of used
personality, and in the definition of a long allele. In studies that involved more than a
sample, a combined estimate was derived. The goal-analysis was made as profiled by the
Bishop & Wahlsten (1997). [10] the Fuentes of numbers of the study: 1, Ebstein et to the
(1996); [34] 2, Benjamin the one to that of the et (1996); [8] 3, Malhotra et to the (1996);
[61] 4, Jonsson et to the (1997); [49] 5, Vandenbergh et to the (1997); [99] 6, to that of et of
Sander (1997); [85] 7, Ono et to the (1997); [73] 8, Ebstein et to the (1997); [33] 9,
Gelernter et to the (1997); [37] 10, Sullivan et to the (1998). [92]

This exercise with goal-analysis and the history of false positive linkage results for
schizophrenia teach important lessons. When to new claim is made of weak allele
association or linkage with some other measure (such ace IQ), experience should caution us
against premature enthusiasm until the result is replicated adequately and survives goal-
analysis. Otherwise, there arises to serious risk that false claims will mislead public
discourse, ace allegations of sex-based differences in the human brain (Bishop & Wahlsten
1997) [10] and an alleged relation between serotonin metabolism and impulsive violence
(et Bleated at the 1996) [4] have already donates.
Presuming the allele association method does eventually point to genetic variant with
reliable behavioral correlates, proof that the connection is causal does not follow
automatically. The one gene might be linked to another locus that is actually responsible for
the observed difference, and hence it would be wise to assess several nearby genes rather
than to restrict the scope of the search too early on. The knockout method will not, of
course, be available for confirmatory studies in humans, but highly specific DNA-based
drugs might be used to substantiate an effect on behavior for the locus in question.
Linkage and allele association methods plows entirely adequate for detecting genes with
large phenotypic effects, but these kinds of genetic variants tend to be uncommon in the
human population. Nevertheless, the work dog be justified because of the potential benefit
new knowledge may provide for the prevention or alleviation of suffering. Meanwhile, the
hunt for ubiquitous polygenes pursues an elusive quarry. Detecting small effects requires
extraordinarily large samples, even if the best available research designs plows employed
(Risch & Merikangas 1996). [79] There is to profound conflict inherent in this enterprise.
In terms of to social calculus of the cost-benefit ratio, the smaller the potential good that
might result from to new discovery, the lives expensive the purchase of that knowledge will
be.
Databases of Genetic Information
Despite my reservations about research on genes of small effect, impressive progress has
been made in the detection of genes affecting the nervous system and behavior; and even to
cursory account of the present state of knowledge exceeds the scope of this review.
Fortunately, to vast reservoir of current genetic information is now readily available on the
World Wide Web at species-specific sites (Table 1). Investigators dog search these
databases for long lists of genes residing on to specific chromosome, detailed information
about to specific gene, or lists of genes with possible relevance to specified phenotype or
syndrome. To formal course on skills for the Web would be to very useful addition to the
neurobehavioral genetics curriculum.
The Mouse Genome Database (MGD) dog be reached via the Jackson Laboratory (jax) site.
In February of 1998, to search for the phenotype "obesity" yielded 13 relevant genes. The
gene symbol Lep, or its yam, leptin (formerly obese), yielded the specifies map location on
chromosome 6, to lengthy abstract, to current bibliography, and other useful information. It
also provided links to the homologous gene LEP in humans and the DNA sequence of
several ESTs. If one does not know the official gene symbol, it is best to start with to search
for to closely related keyword. For example, the calmodulin kinase II alpha subunit gene
symbol is Camk2a. If the protein symbol CaMKII(often cited in the neuroscience literature)
is entered in to search of the MGD, nothing is found, whereas to search using the keyword
"calmodulin" successfully calls up information on the gene in question and several others.
The MGD currently lists 20,080 genetic markers that have been placed on the mouse
chromosome map and 8911 genes, of which 6171 have been mapped and 6396 have at least
partial DNA sequences available. One must exercise caution when searching for genes
affecting phenotypes, because many in the database plows poorly validated and may be
ancient apparitions. One such is the gene absent corpus callosum (ac), originally reported
by Keeler (1933) [51] but not seen by anyone in the past 60 years. Eleven to gene is listed
in the catalog-no matter how flimsy the marries for its existence-it tends to remain there.
Any mouse gene for which an accurate map position is lacking should not be taken
seriously.
After completing to brief registration procedure on the BioMedNet Web site, one dog
access the Mouse Knockout Database, which provides extensive dates on targeted
mutations. To search detected over 300 articles on over 100 sail-gene knockouts that yield
viable animals with alterations in the nervous system and/or behavior.
The Weizmann Institute of Science Gene Cards facility is especially recommended for
accessing human genetics information. It allows searches for gene symbols or keywords
involving phenotypes, yields chromosome map locations, protein characteristics, and
homologies with mice, and offers convenient connections to the Genome Database (GDB)
or Medline literature search. The GDB is presently the most authoritative source on human
genetics, but it may soon cease operations because funding by the US Department of
Energy is being discontinued (Letovsky 1998). [58] Online Mendelian Inheritance in Man
(OMIM) provides to lengthy abstract and bibliography for each gene and dog also be
accessed by entering phenotypic keywords. Searching OMIM for "dyslexia" in February
1998 yielded three gene symbols (DYX1, DYX2, THRB). The GDB listing for DYX1 is
based on a single entry from July 19, 1996, and the existence of this gene is far from
certain; no information is cited on chromosome map location, and the fine print reveals that
it is merely a "reserved symbol," meaning that this will be its official designation if the
gene is ever confirmed. DYX2 yields a map location on chromosome 6 that has been
supported by an independent group of researchers (Grigorenko et al 1997) [42] but only for
one of five reading-related phenotypes (phonological awareness) and only with
nonparametric (rather than parametric) methods. The confidence interval for gene location
is more than 10 cM wide, and no protein or DNA sequence information is known. A search
on "schizophrenia" yielded 40 entries, including the gene symbol SCZD1 assigned on April
12, 1989, to a region on chromosome 5 that is now recognized as not harboring a gene
influencing schizophrenia (Moldin & Gottesman 1997). [71] Any gene name returned by a
search of OMIM should be carefully checked against more authoritative sources, especially
the GDB, where a history of the SCZD1 symbolEste ejercicio con el meta-análisis y la
historia de unión positiva falsa resulta para la esquizofrenia enseña las lecciones
importantes. Cuando una nueva demanda es hecho de asociación del allele débil o unión
con alguna otra medida (como IQ), la experiencia debe avisarnos contra el entusiasmo
prematuro hasta que el resultado se reproduzca adecuadamente y sobrevive el meta-análisis.
Por otra parte, allí se levanta un riesgo serio que las demandas falsas desencaminarán el
discurso público, como las alegaciones de diferencias sexo-basado en el cerebro humano
(Bishop & Wahlsten 1997) [10] y una relación supuesta entre el metabolismo de la
serotonina y violencia impulsiva (el et de Balaban al 1996) [4] ya ha hecho.
Presumiendo el método de asociación de allele apunta en el futuro a una variante genética
con las cosas correlativas conductuales fiables, prueba que la conexión es causal no siga
automáticamente. El un gen podría unirse a otro sitio que es realmente responsable para la
diferencia observada, y de sería sabio evaluar varios genes cercanos en lugar de para
restringir el alcance de la búsqueda demasiado temprano adelante. El método del knockout
no quiere, claro, esté disponible para los estudios del confirmatory en los humanos, pero
podrían usarse las drogas ADN-basado muy específicas para probar un efecto en la
conducta por el sitio en cuestión.
La unión y métodos de asociación de allele son completamente adecuados para los genes
detectores con los efectos del phenotypic grandes, pero estos tipos de variantes genéticas
tienden a ser raros en la población humana. No obstante, el trabajo puede justificarse
debido al beneficio potencial que el nuevo conocimiento puede mantener la prevención o
alivio de sufrir. Entretanto, la caza para el polygenes ubicuo sigue una cantera huidiza.
Descubriendo los efectos pequeños requiere las muestras extremadamente grandes, aun
cuando los planes de la investigación disponibles más buenos son empleado (Risch &
Merikangas 1996). [79] hay un conflicto profundo inherente en esta empresa. Por lo que se
refiere a un cálculo social de la proporción del costo-beneficio, el más pequeño el potencial
bueno eso podría ser el resultado de un nuevo descubrimiento, el más caro la compra de ese
conocimiento será.
Las bases de datos de Información Genética
A pesar de mis reservaciones sobre la investigación en los genes de efecto pequeño, el
progreso impresionante ha sido hecho en el descubrimiento de genes que afectan el sistema
nervioso y conducta; e incluso una cuenta superficial del estado presente de conocimiento
excede el alcance de esta revisión. Afortunadamente, un inmenso depósito de información
genética actual está ahora prontamente disponible en el Web en los sitios especie-
específicos (Mesa 1). Investigadores pueden investigar estas bases de datos para las listas
largas de genes que residen en un cromosoma específico, la información detallada sobre un
gen específico, o listas de genes con la posible relevancia a un phenotype especificado o
síndrome. Un curso formal en las habilidades para el Web sería una suma muy útil al plan
de estudios de genéticas de neurobehavioral.
El Ratón la Base de datos de Genome (MGD) puede alcanzarse vía el Laboratorio de
Jackson (el jax) el sitio. En febrero de 1998, una búsqueda para la "obesidad" del
phenotype rindió 13 genes pertinentes. El símbolo del gen Lep, o su nombre, leptin
(anteriormente obeso), rindió la situación del mapa precisa en cromosoma 6, un lo abstracto
largo, una bibliografía actual, y otra información útil. También proporcionó los eslabones al
gen homólogo LEP en los humanos y la sucesión de ADN de varios ESTs. Si uno no sabe
el símbolo del gen oficial, es mejor empezar con una búsqueda para una palabra clave
estrechamente relacionada. Por ejemplo, el kinase del calmodulin II alfa subunit gen
símbolo es Camk2a. Si el símbolo de la proteína CaMKII(often citó en la literatura del
neuroscience) se entra en una búsqueda del MGD, nada se encuentra, considerando que una
búsqueda que usa el "calmodulin" de la palabra clave con éxito llama la información sobre
el gen en cuestión y algunos otros. El MGD lista 20,080 marcadores genéticos que se han
puesto en el mapa de cromosoma de ratón y 8911 genes de que se han trazado 6171
actualmente y 6396 tienen las sucesiones de ADN parciales por lo menos disponible. Uno
debe ejercer la cuatela al buscar los genes el phenotypes conmovedor, porque muchos en la
base de datos se validan pobremente y pueden ser las apariciones antiguas. Uno cosas así es
el gen el callosum del cuerpo ausente (el ac), originalmente informó por Keeler (1933) [51]
pero no visto por nadie en los últimos 60 años. Una vez un gen se lista en el catálogo-no la
materia cómo débil el caso para su tiende a permanecer allí. Cualquier gen del ratón para
que a una posición del mapa exacta está le faltando no debe tomarse en serio.
Después de completar un procedimiento de la registración breve en el BioMedNet el sitio
de Web, uno puede acceder la Base de datos de Knockout de Ratón que proporciona los
datos extensos en las mutaciones del targeted. Una búsqueda descubrió encima de 300
artículos en encima de 100 knockouts del solo-gen que rinden los animales viables con las
alteraciones en el sistema nervioso y/o conducta.
El Weizmann Institute de Ciencia Gen Tarjetas facilidad se recomienda sobre todo por
acceder la información de las genéticas humana. Permite las búsquedas símbolos del gen o
palabras claves que involucran el phenotypes, rinde situaciones de mapa de cromosoma,
características de la proteína, y homologías con los ratones, y ofertas las conexiones
convenientes a la Base de datos de Genome (GDB) o Medline literatura búsqueda. El GDB
es presentemente la fuente más autoritaria en las genéticas humanas, pero puede cesar los
funcionamientos pronto porque consolidando por el Departamento americano de Energía
está discontinuándose (Letovsky 1998). [58] la Herencia de Mendelian En línea en el
Hombre (OMIM) mantiene un lo abstracto largo y bibliografía cada gen y también puede
accederse entrando en las palabras claves del phenotypic. OMIM escrutador para la
"dislexia" en el 1998 de febrero rindió tres símbolos del gen (DYX1, DYX2, THRB). El
GDB que lista para DYX1 es basado en una sola entrada del 19 de julio de 1996, y la
existencia de este gen es lejos de cierto; ninguna información se cita en la situación de
mapa de cromosoma, y la impresión fina revela que es meramente un símbolo" reservado,
mientras significando que ésta será su designación oficial si el gen es en la vida inveterado.
DYX2 rinde una situación del mapa en cromosoma 6 eso se ha apoyado por un grupobased
on to it sails entry from July 19, 1996, and the existence of this gene is far from certain; not
information is cited on chromosome map location, and the dies print reveals that it is
merely to "reserved symbol, meaning that this will be its official designation if the gene is
ever confirmed. DYX2 yields to map location on chromosome 6 that has been supported by
an independent group of researchers (Grigorenko et at the 1997) [42] but only for one of
five reading-related phenotypes (phonological awareness) and only with nonparametric
(rather than parametric) methods. The confidence interval for gene location is not lives than
10 cM wide, and protein or DNA sequence information is known. To search on
"schizophrenia" yielded 40 entries, including the gene symbol SCZD1 assigned on April
12, 1989, to region on chromosome 5 that is now recognized ace not harboring to gene
influencing schizophrenia (Moldin & Gottesman 1997). [71] Any gene yam returned by to
search of OMIM should be carefully checked against authoritative sources, especially the
lives GDB, where to history of the SCZD1 symbolEste exercise with the goal-analysis and
the history of false positive union is for the schizophrenia he/she teaches the important
lessons. When a new demand is made of association of the weak allele or union with some
other measure (as IQ), the experience should warn us against the premature enthusiasm
until the result reproduces appropriately and the goal-analysis survives. On the other hand,
there a serious risk that the false demands will mislead the public speech rises, as the
allegations of differences sex-based on the human brain (Bishop & Wahlsten 1997) [10]
and a supposed relationship between the metabolism of the serotonin and impulsive
violence (the et of they Bleated at the 1996) [4] he/she has already made.
Showing off the method of allele association points in the future to a genetic variant with
the reliable behavioral correlative things, it proves that the connection is causal it doesn't
continue automatically. The a gene could unite to another place that is really responsible for
the observed difference, and of it would be wise to evaluate several near genes instead of to
restrict the reach of the too early search ahead. The method of the knockout doesn't want,
clear, be available for the studies of the confirmatory in the humans, but the very specific
DNA-based drugs could be used to prove an effect in the behavior for the place in question.
The union and methods of allele association are totally appropriate for the detecting genes
with the effects of the big phenotypic, but these types of genetic variants spread to be
strange in the human population. Nevertheless, the work can be justified due to the
potential benefit that the new knowledge can maintain the prevention or relief of suffering.
Meantime, the hunt for the ubiquitous polygenes follows an elusive quarry. Discovering the
small effects requires the extremely big samples, even when the plans of the best available
investigation are an employee (Risch & Merikangas 1996). [79] there is an inherent deep
conflict in this company. Regarding a social calculation of the proportion of the cost-
benefit, the smallest the good potential that could be the result of a new discovery, the most
expensive the purchase of that knowledge it will be.
The databases of Genetic Information
In spite of my reservations on the investigation in the genes of small effect, the impressive
progress has been made in the discovery of genes that you/they affect the nervous system
and behavior; and a superficial bill of the present state of knowledge even exceeds the
reach of this revision. Fortunately, an immense deposit of current genetic information is
now quickly available in the Web in the species-specific places (Table 1). Investigators can
investigate these databases for the long lists of genes that reside in a specific chromosome,
the detailed information on a specific gene, or you list of genes with the possible relevance
to a specified phenotype or syndrome. A formal course in the abilities for the Web would
be a very useful sum to the plan of studies of genetic of neurobehavioral.
The Mouse the Database of Genome (MGD) it can be reached via Jackson's Laboratory
(the jax) the place. In February of 1998, a search for the "obesity" of the phenotype he/she
surrendered 13 pertinent genes. The symbol of the gene Lep, or their name, leptin
(previously obese), he/she surrendered the situation of the map he/she specifies in
chromosome 6, a the abstract thing long, a current bibliography, and another useful
information. It also provided the links to the homologous gene LEP in the humans and the
succession of DNA of several ESTs. If one doesn't know the symbol of the official gene, it
is better to begin with a search for a closely related key word. For example, the kinase of
the calmodulin II alpha subunit gene symbol is Camk2a. If the symbol of the protein
CaMKII(often mentioned in the literature of the neuroscience) one enters in a search of the
MGD, anything is, considering that a search that uses the "calmodulin" of the key word
with success calls the information on the gene in question and some other ones. The MGD
clever 20,080 genetic markers that have put on in the map of mouse chromosome and 8911
genes that 6171 have been traced at the moment and 6396 have the partial at least available
successions of DNA. One should exercise the caution when looking for the genes the
moving phenotypes, because many in the database are validated poorly and they can be the
old appearances. One things are this way the gene the callosum of the absent body (the ac),
originally he/she informed for Keeler (1933) [51] but not seen by anybody in the last 60
years. Once a gene is listed in the catalog-no the matter how weak the case for its it spreads
to remain there. Any gene of the mouse so that to a position of the exact map it is he
lacking he/she should not take seriously.
After completing a procedure of the brief registration in the BioMedNet the place of Web,
one can consent the Database of Knockout of Mouse that provides the extensive data in the
mutations of the targeted. A search discovered above 300 articles in above 100 knockouts
of the alone-gene that surrender the viable animals with the alterations in the nervous
system and/or behavior.
The Weizmann Institute of Science Gene Cards easiness is recommended mainly to consent
the information of the human genetics. It allows the searches symbols of the gene or key
words that involve the phenotypes, he/she surrenders situations of chromosome map,
characteristic of the protein, and homologies with the mice, and you offer the convenient
connections to the Database of Genome (GDB) or Medline literature search. The GDB is
presently the most authoritarian source in the human genetics, but it can cease the
operations soon because consolidating for the American Department of Energy is being
discontinued (Letovsky 1998). [58] the Inheritance of on-line Mendelian in the Man
(OMIM) it maintains a the abstract thing long and bibliography each gene and it can also be
consented entering in the key words of the phenotypic. OMIM teller for the "dyslexia" in
February 1998 he/she surrendered three symbols of the gene (DYX1, DYX2, THRB). The
GDB that lists for DYX1 is based on a single entrance of July of 1996, 19 and the existence
of this gene is far from certain; no information makes an appointment in the situation of
chromosome map, and the fine impression reveals that it is merely a symbol" reserved,
while meaning that this will be its official appointment if the gene is in the inveterate life.
DYX2 surrenders a situation of the map in chromosome 6 that he/she has leaned on for a
group independiente de investigadores (el et de Grigorenko al 1997) [42] pero sólo para
uno de cinco phenotypes lectura-relacionados (el conocimiento fonológico) y sólo con el
nonparametric (en lugar de paramétrico) los métodos. El intervalo de confianza para la
situación del gen está más de 10 centímetro ancho, y ninguna proteína o la ADN sucesión
información es conocida. Una búsqueda en la "esquizofrenia" rindió 40 entradas, incluso el
símbolo del gen SCZD1 asignó el 12 de abril de 1989, a una región en cromosoma 5 eso se
reconoce ahora como no albergar un gen que influye en la esquizofrenia (Moldin &
Gottesman 1997). [71] Cualquier nombre del gen vuelto por una búsqueda de OMIM debe
verificarse cuidadosamente contra las fuentes más autoritarias, sobre todo el GDB dónde
una historia del símbolo de SCZD1

symbol reveals it was "unassigned" on October 16, 1991. If a protein, DNA

sequence, or homology with a mouse gene is listed, one can be confident that the
gene is real, but a map location by itself provides no guarantee. Several symbols
included in the catalog represent false positives that have not been culled.

The only unequivocal evidence for a gene is elucidation of its DNA sequence and
associated protein structure. The quality control for this kind of biochemical
information on the Web is good, in part because of facilities provided by the Human
Genome Project. Unfortunately, quality control for weaker claims about genes
relevant to phenotypes is inadequate, and speculative assertions in the mass media
about genetic determination of socially significant behaviors (Colt & Hollister
1998) [22] all too often are based on hasty proclamations from behavioral geneticists
who should know better.
el símbolo revela que era el "unassigned" el 16 de octubre de 1991. Si se listan una
proteína, sucesión de ADN, u homología con un gen del ratón, uno puede estar seguro que
el gen es real, pero una situación del mapa solo no proporciona ninguna garantía. Varios
símbolos incluidos en el catálogo representan positivo falsos que no se han escogido.
La única evidencia inequívoca para un gen es elucidación de su sucesión de ADN y
estructura de la proteína asociada. El mando de calidad para este tipo de información
bioquímica en el Web es bueno, en parte debido a medios proporcionados por el Proyecto
de Genome Humano. Desgraciadamente, mando de calidad para las demandas más débiles
sobre los genes pertinente al phenotypes es las aserciones inadecuadas, y especulativas en
los medios de comunicación de masa sobre la determinación genética de conductas
socialmente significantes (Colt & Hollister 1998) [22] todos son demasiado a menudo
basado en las proclamaciones apresurado de genetistas conductuales que deben conocer
bien.

GENE FUNCTION
A cornucopia of genes relevant to the nervous system and behavior is now available
for research on function. The question of how genes influence behavior and how the
activities of genes are themselves regulated is of prime concern for psychology.
Function can be understood at different levels.

LA FUNCIÓN DEL GEN

Una cornucopia de genes pertinente al sistema nervioso y la conducta está ahora disponible
para la investigación en la función. La pregunta de cómo los genes influyen en la conducta
y cómo las actividades de genes son que ellos regulado es de primera preocupación para la
psicología. La función puede entenderse a los niveles diferentes.

Natural Polymorphisms
A mutation that seriously impairs the function of an important gene typically is rare in a
breeding population, but not all major gene effects on behavior are grossly aberrant misfits.
Two remarkable behavioral polymorphisms found in wild fruit flies seem to persist because
they aid a species to exploit a wider variety of environments. The foraging locus influences
activity of larvae in the presence of food; the dominant rover allele (forR) leads to longer
forays into the environment, whereas the recessive sitter allele (fors) results in more
localized feeding. Both alleles are common in wild fruit flies living in an urban habitat
(Toronto). An exemplary series of studies demonstrated that the sitter mutation occurs in a
previously documented gene, dg2, that codes for a cyclic GMP-dependent protein kinase
and causes a small change in activity of the enzyme that is sufficient to alter foraging
behavior (Osborne et al 1997). [74] The rover phenotype predominates in crowded living
conditions, whereas the sitter allele increases in lower population Polymorphisms natural
Una mutación que en serio daña la función de un gen importante típicamente es rara en una
población de la cría, pero no todo el gen del comandante efectúa en la conducta es los
misfits groseramente aberrantes. Dos polymorphisms conductuales notables encontrados en
las moscas de fruta salvajes parecen persistir porque ellos ayudan una especie para
aprovecharse de una variedad más ancha de ambientes. El sitio forrajeando influye en
actividad de larvae en la presencia de comida; el allele del vagabundo dominante (el forR)
lleva a las correrías más largas en el ambiente, considerando que el allele del ave que
empolla recesivo (el fors) los resultados en el alimento más localizado. Ambos alleles son
comúnes en moscas de fruta salvajes que viven en un hábitat urbano (Toronto). Una serie
ejemplar de estudios demostró que la mutación del ave que empolla ocurre en un gen
previamente documentado, dg2 que codifica para un kinase de la proteína GMP-
dependientes cíclicos y causas un dinero suelto en la actividad de la enzima que es
suficiente alterar forrajeando la conducta (el et de Osborne al 1997). [74] El phenotype del
vagabundo predomina en las condiciones vivientes atestado, considerando que el allele del
ave que empolla aumenta en el más bajo populatio

densities where the food supply is not so readily exhausted (Sokolowski et al 1997). [90] A
more subtle polymorphism occurs in the circadian clock gene period, where the allele
which is more common in northern Europe leads to more efficient adaptation of the 24-h
activity rhythm to temperature changes than the allele more common near the
Mediterranean (Sawyer et al 1997). [86] By combining carefully controlled genetic analysis
in the laboratory with studies further afield, the science of individual differences thus
advances our understanding of behavioral ecology and evolution.independent of
investigators (the et of Grigorenko at the 1997) [42] but only for one of five reading-related
phenotypes (the phonological knowledge) and only with the nonparametric (instead of
parametric) the methods. The interval of trust for the situation of the gene is more than 10
wide centimeter, and any protein or the DNA succession information is known. A search in
the "schizophrenia" he/she surrendered 40 entrances, even the symbol of the gene SCZD1
assigned April 12 1989, to a region in chromosome 5 that is recognized now as not
harboring a gene that influences in the schizophrenia (Moldin & Gottesman 1997). [71]
Any name of the gene returned by a search of OMIM should be verified carefully against
the most authoritarian sources, mainly the GDB where a history of the symbol of SCZD1

symbol reveals it was "unassigned" on October 16, 1991. If to protein, DNA sequence, or
homology with to mouse gene is listed, one dog be confident that the gene real is, but to
map location by itself provides non guarantee. Several symbols included in the catalog
represent false positives that have not been culled.
The only unequivocal evidence for to gene is elucidation of its DNA sequence and
associated protein structure. The quality control for this kind of biochemical information on
the Web is good, in part because of facilities provided by the Human Genome Project.
Unfortunately, quality control for weaker claims about genes relevant to phenotypes is
inadequate, and speculative assertions in the mass half about genetic determination of
socially significant behaviors (Colt & Hollister 1998) [22] all too often plows based on
hasty proclamations from behavioral geneticists who should know better.
the symbol reveals that it was the "unassigned" October 16 1991. If a protein, succession of
DNA, or homology are listed with a gene of the mouse, one can be for sure the gene is real,
but a situation of the alone map doesn't provide any guarantee. Several symbols included in
the catalog represent positive false that have not been chosen.
The only unequivocal evidence for a gene is elucidation of its succession of DNA and it
structures of the associate protein. The control of quality for this type of biochemical
information in the Web is good, partly due to means provided by the Project of Human
Genome. Unfortunately, control of quality for the weakest demands on the pertinent genes
to the phenotypes is the inadequate, and speculative assertions in the media of mass on the
genetic determination of socially significant behaviors (Colt & Hollister 1998) [22] all are
too often based on the accelerated proclamations of behavioral geneticists that you/they
should know well.

GENE FUNCTION
To cornucopia of genes relevant to the nervous system and behavior is now available for
research on function. The question of how genes influence behavior and how the activities
of genes plows themselves regulated is of concern for psychology it prevails. Function dog
be understood at different levels.
THE FUNCTION OF THE GENE
A pertinent cornucopia of genes to the nervous system and the behavior is now available
for the investigation in the function. The question of how the genes influence in the
behavior and how the activities of genes are that them regulated it is of first concern for the
psychology. The function can understand each other at the different levels.

Natural Polymorphisms
To mutation that seriously impairs the function of an important gene typically is rare in to
breeding population, but not all major gene effects on behavior plows grossly aberrant
misfits. Two remarkable behavioral polymorphisms found in wild fruit flies seem to persist
because they aid to species to exploit to wider variety of environments. The foraging locus
influences activity of larvae in the presence of food; the dominant rover allele (forR) leads
to longer forays into the environment, whereas the recessive sitter allele (fors) results in
localized feeding lives. Both alleles plows common in wild fruit flies living in an urban
habitat (Toronto). An exemplary series of studies demonstrated that the sitter mutation
occurs in to previously documented gene, dg2, that codes for to cyclic GMP-dependent
protein kinase and causes to small change in activity of the enzyme that is sufficient to alter
foraging behavior (Osborne et at the 1997). [74] The rover phenotype predominates in
crowded living conditions, whereas the sitter allele increases in lower population natural
Polymorphisms
A mutation that seriously damages the function of an important gene typically it is strange
in a population of the breeding, but not the commandant's gene makes in the behavior it is
the grossly aberrant misfits. Two polymorphisms behavioral notables found in the wild fruit
flies seems to persist because they help a species to take advantage of a wider variety of
atmospheres. The place foraging influences in larvae activity in the presence of food; the
dominant vagabond's allele (the forR) it takes to the longest forays in the atmosphere,
considering that the allele of the bird that sits recessive (the fors) the results in the located
food. Both alleles is common in wild fruit flies that live in an urban habitat (Toronto). An
exemplary series of studies demonstrated that the mutation of the bird that sits happens in a
previously documented gene, dg2 that codes for a kinase of the protein recurrent GMP-
clerks and you cause a loose money in the activity of the enzyme that is enough to alter
foraging the behavior (the et of Osborne at the 1997). [74] the vagabond's phenotype
prevails under the crowded alive conditions, considering that the allele of the bird that sits
increases in the lowest populatio

densities where the food supply is not so readily exhausted (Sokolowski et at the 1997).
[90] TO subtle polymorphism occurs it lives in the circadian clock gene period, where the
allele which is lives common in northern Europe leads to efficient adaptation of the 24-h
activity rhythm to temperature changes than the allele it lives common near the it lives
Mediterranean (Sawyer et at the 1997). [86] By combining carefully controlled genetic
analysis in the laboratory with studies further afield, the science of individual differences
thus advances our understanding of behavioral ecology and evolution.

densidades dónde el suministro de comida no es tan prontamente agotado (el et de

Sokolowski al 1997). [90] UN polymorphism más sutil ocurre en el circadian reloj gen
período dónde el allele que es más común en las primacías de Europa norteñas a la
adaptación más eficaz del 24-h ritmo de actividad a la temperatura cambia que el allele más
común cerca del mediterráneo (el et del Aserrador al 1997). [86] combinando más allá lejos
de casa el análisis genético cuidadosamente controlado en el laboratorio con los estudios, la
ciencia de diferencias individuales así los adelantos nuestra comprensión de ecología
conductual y evolución.

Genetic Dissection
Most psychologically interesting behaviors are multifactorial, involving numerous genes
whose actions are influenced by diverse features of the environment. Although individual
studies usually concentrate attention on one specific gene, it is generally understood that
many genes are relevant. As emphasized by Tully (1997), [97] "Single-gene mutant analysis
can be informative only when pursued within the framework of interacting polygenes."
Powerful techniques to create mutations have spawned new possibilities for genetic
dissection of complex processes. No satisfying account of genetic involvement in any
complex behavior has yet been achieved, but significant progress has been made in several
domains. Olfactory learning and memory in fruit flies is a process in which certain
mutations exert their effects primarily on a specific component (see Figure 2), but the famous
flow diagram does not imply that one or two genes provide a sufficient explanation for a
biologically distinct component of memory; yet the diagram is a useful device for
integrating a large corpus of experimental data. The fact that different mutations result in
flies with different temporal profiles of memory loss and different interactions with drugs
that block protein synthesis proves the multifactorial nature of the memory process. By
examining flies affected simultaneously by two different mutations, a scheme for parts
arranged in series or in parallel may be perceived. Numerous other genes are undoubtedly
involved, and pleiotropy, the occurrence of multiple phenotypic effects of one gene, is to be
expected. For example, the turnip mutation reduces motor activity and sensitivity to shock
while also impairing learning (Mihalek et al 1997). [68] To some readers, this may render it
less interesting because its effects are not restricted to the memory process, but genetic
dissection clearly reveals it to be an integral part of the process.La Disección genética
El más psicológicamente las conductas interesantes son los multifactorial, mientras
involucrando numerosos genes cuyas acciones son influenciadas por los rasgos diversos del
ambiente. Aunque los estudios individuales normalmente se concentran la atención en un
gen específico, generalmente se entiende tantos los genes son pertinentes. Como dado
énfasis a por Tully (1997), [97] el "Solo-gen el análisis mutante sólo puede ser informativo
cuando siguió dentro del armazón de polygenes" entrelazado. Las técnicas poderosas para
crear las mutaciones han desovado las nuevas posibilidades para la disección genética de
procesos complejos. Ninguna cuenta satisfaciendo de envolvimiento genético en cualquier
conducta compleja se ha logrado todavía, pero el progreso significante ha sido hecho en
varios dominios. El aprendizaje olfativo y memoria en las moscas de fruta son un proceso
en que ciertas mutaciones ejercen sus efectos principalmente en un componente específico
(vea Figura 2), pero el diagrama de flujo famoso no implica ese un o dos genes mantienen
una explicación suficiente un componente biológicamente distinto de memoria; todavía el
diagrama es un dispositivo útil por integrar un cuerpo grande de datos experimentales. El
hecho que las mutaciones diferentes producen las moscas con los perfiles temporales
diferentes de pérdida de memoria y las interacciones diferentes con drogas que bloquean la
síntesis de la proteína demuestra la naturaleza del multifactorial del proceso de memoria.
Examinando moscas afectadas simultáneamente por dos mutaciones diferentes, un esquema
para partes colocadas en la serie o en paralelo puede percibirse. Los numerosos otros genes
están indudablemente envueltos, y pleiotropy, la ocurrencia de phenotypic múltiple efectúa
de un gen, será esperado. Por ejemplo, la mutación del nabo reduce actividad de motor y
sensibilidad para asustar mientras también dañando el aprendizaje (el et de Mihalek al
1997). [68] A algunos lectores, esto puede darlo menos interesante porque sus efectos no se
restringen al proceso de memoria, pero la disección genética lo revela para ser una parte
íntegra del proceso claramente.

[Help with image viewing]

Figure 2. Genes that influence different components of memory formation in fruit flies. The components are
LRN, learning; STM, short-term memory; MTM, medium-term memory; LTM, long-term memory; ARM,
anesthesia-resistant memory. Adapted with permission from Tully et al (1996). [98]

Targeted mutations have led to a resurgence of interest in learning and memory in

mice, and the list of genes known to be important is rapidly growing (see Table 2).
Although admirable efforts have been made to comprehend the interconnections of
gene-derived proteins involved in memory formation within a synapse (e.g. Abel et
al 1998), [2] the horizons of this metabolic land-scape are rapidly expanding, with
no limit in sight. Many of these genes have pleiotropic effects as well, such as
Camk2a, which is important in spatial memory but also impinges on numerous
other behaviors (Chen et al 1994), [19] and Creb, which also reduces symptoms of
morphine withdrawal (Maldonado et al 1996). [60]

[La ayuda con imagen que ve]

Figure 2. Genes que influyen en componentes diferentes de formación de memoria en las

moscas de fruta. Los componentes son LRN, mientras aprendiendo; STM, la memoria a
corto plazo,; MTM, la memoria a plazo medio,; LTM, la memoria a largo plazo,; ARME, la
memoria anestesia-resistente. Adaptado con el permiso del Tully et al (1996). [98]
Las mutaciones de Targeted han llevado a un resurgimiento de interés aprendiendo y
memoria en los ratones, y la lista de genes conocida para ser importante es rápidamente
creciente (vea Mesa 2). Aunque se han hecho los esfuerzos admirables comprender las
interconexiones de proteínas gen-derivadas involucradas en la formación de memoria
dentro de un synapse (por ejemplo el et de Abel al 1998), [2] los horizontes de este tierra-
bohordo metabólico son rápidamente que ensancha, sin el límite en la vista. Muchos de
estos genes tienen el pleiotropic también efectúa, como Camk2a que es importante en la
memoria espacial pero también choca con en las numerosas otras conductas (el et de Chen
al 1994), [19] y Creb que también reduce síntomas de retiro de morfina (el et de Maldonado
al 1996). [60]

Table 2. Mouse genes on specified chromosomes that are important for psychological processes a

The organism's genes are of course present from conception, and many participate
in formative processes as well as in dynamic adult functions. Embryonic effects can
be notably different from involvement in the mature brain, and to distinguish
between developmental and current effects of a gene knockout is challenging
indeed. Several clever techniques have been employed to overcome this problem.
Tsien and coworkers (1996) [96] deleted the NMDA receptor (Grin1 gene)
selectively from the CA1 region of the hippocampus and obtained memory deficits
similar to those from a nonspecific gene knockout; Mayford and colleagues (1996)
[66] were able to limit the expression of a Camk2a mutation to the forebrain of adult
mice and still obtained memory deficits. Guzowski & McGaugh (1997) [44] altered
spatial memory by injecting synthetic DNA directly into the hippocampus of adult
rats to specifically modify the action of the Creb gene. These sophisticated methods
confer unprecedented clarity on results for psychopharmacology. Molecular
genetics is thus becoming a tool in the kit of physiological psychology.

Appetite and obesity in mice are proving to be physiologically and genetically

complex (Table 2), and conceptual schemes for synthesizing this knowledge are still
lagging behind the burgeoning data. This is happening with regard to circadian
rhythms as well, where newly discovered genes are revealing previously
unimagined elements of a larger picture (Albrecht et al 1997). [3]

Investigations of obesity provide an emerging portrait of diverse organs connected in

feedback loops involving the environment (Figure 3). Under normal conditions, overeating
leads to growth of white fat cells (adipocytes) which in turn synthesize the protein leptin
and secrete it into the bloodstream. One of leptin's effects occurs in the hypothalamus,
where it binds to the leptin receptor and decreases appetite by inhibiting the synthesis of
neuropeptide Y (Npy gene)-a neurotransmitter that tends to increase appetite. The obese
mutation (Lepob/ob) prevents the synthesis of leptin in white fat, thereby increasing appetite
when NPY levels rise unchecked, and gene therapy to restore leptin in the Lepob/ob mice
prevents both obesity and diabetes (Muzzin et al 1996). [72] The diabetes mutation (Lepr
(db/db)) disables the leptin receptor and renders mice insensitive to high levels of leptin in the
blood, which again leads to overeating (Caro et al 1996). [15] By using a double mutant
combining Lepob/ob with the gene knockout Npy-/-, it was shown that there are parallel
pathways for leptin-related appetite control in the hypothalamus (Erickson et alMesa 2. los
genes del Ratón en cromosomas especificados que son importante para el processesa
psicológico

densities where the supply of food is not so quickly out (the et of Sokolowski at the 1997).
[90] A subtler polymorphism happens in the circadian clock gene period where the allele
that is more common in the primacies of northern Europe to the most effective adaptation
of the 24-h activity rhythm to the temperature changes that the most common allele near the
mediterranean (the et of the Sawyer at the 1997). [86] combining further on far from house
the genetic analysis carefully controlled in the laboratory with the studies, the science of
differences singular this way our advances understanding of behavioral ecology and
evolution.

Genetic Dissection
Most psychologically interesting behaviors plows multifactorial, involving numerous genes
whose actions it plows influenced by diverse features of the environment. Although
individual studies usually concentrates attention on one specific gene, it is generally
understood that many genes plows relevant. Ace emphasized by Tully (1997), [97] "Sail-
gene mutant analysis dog be informative only when pursued within the framework of
interacting polygenes." Powerful techniques to believes you mutations have spawned new
possibilities for genetic dissection of complex processes. Not satisfying account of genetic
involvement in any complex behavior has yet been achieved, but significant progress has
been made in several domains. Olfactory learning and memory in fruit flies is to process in
which certain mutations exert their effects primarily on to specific component (see Figures
2), but the famous flow diagram does not imply that one or two genes provide to sufficient
explanation for to biologically distinct component of memory; yet the diagram is to useful
device for integrating to large corpus experimental of dates. The fact that different
mutations result in flies with different temporary profiles of memory loss and different
interactions with drugs that block protein synthesis proves the multifactorial nature of the
memory process. By examining flies affected simultaneously by two different mutations, to
scheme for parts arranged in series or in parallel may be perceived. Numerous other genes
plows undoubtedly involved, and pleiotropy, the occurrence of multiple phenotypic effects
of one gene, is to be expected. For example, the turnip mutation reduces motor activity and
sensitivity to shock while also impairing learning (Mihalek et at the 1997). [68] To some
readers, this may render it less interesting because its effects plows not restricted to the
memory process, but genetic dissection clearly reveals it to be an integral part of the
process.La genetic Dissection
The more ones psychologically the interesting behaviors are the multifactorial, while
involving numerous genes whose actions are influenced by the diverse features of the
atmosphere. Although the individual studies usually concentrate the attention on a specific
gene, he/she generally understands each other so many the genes are pertinent. As having
given emphasis to for Tully (1997), [97] the "Alone-gene the analysis mutant can only be
informative when it continued inside the polygenes frame" crisscross. The powerful
techniques to create the mutations have spawned the new possibilities for the genetic
dissection of complex processes. Any bill satisfying of genetic involvement in any complex
behavior has still been achieved, but the significant progress has been made in several
domains. The smell learning and memory in the fruit flies are a process in that certain
mutations exercise their effects mainly in a specific component (he/she sees Figure 2), but
the diagram of famous flow doesn't imply that an or two genes maintain an enough
explanation by heart a biologically different component; the diagram is still an useful
device to integrate a big body of experimental data. The fact that the different mutations
produce the flies by heart with the temporary profiles different from loss and the
interactions different with drugs that block the synthesis of the protein demonstrate the
nature of the multifactorial of the process by heart. Examining flies affected simultaneously
by two different mutations, an outline for parts placed in the series or in parallel it can be
perceived. The numerous ones other genes are undoubtedly wrapped up, and pleiotropy, the
occurrence of multiple phenotypic makes of a gene, it will be expected. For example, the
mutation of the turnip reduces motor activity and sensibility to scare while also damaging
the learning (the et of Mihalek at the 1997). [68] TO some readers, this can give it less
interesting because its effects are not restricted by heart to the process, but the genetic
dissection reveals it to be clearly an entire part of the process.

[Help with image viewing]

Figure 2. Genes that influence different components of memory formation in fruit flies. The
components plows LRN, learning; STM, short-term memory; MTM, medium-term
memory; LTM, long-term memory; ARM, anesthesia-resistant memory. Adapted with
permission from Tully et to the (1996). [98]

Targeted mutations have led to resurgence of interest in learning and memory in mice, and
the list of genes known to be important is rapidly growing (see Table 2). Although
admirable efforts have been made to comprehend the interconnections of gene-derived
proteins involved in memory formation within to synapse (e.g. Abel et at the 1998), [2] the
horizons of this metabolic land-scape plows rapidly expanding, with non limit in sight.
Many of these genes have pleiotropic effects ace well, such ace Camk2a, which is
important in spatial memory but also impinges on numerous other behaviors (Chen et at the
1994), [19] and Creb, which also reduces symptoms of morphine withdrawal (Maldonado
et at the 1996). [60]
[The help with image that you go]

Figure 2. Genes that influence by heart in components different from formation in the fruit
flies. The components are LRN, while learning; STM, the short term memory,; MTM, the
memory to half term,; LTM, the long term memory,; ARM, the anesthesia-resistant
memory. Adapted with the permission from the Tully et to the (1996). [98]

The mutations of Targeted have taken to a resurgence of interest learning and memory in
the mice, and the well-known list of genes to be important is quickly growing (he/she sees
Table 2). Although the admirable efforts have been made understand the interconnections
of gene-derived proteins involved by heart in the formation inside a synapse (for example
the et of Abel at the 1998), [2] the horizons of this metabolic earth-scape are quickly that it
enlarges, without the limit in the view. Many of these genes have the pleiotropic it also
makes, as Camk2a that is important in the space memory but it also collides with in the
numerous ones other behaviors (the et of Chen at the 1994), [19] and Creb that also reduces
symptoms of retirement of morphine (the et of Maldonado at the 1996). [60]

Table 2. Mouse genes on specified chromosomes that plows important for psychological
processesa

The organism's genes plows of course present from conception, and many you participate
yourself in formative processes ace well ace in dynamic adult functions. Embryonic effects
dog be notably different from involvement in the mature brain, and to distinguish between
developmental and current effects of to gene knockout is challenging indeed. Several clever
techniques have been employed to overcome this problem. Tsien and coworkers (1996)
[96] deleted the NMDA receiver (Grin1 gene) selectively from the CA1 region of the
hippocampus and obtained memory deficits similar to those from to nonspecific gene
knockout; Mayford and colleagues (1996) [66] were able to limit the expression of to
Camk2a mutation to the forebrain of adult mice and still obtained memory deficits.
Guzowski & McGaugh (1997) [44] altered spatial memory by injecting synthetic DNA
directly into the hippocampus of adult rats to specifically modify the action of the Creb
gene. These sophisticated methods confer unprecedented clarity on results for
psychopharmacology. Molecular genetics is thus becoming to tool in the kit of
physiological psychology.
Appetite and obesity in mice plows proving to be physiologically and genetically complex
(Table 2), and conceptual schemes for synthesizing this knowledge plows still lagging
behind the burgeoning it dates. This is happening with regard to circadian rhythms ace well,
where newly discovered genes plows revealing previously unimagined elements of to larger
picture (Albrecht et at the 1997). [3]
Investigations of obesity provide an emerging portrait of diverse organs connected in
feedback loops involving the environment (it Figures 3). Under normal conditions,
overeating leads to growth of white fat cells (adipocytes) which in turn synthesize the
protein leptin and secretes it into the bloodstream. One of leptin's effects occurs in the
hypothalamus, where it binds to the leptin receiving and decreases appetite by inhibiting the
synthesis of neuropeptide AND (Npy gene)-to neurotransmitter that tends to increase
appetite. The obese mutation (Lepob/ob) prevents the synthesis of leptin in white fat,
thereby increasing appetite when NPY levels rise unchecked, and gene therapy to restore
leptin in the Lepob/ob mice prevents both obesity and diabetes (Muzzin et at the 1996).
[72] The diabetes mutation (Lepr (db/db)) disables the leptin receiving and renders mice
insensitive to high levels of leptin in the blood, which again leads to overeating (Expensive
et at the 1996). [15] By using to double mutant combining Lepob/ob with the gene
knockout Npy - / -, it was shown that there plows parallel pathways for leptin-related
appetite control in the hypothalamus (Erickson et alMesa 2. the genes of the Mouse in
specified chromosomes that they are important for the psychological processesa
Los genes del organismo están claro presentes de la concepción, y muchos participan en los
procesos formativos así como en las funciones del adulto dinámicas. Los efectos
embrionarios pueden ser notablemente diferentes del envolvimiento en el cerebro maduro,
y distinguir entre los efectos de desarrollo y actuales de un knockout del gen está
desafiando de hecho. Se han empleado varias técnicas diestras para superar este problema.
Tsien y coworkers (1996) [96] anuló el receptor de NMDA (el gen de Grin1)
selectivamente de la región de CA1 del hipocampo y obtuvo los déficites de memoria
similar a aquéllos de un knockout de gen de nonspecific; Mayford y colegas (1996) [66]
pudo limitar la expresión de una mutación de Camk2a al forebrain de ratones adultos y los
déficites de memoria todavía obtenidos. El Guzowski & McGaugh (1997) [44] la memoria
espacial alterada inyectando ADN sintético directamente en el hipocampo de ratas adultas
modificar la acción del gen de Creb específicamente. Estos métodos sofisticados confieren
la claridad inaudita en los resultados para el psychopharmacology. Las genéticas
moleculares están volviéndose una herramienta así en el equipo de psicología fisiológica.
El apetito y obesidad en los ratones están demostrando ser fisiológicamente y
genéticamente complejo (Mesa 2), y los esquemas conceptuales por sintetizar este
conocimiento todavía están retrasándose detrás de los datos del burgeoning. Esto también
está pasando con respecto a los ritmos del circadian, dónde recientemente descubrió los
genes están revelando elementos del unimagined de un cuadro más grande previamente (el
et de Albrecht al 1997). [3]
Las investigaciones de obesidad proporcionan un retrato surgiendo de órganos diversos
conectado en vueltas de la regeneración que involucran el ambiente (Figura 3). Bajo las
condiciones normales, el overeating lleva al crecimiento de células gordas blancas (el
adipocytes) qué a su vez sintetiza el leptin de la proteína y lo secreta en el torrente
sanguíneo. Uno de los efectos de leptin ocurre en el hypothalamus dónde liga al receptor
del leptin y apetito de disminuciones inhibiendo la síntesis de neuropeptide Y (Npy gene)-
un neurotransmitter que tienden a aumentar el apetito. La mutación obesa (Lepob/ob)
previene la síntesis de leptin en la grasa blanca, por eso el apetito creciente cuando NPY
nivela suba desenfrenado, y la terapia del gen para restaurar el leptin en los ratones de
Lepob/ob previene obesidad y diabetes (el et de Muzzin al 1996). [72] La mutación de la
diabetes (Lepr (el db/db)) desactiva el receptor del leptin y da los ratones insensible a los
niveles altos de leptin en la sangre que de nuevo lleva al overeating (el et de Caro al 1996).
[15] usando un mutante doble que combina Lepob/ob con el knockout del gen Npy - / -, fue
mostrado que hay sendas paralelas para el mando del apetito leptin-relacionado en el
hypothalamus (el Erickson et al

1996). [35] The Lepob/ob plus lethal yellow (AY/a) double mutant revealed another parallel
pathway that acts via the melanocortin-4 receptor (Mc4r gene) where normal stimulation of
MC4-R decreases appetite but the AY gene product antagonizes it (Boston et al 1997). [12]
Not all obesity is mediated by the leptin loop (Schonfeld-Warden & Warden 1997), [88] not
all leptin effects are mediated by appetite changes (Yu et al 1997), [109] and diabetic
symptoms are not joined inexorably with obesity (Hotamisligil et al 1996). [47] Although
Table 2 suggests that separate sets of genes impact learning and appetite, this inference may
not be
The genes of the organism are clear present of the conception, and many participate in the
formative processes as well as in the dynamic adult's functions. The embryonic effects can
be notably different from the involvement in the mature brain, and to distinguish among the
development effects and current of a knockout of the gene it is challenging in fact. Several
skillful techniques have been used to overcome this problem. Tsien and coworkers (1996)
[96] it annulled the receiver of NMDA (the gene of Grin1) selectively of the region of CA1
of the seahorse and he/she obtained the deficits by heart similar to those of a knockout of
nonspecific gene; Mayford and colleagues (1996) [66] it could limit the expression of a
mutation from Camk2a to the forebrain of mature mice and the deficits by heart still
obtained. The Guzowski & McGaugh (1997) [44] the altered space memory injecting
synthetic DNA directly in the seahorse of mature rats to modify the action of the gene of
Creb specifically. These sophisticated methods confer the unheard clarity in the results for
the psychopharmacology. The molecular genetics are becoming this way a tool in the team
of physiologic psychology.
The appetite and obesity in the mice are demonstrating to be physiologically and
genetically complex (Table 2), and the conceptual outlines to synthesize this knowledge are
still being delayed behind the data of the burgeoning. This is also passing with regard to the
rhythms of the circadian, where recently he/she discovered the genes they are revealing
elements of the unimagined of a bigger square previously (the et of Albrecht at the 1997).
[3]
The investigations of obesity provide a portrait arising of diverse organs connected in turns
of the regeneration that involve the atmosphere (it Figures 3). Under the normal conditions,
the overeating takes to the growth of white fat cells (the adipocytes) how in turn it
synthesizes the leptin of the protein and the secret thing in the sanguine torrent. One of the
leptin effects happens in the hypothalamus where it ties to the receiver of the leptin and
appetite of decreases inhibiting the neuropeptide synthesis AND (Npy gene)-a
neurotransmitter that spread to increase the appetite. The obese mutation (Lepob/ob) it
prevents the leptin synthesis in the white fat, for that reason the growing appetite when
NPY evens it ascends wild, and the therapy of the gene to restore the leptin in the mice of
Lepob/ob prevents obesity and diabetes (the et of Muzzin at the 1996). [72] The mutation
of the diabetes (Lepr (the db/db)) it disables the receiver of the leptin and he/she gives the
insensitive mice at the high levels of leptin in the blood that again takes to the overeating
(the et of Expensive at the 1996). [15] using a double mutant that Lepob/ob combines with
the knockout of the gene Npy - / -, it was shown that there are parallel paths for the control
of the appetite leptin-related in the hypothalamus (the Erickson et to the one

1996). [35] The Lepob/ob bonus lethal yellow (AY/a) double mutant revealed
another parallel pathway that acts via the receiving melanocortin-4 (Mc4r gene)
where normal stimulation of MC4-R decreases appetite but the OH gene product
antagonizes it (Boston et at the 1997). [12] Not all obesity is mediated by the leptin
loop (Schonfeld-Warden & Warden 1997), [88] not all leptin effects plows
mediated by appetite changes (Yu et at the 1997), [109] and diabetic symptoms
plows not joined inexorably with obesity (Hotamisligil et at the 1996). [47]
Although Table 2 suggests that separates sets of genes impact learning and appetite,
this inference may not be warranted because those working with obesity typically
do not assess a wide range of behavioral phenotypes. It seems highly likely that
variations in appetite would indeed influence the acquisition of certain kinds of
tasks, but little recent work with obesity mutations has been done by psychologists
interested in motivation.
 [Help with image viewing]

Figure 3. Major components of a system that regulates appetite and leads to obesity in mutant mice. Only the
protein products of genes are shown. (Arrow) One component stimulates another; (vertical bar) a component
inhibits or antagonizes another. Abbreviations: AY, the mutant agouti peptide; aFABP, alpha-fatty acid binding
protein; INSr, insulin receptor; LEPr, leptin receptor; MC4-R, melanocortin-4 receptor; NPY, neuropeptide Y;
NPYr, NPY receptor; POMC, pro-opiomelanocortin-alpha; TNF, tumor necrosis factor. The genes
corresponding to these proteins are AY, Ap2, Insr, Lepr, Mc4r, Npy, Npy1r, Pomc1, and Tnf, respectively. LH is
lutenizing hormone. See section on Genetic Dissection for explanation.

warranted because those working with obesity typically do not assess to wide range of
behavioral phenotypes. It seems highly likely that variations in appetite would indeed
influence the acquisition of certain kinds of tasks, but little recent work with obesity
mutations has been it donates by psychologists interested in motivation.

[Help with image viewing]

Figure 3. Major components of to system that regulates appetite and leads to obesity in
mutant mice. Only the protein products of genes plows shown. (Arrow) One component
stimulates another; (vertical bar) to component inhibits or antagonizes another.
Abbreviations: OH, the mutant agouti peptide; aFABP, alpha-fatty acid binding protein;
INSr, receiving insulin; LEPr, receiving leptin; MC4-R, receiving melanocortin-4; NPY,
neuropeptide AND; NPYr, NPY receiver; POMC, pro-opiomelanocortin-alpha; TNF,
tumor necrosis factor. The genes corresponding to these proteins plows OH, Ap2, Insr,
Lepr, Mc4r, Npy, Npy1r, Pomc1, and Tnf, respectively. LH is lutenizing hormone. See
section on Genetic Dissection for explanation.

Genetic dissection thus proceeds through several stages. (a) Research projects in
the early stages seek to discover a single mutation and explore its phenotypic
effects. (b) After several genes are known to be important parts of the system, work
begins with double mutants and factorial gene-environment or gene-drug interaction
studies to elucidate serial and parallel processes, each study focusing on a limited
sector of the larger system. (c) Eventually, attempts are made to integrate this
knowledge into comprehensive models that can be tested with multifactorial
experiments. Most research in neurobehavioral genetics is presently entering the
second stage, and none has yet reached the third.

warranted because those working with obesity typically do not assess a wide range of
behavioral phenotypes. It seems highly likely that variations in appetite would indeed
influence the acquisition of certain kinds of tasks, but little recent work with obesity
mutations has been done by psychologists interested in motivation.

[Help with image viewing]

Figure 3. Major components of a system that regulates appetite and leads to obesity in
mutant mice. Only the protein products of genes are shown. (Arrow) One component
stimulates another; (vertical bar) a component inhibits or antagonizes another.
Abbreviations: AY, the mutant agouti peptide; aFABP, alpha-fatty acid binding protein;
INSr, insulin receptor; LEPr, leptin receptor; MC4-R, melanocortin-4 receptor; NPY,
neuropeptide Y; NPYr, NPY receptor; POMC, pro-opiomelanocortin-alpha; TNF, tumor
necrosis factor. The genes corresponding to these proteins are AY, Ap2, Insr, Lepr, Mc4r,
Npy, Npy1r, Pomc1, and Tnf, respectively. LH is lutenizing hormone. See section on
Genetic Dissection for explanation.

warranted because those working with obesity typically do not assess to wide range of
behavioral phenotypes. It seems highly likely that variations in appetite would indeed
influence the acquisition of certain kinds of tasks, but little recent work with obesity
mutations has been it donates by psychologists interested in motivation.

[Help with image viewing]

Figure 3. Major components of to system that regulates appetite and leads to obesity in
mutant mice. Only the protein products of genes plows shown. (Arrow) One component
stimulates another; (vertical bar) to component inhibits or antagonizes another.
Abbreviations: OH, the mutant agouti peptide; aFABP, alpha-fatty acid binding protein;
INSr, receiving insulin; LEPr, receiving leptin; MC4-R, receiving melanocortin-4; NPY,
neuropeptide AND; NPYr, NPY receiver; POMC, pro-opiomelanocortin-alpha; TNF,
tumor necrosis factor. The genes corresponding to these proteins plows OH, Ap2, Insr,
Lepr, Mc4r, Npy, Npy1r, Pomc1, and Tnf, respectively. LH is lutenizing hormone. See
section on Genetic Dissection for explanation.

Systems of Genes
The question remains of how many genes are involved in memory, appetite, or circadian
rhythm. A first approximation can be achieved by examining the array of genes expressed
in mRNA under specified conditions. A sensitive and rapid method is now available to
assess simultaneously the expression of hundreds of genes in mice (Figure 4) and over 1000
in humans, and customized arrays for screening any desired subset of genes may be
anticipated (see Web sites www.resgen.com and atlas.clontech.com). One might contrast
brains of trained and untrained mice to assess memory, or brains at midnight and at high
noon under a normal light cycle or 1996). [35] el Lepob/ob más letal amarillo (AY/a) el
mutante doble reveló otra senda paralela que actúa vía el receptor del melanocortin-4 (el
gen de Mc4r) donde el estímulo normal de MC4-R disminuciones apetito pero el AY gen
producto se lo opone a (el et de Boston al 1997). [12] No toda la obesidad se media por la
Systems of Genes
The question remains of how many genes plows involved in memory, appetite, or circadian
rhythm. To first approximation dog be achieved by examining the array of genes expressed
in mRNA under specified conditions. To sensitive and rapid method is now available to
assess simultaneously the expression of hundreds of genes in mice (it Figures 4) and over
1000 in humans, and customized arrays for screening any desired subset of genes may be
anticipated (see Web sites www.resgen.com and atlas.clontech.com). One might contrast
brains of trained and untrained mice to assess memory, or brains at midnight and at high
noon under to normal light cycle or 1996). [35] the yellow more lethal Lepob/ob (AY/a) the
double mutant revealed another parallel path that acts via the receiver of the melanocortin-4
(the gene of Mc4r) where the normal stimulus of MC4-R decreases appetite but the OH
gene product opposes it to him to (the et of Boston at the 1997). [12] Not all the obesity one
mediates for the vuelta del leptin (Schonfeld-Warden & Warden 1997), [88] no todo los
efectos del leptin se median por los cambios del apetito (el et de Yu al 1997), [109] y no se
unen los síntomas diabéticos inexorablemente con la obesidad (el et de Hotamisligil al
1996). [47] Aunque Mesa 2 sugiere que los juegos separados de impacto de los genes que
aprende y apetito, esta inferencia no puede garantizarse porque esos trabajando típicamente
con la obesidad no evalúan una gama amplia de phenotypes conductual. Parece muy
probable que las variaciones en el apetito influirían en la adquisición de ciertos tipos de
tareas de hecho, pero el reciente trabajo pequeño con las mutaciones de obesidad se ha
hecho por psicólogos interesados en la motivación.
turn of the leptin (Schonfeld-Warden & Warden 1997), [88] not the whole effects of the
leptin are mediated by the changes of the appetite (the et of Yu at the 1997), [109] and they
don't unite the diabetic symptoms inexorably with the obesity (the et of Hotamisligil at the
1996). [47] Although Table 2 suggest that the games separated from impact of the genes
that he/she learns and appetite, this inference cannot be guaranteed because those working
typically with the obesity doesn't evaluate a wide range of behavioral phenotypes. It seems
very probable that the variations in the appetite would influence in fact in the acquisition of
certain types of tasks, but the recent small work with the mutations of obesity has been
made by psychologists interested in the motivation.
[La ayuda con imagen que ve]

Figure 3. los componentes Mayores de un sistema que regula apetito y primacías a la

obesidad en los ratones mutante. Se muestran sólo los productos de la proteína de genes.
(La flecha) Un componente estimula otro; (la barra vertical) un componente inhibe o se
opone a otro. Las abreviaciones: AY, el peptide del agouti mutante,; el aFABP, el ácido
alfa-graso la proteína obligatoria; INSr, el receptor de insulina,; LEPr, el receptor del
leptin,; MC4-R, el receptor del melanocortin-4,; NPY, neuropeptide Y; NPYr, el receptor
de NPY,; POMC, el en pro de-opiomelanocortin-alfa,; TNF, el factor de necrosis de tumor.
Los genes que corresponden a estas proteínas son AY, Ap2, Insr, Lepr, Mc4r, Npy, Npy1r,
Pomc1, y Tnf, respectivamente. LH es la hormona del lutenizing. Vea la sección en la
Disección Genética para la explicación.

La disección genética así los beneficios a través de varias fases. (un) los proyectos de la
Investigación en las fases tempranas buscan descubrir una sola mutación y explorar sus
efectos del phenotypic. (b) Después de varios genes se conoce para ser partes importantes
del sistema, el trabajo empieza con los mutantes dobles y el gen-ambiente factorial o la
interacción del gen-droga estudia elucidar folletín y los procesos paralelos, cada estudio
que enfoca en un sector limitado del sistema más grande. (c) En el futuro, se hacen los
esfuerzos integrar este conocimiento en modelos comprensivos que pueden probarse con
los experimentos del multifactorial. Más investigación en las genéticas del neurobehavioral
está entrando en la segunda fase presentemente, y ninguno ha alcanzado el tercio todavía.
Los sistemas de Genes
La pregunta permanece de cuántos genes está envuelto en la memoria, apetito, o ritmo del
circadian. Una primera aproximación puede lograrse examinando la serie de genes
expresada en el mRNA bajo las condiciones especificadas. Un método sensible y rápido
está ahora disponible evaluar la expresión de centenares de genes simultáneamente en los
ratones (Figura 4) y encima de 1000 en los humanos, y personalizó las series por proteger
cualquiera deseado el subconjunto de genes puede preverse (vea los sitios de Web
www.resgen.com y atlas.clontech.com). Uno podría contrastar inteligencias de ratones
especializados e inexpertos para evaluar la memoria, o inteligencias a medianoche y al
mediodía alto bajo un ciclo ligero normal o

constant darkness to reveal circadian mechanisms. Furthermore, tissue from mutants

and normal siblings tested under the same circumstances could be used to assess
pleiotropic effects.

[The help with image that you go]

Figure 3. the components bigger than a system that regulates appetite and primacies to the
obesity in the mice mutant. They are only shown the products of the protein of genes. (The
arrow) A component stimulates another; (the vertical bar) a component inhibits or it
opposes himself to another. The abbreviations: OH, the peptide of the agouti mutant,; the
aFABP, the alpha-fatty acid the obligatory protein; INSr, the receiver of insulin,; LEPr, the
receiver of the leptin,; MC4-R, the receiver of the melanocortin-4,; NPY, neuropeptide
AND; NPYr, the receiver of NPY,; POMC, the one in pro of-opiomelanocortin-alpha,;
TNF, the factor of tumor necrosis. The genes that correspond to these proteins are OH,
Ap2, Insr, Lepr, Mc4r, Npy, Npy1r, Pomc1, and Tnf, respectively. LH is the hormone of
the lutenizing. See the section in the Genetic Dissection for the explanation.

The genetic dissection this way the benefits through several phases. (a) the projects of the
Investigation in the early phases look for to discover a single mutation and to explore their
effects of the phenotypic. (b) after several genes it is known to be important parts of the
system, the work begins with the double mutants and the factorial gene-atmosphere or the
interaction of the gene-drug studies to elucidate melodrama and the parallel processes, each
study that focuses in a limited sector of the biggest system. (c) In the future, the efforts are
made integrate this knowledge in understanding models that can be proven with the
experiments of the multifactorial. More investigation in the genetics of the neurobehavioral
is entering presently in the second phase, and none has still reached the third.
The systems of Genes
The question remains of how many genes it is wrapped in the memory, appetite, or rhythm
of the circadian. A first approach can be achieved examining the series of genes expressed
in the low mRNA the specified conditions. A sensitive method and express is now available
to evaluate the expression of hundreds of genes simultaneously in the mice (it Figures 4)
and above 1000 in the humans, and it personalized the series to protect anyone wanted the
subset of genes it can be foreseen (he/she sees the places of Web www.resgen.com and
atlas.clontech.com). One could contrast intelligence of specialized and inexpert mice to
evaluate the memory, or intelligence to midnight and at noon high under a normal slight
cycle or

constant darkness to reveal circadian mechanisms. Furthermore, tissue from mutants

and normal siblings tested under the same circumstance could be used to assess
pleiotropic effects.

[Help with image viewing]

Figure 4. A comparison of profiles of gene expression in tissue from two mice. Complementary cDNA is made
from RNA expressed in the tissue, and it binds or hybridizes to a DNA sample from the gene that gave rise to
the specific RNA molecule. Each pair of dots on the plate represents a different gene that is expressed in the
tissue. The large dots pointed out by small arrows symbolize genes expressed in only one of the samples. The
full Atlas[trade mark sign] Mouse cDNA Expression Array from CLONTECH Laboratories, Inc., can detect
expression of 588 different genes in one tissue sample. Adapted with permission of CLONTECH Laboratories,
Inc., from CLONTECHniques, January 1998, p. 2.

[Help with image viewing]

Figure 4. TO comparison of profiles of gene expression in tissue from two mice.

Complementary cDNA is made from RNA expressed in the tissue, and it binds or
hybridizes to DNA sample from the gene that gave rise to the specific RNA molecule. Each
pair of dots on the plate represents to different gene that is expressed in the tissue. The large
dots pointed out by small arrows symbolize genes expressed in only one of the samples.
The full Atlas[trade mark sign] Mouse cDNA Expression Array from CLONTECH
Laboratories, Inc., dog detect expression of 588 different genes in one tissue sample.
Adapted with permission of CLONTECH Laboratories, Inc., from CLONTECHniques,
January 1998, p. 2.

An extraordinary glimpse of complex gene action has been obtained recently for
yeast, an organism best known to psychologists for its vital role in synthesizing
ethanol from sugar. As the sugar in the yeast's environment is consumed, its
metabolism shifts from anerobic fermentation to aerobic respiration. Researchers
were able to attach DNA sequences of almost all the 6297 yeast genes to a single
glass plate 18 mm by 18 mm and record the abundance of all mRNAs at different
stages of the metabolic process (DeRisi et al 1997). [30] During the transition from
anerobic to aerobic metabolism, the expression of 1740 genes increased or
decreased at least twofold. About half of these genes were new to science, had not
yet been named, and had no recognized functions. A mutation in a single gene
(tup1) altered the expression of 355 other genes. In a remarkable understatement,
 the authors observed: "The large number of genes whose expression is altered and
the diversity of temporal expression profiles highlighted the challenge of
understanding the underlying regulatory mechanisms."

The one-celled yeast, of course, is a relatively simple creature that has been
thoroughly studied since the time of Pasteur. It seems likely that the complete
picture of gene activity during mammalian learning and memory will be even more
complex. The molecular tools are close at hand but the prevailing conceptual
framework in biological psychology may not be equal to the task of integrating so
vast an array of data.

DNA analysis and gene discovery have been dominated by a very successful reductionistic
perspective (Beckwith 1996), [5] but research on gene function reveals the necessity of
systems-oriented thinking (Gottlieb et al 1998, Strohman 1997). [41,91] The idea that a gene
determines a specific component of a behavioral phenotype is losing scientific credibility.
Chenchik and coworkers (1998) [20] forsee that new methods "will lead researchers away
from reductionistic approaches which focus on single genes, and towards more systemic
approaches that involve the simultaneous, parallel analysis of hundreds or thousands of
genes." It must be acknowledged that almost every gene has widespread pleiotropic effects
(Miklos & la oscuridad constante para revelar los mecanismos del circadian. Además, el
tejido de los mutantes y los hermanos normales probados bajo las mismas circunstancias
podría usarse para evaluar los efectos del pleiotropic.

[La ayuda con imagen que ve]

Figure 4. UNA comparación de perfiles de expresión del gen en el tejido de dos ratones. El
cDNA complementario es hecho de ARN expresó en el tejido, y liga o hace híbrido a una
muestra de ADN del gen que dio lugar a la molécula de ARN específica. Cada par de
puntos en el plato representa un gen diferente que se expresa en el tejido. Los puntos
grandes señalados por las flechas pequeñas simbolizan genes expresados en única de las
muestras. Los Atlas[trade llenos marcan la señal] la Ratón cDNA Expresión Serie de los
Laboratorios de CLONTECH, Inc., puede descubrir expresión de 588 genes diferentes en
una muestra del tejido. Adaptado con el permiso de Laboratorios de CLONTECH, Inc., de
CLONTECHniques, el 1998 de enero, pág. 2.

Un vislumbre extraordinario de acción del gen compleja se ha obtenido recientemente para

la levadura, un organismo el mejor conocido a psicólogos por su papel vital sintetizando el
etanol del azúcar. Como el azúcar en el ambiente de la levadura se consume, su
metabolismo cambia de la fermentación anerobia a la respiración aerobic. Investigadores
pudieron atar sucesiones de ADN de casi todos los 6297 genes de levadura a un solo vaso
chape 18 mm por 18 mm y grabe la abundancia de todo el mRNAs en las fases diferentes
del proceso metabólico (el et de DeRisi al 1997). [30] Durante la transición de anerobio al
metabolismo aerobic, la expresión de 1740 genes aumentó o disminuyó por lo menos dos
veces. Sobre la la mitad de estos genes era nuevo a la ciencia, no se había nombrado
todavía, y no tenía ninguna función reconocida. Una mutación en un solo gen (el tup1)
alterado la expresión de 355 otros genes. En una subestimación notable, los autores
observaron: "El número grande de genes cuya expresión es alterada y la diversidad de
perfiles de la expresión temporales resaltó el desafío de entender los mecanismos"
regulador subyacentes.
El uno-celled la levadura, claro, es una criatura relativamente simple que se ha estudiado
completamente desde el tiempo de Pasteur. Probablemente parece que el cuadro completo
de actividad del gen durante el aprendizaje del mamífero y memoria será más aun
complejo. Las herramientas moleculares son a mano íntimas pero el armazón conceptual
prevaleciendo en la psicología biológica no puede tener fuerzas para la tarea de integrar tan
inmenso una serie de datos.
El análisis de ADN y descubrimiento del gen han sido dominados por una perspectiva del
reductionistic muy exitosa (Beckwith 1996), [5] pero investiga en la función del gen revela
la necesidad de pensar sistema-orientar (el et de Gottlieb al 1998, Strohman 1997). [41,91]
La idea que un gen determina un componente específico de un phenotype conductual está
perdiendo la credibilidad científica. Chenchik y coworkers (1998) [20] el forsee que los
nuevos métodos "llevarán a investigadores fuera de acercamientos del reductionistic que
enfocan en los solos genes, y hacia acercamientos más sistémicos que involucran el análisis
simultáneo, paralelo de centenares o miles de genes." Debe reconocerse que casi cada gen
tiene que el pleiotropic extendido efectúa (Miklos & (Miklos & the constant darkness to
reveal the mechanisms of the circadian. Also, the fabric of the mutants and the normal
siblings proven under the same circumstances could be used to evaluate the effects of the
pleiotropic.

[The help with image that you go]

Figure 4. A comparison of profiles of expression of the gene in the fabric of two mice. The
complementary cDNA is made of RNA it expressed in the fabric, and it ties or he/she
makes hybrid to a sample of DNA of the gene that gave place to the specific molecule of
RNA. Each couple of points in the plate represents a different gene that is expressed in the
fabric. The big points pointed out by the small arrows symbolize genes expressed in only of
the samples. The full Atlas[trade marks the sign] the Mouse cDNA Expression Series of the
Laboratories of CLONTECH, Inc., he/she can discover expression of 588 different genes in
a sample of the fabric. Adapted with the permission of Laboratories of CLONTECH, Inc.,
of CLONTECHniques, January 1998, p. 2.

An extraordinary glimmer of action of the complex gene has been obtained recently for the
yeast, an organism the best acquaintance to psychologists for its vital paper synthesizing the
ethanol of the sugar. As the sugar in the atmosphere of the yeast wastes away, their
metabolism changes the anerobic fermentation to the breathing aerobic. Investigators could
tie successions of DNA of almost all the 6297 yeast genes to a single glass plate 18 mm for
18 mm and record the abundance of the whole mRNAs in the phases different from the
metabolic process (the et of DeRisi at the 1997). [30] During the transition of anerobic to
the metabolism aerobic, the expression of 1740 genes increased or it diminished at least
twice. On the half of these genes was new to the science, it had not still been named, and
he/she didn't have any grateful function. A mutation in a single gene (the tup1) altered the
expression of 355 other genes. In a remarkable underestimate, the authors observed: "The
big number of genes whose expression is altered and the diversity of profiles of the
expression storms stood out the challenge of understanding the mechanisms" underlying
regulator.
The one-celled the yeast, clear, he/she is a relatively simple creature that has been studied
completely from the time of Pasteur. It seems probably that the complete square of activity
of the gene during the learning of the mammal and memory will more even be complex.
The molecular tools are by hand intimate but the conceptual frame prevailing in the
biological psychology cannot have forces for the task of integrating so immense a series of
data.

The analysis of DNA and discovery of the gene have been dominated by a
perspective of the very successful reductionistic (Beckwith 1996), [5] but he/she
investigates in the function of the gene he/she reveals the necessity to plan to
system-guide (the et of Gottlieb at the 1998, Strohman 1997). [41,91] The idea that
a gene determines a specific component of a behavioral phenotype is losing the
scientific credibility. Chenchik and coworkers (1998) [20] the forsee that the new
methods "they will take to investigators outside of approaches of the reductionistic
that focus in the single genes, and toward more systemic approaches that involve the
simultaneous analysis, parallel of hundreds or thousands of genes." It should be
recognized that almost each gene has that the extended pleiotropic makes (Miklos &
Rubin 1996), [69] that actions of genes are commonly altered by the organism's
environment (Gottlieb 1998), [40] and that the consequences of a specific mutation
often depend on genotypes at other loci (Varnam et al 1996) [100] and the genetic
background (de Belle & Heisenberg 1996, Kelly et al 1998, Miklos & Rubin 1996)
[29,52,69] as well as on epigenetic effects (Wolf 1997). [107] Strohman (1997) [91]
concludes that the origins of complex systems "are not to be found in the matter
itself, but in its interactions."

BEHAVIORAL TESTING
Spectacular advances in genetic analysis have captured the imagination of the
public and drawn legions of students into molecular biology. The effect has not
been to impoverish psychology but to renew interest in the psychology of
behavioral testing-especially regarding lab mice-as testified to by the 1996 Society
for Neuroscience short course entitled "What's wrong with my mouse?" (Takahashi
1996). [93] Specialists in behavioral genetics have been both impressed by the
enthusiasm and appalled at the naivete of molecular geneticists who believe
psychology can provide an off-the-shelf device to measure a specific construct in
mice and model its human counterpart. The new molecular genetics has created a
need for a wider variety of behavioral testing and for improved test construction and
standardization. The skills of psychologists are uniquely suited to this task.

Interactions with Test Situation and Environment

There is a rich variety of tests available for use with mice (Crawley et al 1997,
Crawley & Paylor 1997), [24,25] and it is important to know whether these are likely
to yield the same results in the hands of most investigators working with the same
strain or mutation. The test situation and the pretest environment are virtually never
the same in different laboratories. The central issue is therefore whether genetic and
environmental effects are additive or interactive. If additive, then differences among
labs will merely change the overall average score but will not alter the pattern of
results or rank orders of genotypes, and most tests should yield valid results even in
the hands of amateurs.

A clear answer can be provided to this question. Seemingly minor task-specific

factors interact strongly with genotype, and reversals of rank orders of strains are
commonplace when comparing results across labs. Recent work has emphasized the
importance of relatively subtle variations in protocols. Poderycki and coworkers
(1998) [77] evaluated hybrid crosses of mice for seizures induced by 5-15 repetitions
of gentle tossing. Genetic analysis revealed strong evidence of linkage with a
marker on chromosome 9 after 6 tests but not after 15 tests, whereas another gene
on chromosome 2 was not apparent after 6 tests but showed clear signs of linkage
after 15 tests. Maxson (1992) [64] reported that the effects of the Y chromosome on
agonistic behavior in his congenic strains disappeared when the colony was moved
to a cleaner environment where the drinking water was acidified to suppress
bacteria. Certain Y chromosome effects were most pronounced when males were
reared in isolation and tested against males of the same genotype, rather than reared
with a sister and tested against a standard opponent strain (Guillot et al 1995). [43]
Peeler (1995) [75] conducted avoidance training at different times of day, all during
the light phase of the cycle, and found substantial effects on some strains but not
others.

Apparatus design and testing protocol are crucially important. Roullet and
colleagues (1993) [82] found that BALB/c mice used odor cues and C57BL/6 mice
used spatial cues to learn a radial maze, whereas F1 hybrids could utilize either cue.
Crusio and coworkers (1993) [27] found large changes in strain rank orders on
spatial versus nonspatial versions of a radial maze; only the spatial version revealed
genetic correlations with hippocampal mossy fiber anatomy. Peeler (1995) [75]
noted differences in strain rank order depending on whether the mice had to run
through a hole or slot or jump a barrier to avoid shock. These and other findings
show clearly that a single test configuration and procedure cannot define a single
psychological construct, although two tests differing in a specific element may
indicate a change in a specific construct.

Growing Need for Test Standardization

In view of these findings, there are grounds for concern about the almost universal
lack of standardized apparatuses, protocols, and lab environments in psychological
testing of animals. In contrast, test construction and standardization are taken more
seriously in evaluation of humans. Reviews among labs of the plus-maze, a popular
means for assessing anxiety, reveal numerous idiosyncratic variations that are
potentially important (Hogg 1996; Rodgers & Dalvi 1997). [46,80] Tests known to be
valid for rats are often used inappropriately with mice. The Morris swimming pool
 is particularly problematic when used with mice (Whishaw & Tomie 1996). [105]
Some common inbred strains (BALB/c, 129) respond quite badly in this device
(Francis et al 1995) [36] and often resort to floating after becoming exhausted
(Wolfer et al 1997). [108] When mice can locate a submerged platform, they must be
using spatial cues, but failure to learn does not necessarily signal a lack of spatial
memory (unless only the cues are manipulated in different versions of the task, and
a strain can learn one cue but not the other). Additional difficulties are present when
investigators submit an individual animal to a battery of tests, each of which was
designed and validated for use by itself: Order of testing can markedly alter results
when such tests are combined.

Validity of Animal Models

Whereas homology among flies, mice, and humans at the molecular genetic level is
undeniable, homology-and even analogy-at the level of the behaving organism is not so
clear. Certain genes important for memory in flies (Figure 2) are involved in memory in
mammals (e.g. the fly gene rutabaga, the mouse gene barrelless, and the human gene
ADCY1 all encode an adenylate cyclase), yet the complex nature of metabolic and
developmental systems (characterized by pleiotropic and epistatic Rubin 1996), [69] que las
acciones de genes son normalmente alteradas por el ambiente del organismo (Gottlieb
1998), [40] y que las consecuencias de una mutación específica dependen a menudo de los
genotipos a otros sitios (el et de Varnam al 1996) [100] y el fondo genético (de Belle &
Heisenberg 1996, et de Kelly al 1998, Miklos & Rubin 1996) [29,52,69] así como en los
efectos del epigenetic (Lobo 1997). [107] Strohman (1997) [91] concluye que los orígenes
de sistemas complejos no serán encontrados en la propia materia, pero en sus
interacciones."
LA COMPROBACIÓN CONDUCTUAL
Los adelantos espectaculares en el análisis genético han capturado la imaginación de las
legiones públicas y arrastrado de estudiantes en la biología molecular. El efecto no ha sido
empobrecer la psicología pero renovar el interés comprobación-sobre todo en la psicología
de conductual con respecto al laboratorio ratón-como testificó a por la 1996 Sociedad para
Neuroscience el curso corto tituló lo que está equivocado con mi ratón? " (Takahashi 1996).
[93] Especialistas en las genéticas conductuales han sido los dos impresionados por el
entusiasmo y han espantado a la candidez de genetistas moleculares que creen la psicología
puede proporcionar un dispositivo del fuera de-el-estante para medir una estructura
específica en los ratones y modelar a su colega humano. Las nuevas genéticas moleculares
han creado una necesidad por una variedad más ancha de comprobación conductual y para
la construcción de la prueba mejorada y estandarización. Se satisfacen las habilidades de
psicólogos singularmente a esta tarea.
Las interacciones con la Situación de la Prueba y Ambiente
Hay una variedad rica de pruebas disponible para el uso con los ratones (el et de Crawley al
1997, Crawley & Paylor 1997), [24,25] y es importante saber si es probable que éstos
rindan los mismos resultados en las manos de la mayoría de los investigadores que trabajan
con la misma tensión o mutación. La situación de la prueba y el ambiente más atrevido casi
nunca son el mismo en los laboratorios diferentes. El problema central es por consiguiente
si los efectos genéticos y medioambientales son aditivo o interactivos. Si el aditivo,
entonces las diferencias entre los laboratorios cambiarán la media cuenta global meramente
pero no alterarán el modelo de resultados o órdenes de la línea de genotipos, y la mayoría
de las pruebas debe rendir los resultados válidos incluso en las manos de aficionados.
Una respuesta clara puede proporcionarse a esta pregunta. Los factores tarea-específicos
aparentemente menores actúan recíprocamente fuertemente con el genotipo, y las
inversiones de órdenes groseros de tensiones son comúnes al comparar los resultados por
los laboratorios. El reciente trabajo ha dado énfasis a la importancia de variaciones
relativamente sutiles en los protocolos. Poderycki y coworkers (1998) [77] evaluó cruces
híbridas de ratones para cogida inducidos por 5-15 repeticiones de echar manso. El análisis
genético reveló evidencia fuerte de unión con un marcador en cromosoma 9 después de 6
pruebas pero no después de 15 pruebas, considerando que otro gen en cromosoma 2 no
estaba claro después de 6 pruebas pero mostró señales claras de unión después de 15
pruebas. Maxson (1992) [64] informó que los efectos del cromosoma de Y en la conducta
del agonistic en sus tensiones del congenic desaparecieron cuando la colonia se movió a un
ambiente más limpio dónde el agua bebiendo fue acidificada para suprimir las bacterias.
Ciertos Y cromosoma efectos eran la mayoría pronunciado cuando se criaron los varones
en el aislamiento y probaron contra los varones del mismo genotipo, en lugar de crió con
una hermana y probó contra una tensión antagonista normal (el et de Guillot al 1995). [43]
la Peladora (1995) [75] dirigió anulación que entrena en los momentos diferentes de día,
todos durante la fase ligera del ciclo, y encontró los efectos sustanciales en algunas
tensiones pero no otros.
El plan del aparato y el protocolo probando son crucialmente importantes. Roullet y colegas
(1993) [82] encuentre ese ratones de BALB/c usados las señales de olor y ratones de
C57BL/6 usaron las señales espaciales para aprender un laberinto radial, considerando que
los hybrids de F1 podrían utilizar cualquier señal. Crusio y coworkers (1993) [27]
encuentre los cambios grandes en la tensión los órdenes groseros adelante espacial contra
las versiones del nonspatial de un laberinto radial; sólo la versión espacial reveló las
correlaciones genéticas con el hippocampal la anatomía de fibra musgosa. La peladora
(1995) [75] las diferencias nombradas en la tensión orden grosero que depende adelante si
los ratones tenían que atravesar un agujero o hendedura o saltar una barrera para evitar el
susto. Éstos y otros resultados muestran claramente que una sola configuración de la prueba
y procedimiento no pueden definir una sola estructura psicológica, aunque dos pruebas que
difieren en un elemento específico pueden indicar un cambio en una estructura específica.
La Necesidad creciente para la Estandarización de la Prueba
Hay heceses para la preocupación sobre la falta casi universal de aparatos estandarizados,
protocolos, y ambientes del laboratorio en la comprobación psicológica de animales en
vista de estos resultados. En el contraste, se toman construcción de la prueba y
estandarización más en serio en la evaluación de humanos. Las revisiones entre los
laboratorios del más-laberinto, un medios populares por evaluar la ansiedad, revele
numerosas variaciones idiosincrásicas que son potencialmente importantes (Hogg 1996;
Rodgers & Dalvi 1997). [46,80] se usan a menudo impropiamente Pruebas conocidas para
ser válido para las ratas con los ratones. El Morris la piscina que nada es particularmente
problemática cuando usó con los ratones (Whishaw & Tomie 1996). [105] Algunas
tensiones innatas comúnes (BALB/c, 129) responda bastante mal en este dispositivo
(Francis el et al 1995) [36] y a menudo acude a flotar después de ponerse exhausto (el et de
Wolfer al 1997). [108] Cuando los ratones pueden localizar una plataforma sumergida,
ellos deben estar usando las señales espaciales, pero el fracaso para aprender
necesariamente no señala una falta de memoria espacial (a menos que sólo las señales se
manipulan en las versiones diferentes de la tarea, y una tensión puede aprender una señal
pero no el otro). las dificultades Adicionales están presentes cuando investigadores someten
un animal individual a una batería de pruebas cada uno de los cuales se diseñaron y
validaron para el uso solo: El orden de probar puede alterar los resultados notablemente
cuando se combinan las tales pruebas.
La validez de Modelos Animales
Considerando que la homología entre las moscas, ratones, y humanos al nivel genético
molecular es innegable, homología-y incluso analogía-a el nivel del organismo
comportándose no está tan claro. Ciertos genes importante para la memoria en las moscas
(Figura 2) está envuelto en la memoria en los mamíferos (por ejemplo el rutabaga de gen de
mosca, el barrelless de gen de ratón, y el gen humano ADCY1 todos ponen en código un
cyclase del adenylate), todavía la naturaleza compleja de sistemas metabólicos y de
desarrollo (caracterizó por el pleiotropic y epistatic ADCY1 all encode an adenylate
cyclase), yet the complex nature of metabolic and developmental systems (characterized by
pleiotropic and epistatic Rubin 1996), [69] that the actions of genes are usually altered for
the atmosphere of the organism (Gottlieb 1998), [40] and that the consequences of a
specific mutation often depend from the genotypes to other places (the et of Varnam at the
1996) [100] and the genetic bottom (of Belle & Heisenberg 1996, et of Kelly at the 1998,
Miklos & Rubin 1996) [29,52,69] as well as in the effects of the epigenetic (Wolf 1997).
[107] Strohman (1997) [91] it concludes that the origins of complex systems won't be
found in the own matter, but in their interactions."
THE BEHAVIORAL CONFIRMATION
The spectacular advances in the genetic analysis have captured the imagination of the
public and dragged legions of students in the molecular biology. Has not the effect been to
impoverish the psychology but to renovate the interest confirmation-on everything in the
psychology of behavioral with regard to the laboratory mouse-like he/she testified to for the
1996 Society for Neuroscience the short course titled what is mistaken with my mouse? "
(Takahashi 1996). [93] Specialists in the behavioral genetics have been both impressed by
the enthusiasm and they have frightened to the candor of molecular geneticists that
you/they believe the psychology it can provide a device of the one it was of-the-shelf to
measure a specific structure in the mice and to model their human colleague. The new
molecular genetics have created a necessity for a wider variety of behavioral confirmation
and for the construction of the improved test and standardization. The abilities of
psychologists are satisfied singly to this task.
The interactions with the Situation of the Test and Atmosphere
There is an available rich variety of tests for the use with the mice (the et of Crawley at the
1997, Crawley & Paylor 1997), [24,25] and it is important to know if it is probable that
these surrender the same results in the hands of most of the investigators that work with the
same tension or mutation. The situation of the test and the most daring atmosphere are
hardly ever the same one in the different laboratories. The central problem is consequently
if the genetic and environmental effects are preservative or interactive. If the preservative,
then the differences among the laboratories will change the stocking it counts global merely
but they won't alter the pattern of results or orders of the line of genotypes, and most of the
tests should even surrender the valid results in the hands of fans.
A clear answer can be provided to this question. The seemingly smaller task-specific
factors act reciprocally strongly with the genotype, and the investments of rude orders of
tensions are common to comparing the results for the laboratories. The recent work has
given emphasis to the importance of relatively subtle variations in the protocols. Poderycki
and coworkers (1998) [77] it evaluated hybrid crossings of mice for caught induced by 5-15
repetitions of tossing meek. The genetic analysis revealed strong evidence of union with a
marker in chromosome 9 after 6 tests but not after 15 tests, considering that another gene in
chromosome 2 were not clear after 6 tests but it showed clear signs of union after 15 tests.
Maxson (1992) [64] he/she informed that the effects of the chromosome of AND in the
behavior of the agonistic in their tensions of the congenic disappeared when the colony
moved to a cleaner atmosphere where the water drinking was acidified to suppress the
bacterias. Certain AND chromosome effects were most marked when the males were raised
in the isolation and they proved against the males of the same genotype, instead of it raised
with a sister and it proved against a normal antagonistic tension (the et of Guillot at the
1995). [43] the Peeler (1995) [75] it directed annulment that trains by day in the different
moments, all during the slight phase of the cycle, and he/she found the substantial effects in
some tensions but not others.
The plan of the apparatus and the protocol proving is crucially important. Roullet and
colleagues (1993) [82] he/she finds that mice of used BALB/c the signs of scent and mice
of C57BL/6 used the space signs to learn a radial labyrinth, considering that the hybrids of
F1 could use any sign. Crusio and coworkers (1993) [27] he/she finds the big changes in
the tension the rude orders ahead space against the versions of the nonspatial of a radial
labyrinth; the space version only revealed the genetic correlations with the hippocampal the
anatomy of mossy fiber. The peeler (1995) [75] the differences named in the tension rude
order that depends ahead if the mice had to cross a hole or rift or to jump a barrier to avoid
the fright. These and other results show clearly that a single configuration of the test and
procedure cannot define a single psychological structure, although two tests that differ in a
specific element can indicate a change in a specific structure.
The growing Necessity for the Standardization of the Test
There are grounds for the concern on the almost universal lack of standardized apparatuses,
protocols, and set of the laboratory in the psychological confirmation of animals in view of
these results. In the contrast, they take construction of the test and standardization more
seriously in the evaluation of human. The revisions among the laboratories of the more-
labyrinth, a popular means to evaluate the anxiety, reveal numerous idiosyncratic variations
that are potentially important (Hogg 1996; Rodgers & Dalvi 1997). [46,80] they are often
used inappropriately Tests acquaintances to be valid for the rats with the mice. The Morris
the pool that anything is particularly problematic when it used with the mice (Whishaw &
Tomie 1996). [105] Some common innate tensions (BALB/c, 129) he/she responds quite
bad in this device (Francis the et at the 1995) [36] and often he/she goes to float after
becoming exhausted (the et of Wolfer at the 1997). [108] When the mice can locate a
submerged platform, they should be using the space signs, but the failure to learn it doesn't
necessarily point out by heart a lack space (unless the signs are only manipulated in the
versions different from the task, and a tension can learn a sign but not the other one). the
Additional difficulties are present when investigators subject an individual animal to a
battery of tests each one of which were designed and they validated for the alone use: The
order of proving can alter the results notably when they combine the such tests.
The validity of Animal Models

Considering that the homology among the flies, mice, and human at the molecular
genetic level it is undeniable, homology-and even analogy-to the level of the
organism behaving is not so clear. Certain important genes for the memory in the
flies (it Figures 2) it is wrapped in the memory in the mammals (for example the
rutabaga of fly gene, the barrelless of mouse gene, and the human gene ADCY1 all
put in code a cyclase of the adenylate), still the complex nature of metabolic
systems and of development (it characterized for the pleiotropic and epistatic gene
actions plus gene-environment interactions) implies that the function of a particular
gene depends on its context. Homology of behaviors must be demonstrated, not
assumed. In the domain of agonistic behavior, for example, mice engage in
offensive and defensive attacks that appear to be adaptive under appropriate
circumstances, but do these provide good models of human violence? According to
Maxson (1998), [65] offensive behavior of male mice is not a good model of
impulsive aggression in humans, although several recent publications assume
uncritically that the two are essentially the same. Balaban and colleagues (1996) [4]
also stress the importance of careful definition of behaviors and contexts when
seeking to establish the relevance to humans of animal models, and they question
the similarity of rodent attack behavior to human crime. A good case can be made
for valid mouse models of several severe medical disorders caused by single-gene
mutations, but the validity of mouse or fly models for the normal range of variation
in human social behavior requires convincing evidence that is generally lacking.

CONCLUSIONS
In his review of human behavioral genetics, Rose (1995) [81] foresaw that "Future
reviews of the field are likely to read very differently than this one." The field has
indeed changed direction and is advancing like a sailboat with spinnaker unfurled,
rather than tacking and making little headway. Many outstanding contributions to
neurobehavioral genetics are now published in leading scientific journals with a
broad readership rather than in specialty journals. Not long ago, the field was
trammeled by crude techniques for detecting the presence and activities of single
genes, whereas today we have a panoply of molecular methods and a rich factual
base of knowledge about specific genes in relation to brain and behavior. Long lists
of human attributes, each accompanied by a terse summary of the latest findings
from twin or adoption studies, have become passe. The challenge of keeping aware
of current developments in this field is now quite formidable, even with the aid of
marvelous Internet and bibliographic search programs. As the individual research
project probes ever more deeply into an ever-narrower domain of knowledge, there
is a growing need to synthesize existing knowledge and make connections among
the isolated parts of an expanding discipline. The next major advance must come in
the domain of theory.

ACKNOWLEDGMENTS
I am grateful to John Crabbe, Gilbert Gottlieb, and Pierre Roubertoux for their
critical comments on this article and to Sharon Doerksen for assistance with Web
searches. Supported by a grant from the Natural Sciences and Engineering Research
Council of Canada.
 Visit the Annual Reviews home page at http://www.AnnualReviews.org.

Rubin 1996), [69] that actions of genes are commonly altered by the organism's
environment (Gottlieb 1998), [40] and that the consequences of a specific mutation often
depend on genotypes at other loci (Varnam et al 1996) [100] and the genetic background
(de Belle & Heisenberg 1996, Kelly et al 1998, Miklos & Rubin 1996) [29,52,69] as well as
on epigenetic effects (Wolf 1997). [107] Strohman (1997) [91] concludes that the origins of
complex systems "are not to be found in the matter itself, but in its interactions."
BEHAVIORAL TESTING
Spectacular advances in genetic analysis have captured the imagination of the public and
drawn legions of students into molecular biology. The effect has not been to impoverish
psychology but to renew interest in the psychology of behavioral testing-especially
regarding lab mice-as testified to by the 1996 Society for Neuroscience short course
entitled "What's wrong with my mouse?" (Takahashi 1996). [93] Specialists in behavioral
genetics have been both impressed by the enthusiasm and appalled at the naivete of
molecular geneticists who believe psychology can provide an off-the-shelf device to
measure a specific construct in mice and model its human counterpart. The new molecular
genetics has created a need for a wider variety of behavioral testing and for improved test
construction and standardization. The skills of psychologists are uniquely suited to this
task.
Interactions with Test Situation and Environment
There is a rich variety of tests available for use with mice (Crawley et al 1997, Crawley &
Paylor 1997), [24,25] and it is important to know whether these are likely to yield the same
results in the hands of most investigators working with the same strain or mutation. The test
situation and the pretest environment are virtually never the same in different laboratories.
The central issue is therefore whether genetic and environmental effects are additive or
interactive. If additive, then differences among labs will merely change the overall average
score but will not alter the pattern of results or rank orders of genotypes, and most tests
should yield valid results even in the hands of amateurs.
A clear answer can be provided to this question. Seemingly minor task-specific factors
interact strongly with genotype, and reversals of rank orders of strains are commonplace
when comparing results across labs. Recent work has emphasized the importance of
relatively subtle variations in protocols. Poderycki and coworkers (1998) [77] evaluated
hybrid crosses of mice for seizures induced by 5-15 repetitions of gentle tossing. Genetic
analysis revealed strong evidence of linkage with a marker on chromosome 9 after 6 tests
but not after 15 tests, whereas another gene on chromosome 2 was not apparent after 6 tests
but showed clear signs of linkage after 15 tests. Maxson (1992) [64] reported that the
effects of the Y chromosome on agonistic behavior in his congenic strains disappeared
when the colony was moved to a cleaner environment where the drinking water was
acidified to suppress bacteria. Certain Y chromosome effects were most pronounced when
males were reared in isolation and tested against males of the same genotype, rather than
reared with a sister and tested against a standard opponent strain (Guillot et al 1995). [43]
Peeler (1995) [75] conducted avoidance training at different times of day, all during the
light phase of the cycle, and found substantial effects on some strains but not others.
gene actions bonus gene-environment interactions) implies that the function of to particular
gene depends on its context. Homology of behaviors must be demonstrated, not assumed.
In the domain of agonistic behavior, for example, mice engage in offensive and defensive
attacks that appear to be adaptive under appropriate circumstance, but do these provide
good models of human violence? According to Maxson (1998), [65] offensive behavior of
male mice is not to good model of impulsive aggression in humans, although several recent
publications assume uncritically that the two plows essentially the same. And colleagues
bleated (1996) [4] also stress the importance of careful definition of behaviors and contexts
when seeking to establish the relevance to humans of animal models, and they question the
similarity of rodent attack behavior to human crime. To good he/she marries dog be made
for valid mouse models of several severe medical disorders caused by sail-gene mutations,
but the validity of mouse or fly models for the normal range of variation in human social
behavior requires convincing evidence that is generally lacking.
CONCLUSIONS
In his review of human behavioral genetics, Rose (1995) [81] foresaw that "Future reviews
of the field plows likely to read very differently than this one." The field has indeed
changed direction and is advancing like to sailboat with spinnaker unfurled, rather than
tacking and making little headway. Many outstanding contributions to neurobehavioral
genetics plows now published in leading scientific journals with to broad readership rather
than in specialty journals. Not long Aug, the field was trammeled by crude techniques for
detecting the presence and activities of sails genes, whereas today we have to panoply of
molecular methods and to rich factual bases of knowledge about specific genes in relation
to brain and behavior. Long lists of human attributes, each accompanied by to terse
summary of the latest findings from twin or adoption studies, have become passe. The
challenge of keeping aware of current developments in this field is now removes
formidable, even with the aid of marvelous Internet and bibliographic search programs. Ace
the individual research project probes ever lives deeply into an ever-narrower domain of
knowledge, there is to growing need to synthesize existing knowledge and make
connections among the isolated parts of an expanding it disciplines. The next major
advance must eats in the domain of theory.
ACKNOWLEDGMENTS
I am grateful to John Crabbe, Gilbert Gottlieb, and Pierre Roubertoux for their critical
comments on this article and to Sharon Doerksen for assistance with Web searches.
Supported by to grant from Natural the Sciences and Engineering Research Council of
Canada.
Visit the Annual Reviews home page at http://www.AnnualReviews.org.
Rubin 1996), [69] that actions of genes plows commonly altered by the organism's
environment (Gottlieb 1998), [40] and that the consequences of to specific mutation often
depend on genotypes at other loci (Varnam et at the 1996) [100] and the genetic
background (of Belle & Heisenberg 1996, Kelly et at the 1998, Miklos & Rubin 1996)
[29,52,69] ace well ace on epigenetic effects (Wolf 1997). [107] Strohman (1997) [91]
concludes that the origins of complex systems "it plows not to be found in the matter itself,
but in its interactions."
BEHAVIORAL TESTING
Spectacular advances in genetic analysis have captured the imagination of the public and
drawn legions of students into molecular biology. Does The effect have not been to
impoverish psychology but to renew interest in the psychology of behavioral testing-
especially regarding lab mice-ace testified to by the 1996 Society for Neuroscience short
course entitled "What's wrong with my mouse? " (Takahashi 1996). [93] Specialists in
behavioral genetics have been both impressed by the enthusiasm and appalled at the naivete
of molecular geneticists who believe psychology dog provide an off-the-shelf device to
measure to specific construct in mice and model its human counterpart. The new molecular
genetics has created to need for to wider variety of behavioral testing and for improved test
construction and standardization. The skills of psychologists plows uniquely suited to this
task.
Interactions with Test Situation and Environment
There is to rich variety of tests available for uses with mice (Crawley et at the 1997,
Crawley & Paylor 1997), [24,25] and it is important to know whether these plows likely to
yield the same results in the hands of most investigators working with the same strain or
mutation. The test situation and the pretest environment plows virtually never the same in
different laboratories. The central issue is therefore whether genetic and environmental
effects plows additive or interactive. If additive, then differences among labs will merely
change the overall average score but will not alter the pattern of results or rank orders of
genotypes, and most tests should yield valid results even in the hands of amateurs.
To clear answer dog be provided to this question. Seemingly minor task-specific factors
interact strongly with genotype, and reversals of rank orders of strains plows commonplace
when comparing results across labs. Recent work has emphasized the importance of
relatively subtle variations in protocols. Poderycki and coworkers (1998) [77] evaluated
hybrid crosses of mice for seizures induced by 5-15 repetitions of gentle tossing. Genetic
analysis revealed strong evidence of linkage with to marker on chromosome 9 after 6 tests
but not after 15 tests, whereas another gene on chromosome 2 was not apparent after 6 tests
but showed clear signs of linkage after 15 tests. Maxson (1992) [64] reported that the
effects of the AND chromosome on agonistic behavior in his congenic strains disappeared
when the colony was move to cleaner environment where the drinking water was acidified
to suppress bacteria. Certain AND chromosome effects were most pronounced when bad
were reared in isolation and tested against bad of the same genotype, rather than reared with
to sister and tested against to standard opponent strain (Guillot et at the 1995). [43] Peeler
(1995) [75] conducted avoidance training at different cheats of day, all during the light
phase of the cycle, and found substantial effects on some strains but not others. Apparatus
design and testing protocol are crucially important. Roullet and colleagues (1993) [82]
found that BALB/c mice used odor cues and C57BL/6 mice used spatial cues to learn a
radial maze, whereas F1 hybrids could utilize either cue. Crusio and coworkers (1993) [27]
found large changes in strain rank orders on spatial versus nonspatial versions of a radial
maze; only the spatial version revealed genetic correlations with hippocampal mossy fiber
anatomy. Peeler (1995) [75] noted differences in strain rank order depending on whether
the mice had to run through a hole or slot or jump a barrier to avoid shock. These and other
findings show clearly that a single test configuration and procedure cannot define a single
psychological construct, although two tests differing in a specific element may indicate a
change in a specific construct.
Growing Need for Test Standardization
In view of these findings, there are grounds for concern about the almost universal lack of
standardized apparatuses, protocols, and lab environments in psychological testing of
animals. In contrast, test construction and standardization are taken more seriously in
evaluation of humans. Reviews among labs of the plus-maze, a popular means for assessing
anxiety, reveal numerous idiosyncratic variations that are potentially important (Hogg
1996; Rodgers & Dalvi 1997). [46,80] Tests known to be valid for rats are often used
inappropriately with mice. The Morris swimming pool is particularly problematic when
used with mice (Whishaw & Tomie 1996). [105] Some common inbred strains (BALB/c,
129) respond quite badly in this device (Francis et al 1995) [36] and often resort to floating
after becoming exhausted (Wolfer et al 1997). [108] When mice can locate a submerged
platform, they must be using spatial cues, but failure to learn does not necessarily signal a
lack of spatial memory (unless only the cues are manipulated in different versions of the
task, and a strain can learn one cue but not the other). Additional difficulties are present
when investigators submit an individual animal to a battery of tests, each of which was
designed and validated for use by itself: Order of testing can markedly alter results when
such tests are combined.
Validity of Animal Models
Whereas homology among flies, mice, and humans at the molecular genetic level is
undeniable, homology-and even analogy-at the level of the behaving organism is not so
clear. Certain genes important for memory in flies (Figure 2) are involved in memory in
mammals (e.g. the fly gene rutabaga, the mouse gene barrelless, and the human gene
ADCY1 all encode an adenylate cyclase), yet the complex nature of metabolic and
developmental systems (characterized by pleiotropic and epistatic Rubin 1996), [69] que las
acciones de genes son normalmente alteradas por el ambiente del organismo (Gottlieb
1998), [40] y que las consecuencias de una mutación específica dependen a menudo de los
genotipos a otros sitios (el et de Varnam al 1996) [100] y el fondo genético (de Belle &
Heisenberg 1996, et de Kelly al 1998, Miklos & Rubin 1996) [29,52,69] así como en los
efectos del epigenetic (Lobo 1997). [107] Strohman (1997) [91] concluye que los orígenes
de sistemas complejos no serán encontrados en la propia materia, pero en sus
interacciones."
LA COMPROBACIÓN CONDUCTUAL
Los adelantos espectaculares en el análisis genético han capturado la imaginación de las
legiones públicas y arrastrado de estudiantes en la biología molecular. El efecto no ha sido
empobrecer la psicología pero renovar el interés comprobación-sobre todo en la psicología
de conductual con respecto al laboratorio ratón-como testificó a por la 1996 Sociedad para
Neuroscience el curso corto tituló lo que está equivocado con mi ratón? " (Takahashi 1996).
[93] Especialistas en las genéticas conductuales han sido los dos impresionados por el
entusiasmo y han espantado a la candidez de genetistas moleculares que creen la psicología
puede proporcionar un dispositivo del fuera de-el-estante para medir una estructura
específica en los ratones y modelar a su colega humano. Las nuevas genéticas moleculares
han creado una necesidad por una variedad más ancha de comprobación conductual y para
la construcción de la prueba mejorada y estandarización. Se satisfacen las habilidades de
psicólogos singularmente a esta tarea.
Las interacciones con la Situación de la Prueba y Ambiente
Hay una variedad rica de pruebas disponible para el uso con los ratones (el et de Crawley al
1997, Crawley & Paylor 1997), [24,25] y es importante saber si es probable que éstos
rindan los mismos resultados en las manos de la mayoría de los investigadores que trabajan
con la misma tensión o mutación. La situación de la prueba y el ambiente más atrevido casi
nunca son el mismo en los laboratorios diferentes. El problema central es por consiguiente
si los efectos genéticos y medioambientales son aditivo o interactivos. Si el aditivo,
entonces las diferencias entre los laboratorios cambiarán la media cuenta global meramente
pero no alterarán el modelo de resultados o órdenes de la línea de genotipos, y la mayoría
de las pruebas debe rendir los resultados válidos incluso en las manos de aficionados.
Una respuesta clara puede proporcionarse a esta pregunta. Los factores tarea-específicos
aparentemente menores actúan recíprocamente fuertemente con el genotipo, y las
inversiones de órdenes groseros de tensiones son comúnes al comparar los resultados por
los laboratorios. El reciente trabajo ha dado énfasis a la importancia de variaciones
relativamente sutiles en los protocolos. Poderycki y coworkers (1998) [77] evaluó cruces
híbridas de ratones para cogida inducidos por 5-15 repeticiones de echar manso. El análisis
genético reveló evidencia fuerte de unión con un marcador en cromosoma 9 después de 6
pruebas pero no después de 15 pruebas, considerando que otro gen en cromosoma 2 no
estaba claro después de 6 pruebas pero mostró señales claras de unión después de 15
pruebas. Maxson (1992) [64] informó que los efectos del cromosoma de Y en la conducta
del agonistic en sus tensiones del congenic desaparecieron cuando la colonia se movió a un
ambiente más limpio dónde el agua bebiendo fue acidificada para suprimir las bacterias.
Ciertos Y cromosoma efectos eran la mayoría pronunciado cuando se criaron los varones
en el aislamiento y probaron contra los varones del mismo genotipo, en lugar de crió con
una hermana y probó contra una tensión antagonista normal (el et de Guillot al 1995). [43]
la Peladora (1995) [75] dirigió anulación que entrena en los momentos diferentes de día,
todos durante la fase ligera del ciclo, y encontró los efectos sustanciales en algunas
tensiones pero no otros.
El plan del aparato y el protocolo probando son crucialmente importantes. Roullet y colegas
(1993) [82] encuentre ese ratones de BALB/c usados las señales de olor y ratones de
C57BL/6 usaron las señales espaciales para aprender un laberinto radial, considerando que
los hybrids de F1 podrían utilizar cualquier señal. Crusio y coworkers (1993) [27]
encuentre los cambios grandes en la tensión los órdenes groseros adelante espacial contra
las versiones del nonspatial de un laberinto radial; sólo la versión espacial reveló las
correlaciones genéticas con el hippocampal la anatomía de fibra musgosa. La peladora
Apparatus design and testing protocol plows crucially important. Roullet and colleagues
(1993) [82] found that BALB/c mice used odor cues and C57BL/6 mice used spatial cues to
learn to radial maze, whereas F1 hybrids could utilize either cue. Crusio and coworkers
(1993) [27] found large changes in strain rank orders on spatial versus nonspatial versions
of to radial maze; only the spatial version revealed genetic correlations with hippocampal
mossy fiber anatomy. Peeler (1995) [75] noted differences in strain rank order depending
on whether the mice had to run through to hole or slot or jump to barrier to avoid shock.
These and other findings show clearly that to it sails test configuration and procedure
cannot it defines to it sails psychological construct, although two tests differing in to
specific element may you indicate yourself to change in to specific construct.
Growing Need for Test Standardization
In view of these findings, there plows grounds for concern about the almost universal lack
of standardized apparatuses, protocols, and lab environments in psychological testing of
animals. In contrast, test construction and standardization plows taken seriously it lives in
evaluation of humans. Reviews among labs of the bonus-maze, to popular means for
assessing anxiety, reveal numerous idiosyncratic variations that plows potentially important
(Hogg 1996; Rodgers & Dalvi 1997). [46,80] Tests known to be valid for rats plows often
used inappropriately with mice. The Morris swimming pool is particularly problematic
when used with mice (Whishaw & Tomie 1996). [105] Some common inbred strains
(BALB/c, 129) respond removes badly in this device (Francis et at the 1995) [36] and often
resort to floating after becoming exhausted (Wolfer et at the 1997). [108] When mice dog
locate to submerged platform, they must be using spatial cues, but failure to learn does not
necessarily signal to lack of spatial memory (unless only the cues plows manipulated in
different versions of the task, and to strain dog learn one cue but not the other). Additional
difficulties plows present when investigators submit an individual animal to battery of tests,
each of which was designed and validated for uses by itself: Order of testing dog markedly
alter results when such tests plows combined.
Validity Animal of Models
Whereas homology among flies, mice, and humans at the molecular genetic level is
undeniable, homology-and even analogy-at the level of the behaving organism is not so
clear. Certain genes important for memory in flies (it Figures 2) it plows involved in
memory in mammals (e.g. the fly gene rutabaga, the mouse gene barrelless, and the human
gene ADCY1 all encode an adenylate cyclase), yet the complex nature of metabolic and
developmental systems (characterized by pleiotropic and epistatic Rubin 1996), [69] that
the actions of genes are usually altered for the atmosphere of the organism (Gottlieb 1998),
[40] and that the consequences of a specific mutation often depend from the genotypes to
other places (the et of Varnam at the 1996) [100] and the genetic bottom (of Belle &
Heisenberg 1996, et of Kelly at the 1998, Miklos & Rubin 1996) [29,52,69] as well as in
the effects of the epigenetic (Wolf 1997). [107] Strohman (1997) [91] it concludes that the
origins of complex systems won't be found in the own matter, but in their interactions."
THE BEHAVIORAL CONFIRMATION
The spectacular advances in the genetic analysis have captured the imagination of the
public and dragged legions of students in the molecular biology. Has not the effect been to
impoverish the psychology but to renovate the interest confirmation-on everything in the
psychology of behavioral with regard to the laboratory mouse-like he/she testified to for the
1996 Society for Neuroscience the short course titled what is mistaken with my mouse? "
(Takahashi 1996). [93] Specialists in the behavioral genetics have been both impressed by
the enthusiasm and they have frightened to the candor of molecular geneticists that
you/they believe the psychology it can provide a device of the one it was of-the-shelf to
measure a specific structure in the mice and to model their human colleague. The new
molecular genetics have created a necessity for a wider variety of behavioral confirmation
and for the construction of the improved test and standardization. The abilities of
psychologists are satisfied singly to this task.
The interactions with the Situation of the Test and Atmosphere
There is an available rich variety of tests for the use with the mice (the et of Crawley at the
1997, Crawley & Paylor 1997), [24,25] and it is important to know if it is probable that
these surrender the same results in the hands of most of the investigators that work with the
same tension or mutation. The situation of the test and the most daring atmosphere are
hardly ever the same one in the different laboratories. The central problem is consequently
if the genetic and environmental effects are preservative or interactive. If the preservative,
then the differences among the laboratories will change the stocking it counts global merely
but they won't alter the pattern of results or orders of the line of genotypes, and most of the
tests should even surrender the valid results in the hands of fans.
A clear answer can be provided to this question. The seemingly smaller task-specific
factors act reciprocally strongly with the genotype, and the investments of rude orders of
tensions are common to comparing the results for the laboratories. The recent work has
given emphasis to the importance of relatively subtle variations in the protocols. Poderycki
and coworkers (1998) [77] it evaluated hybrid crossings of mice for caught induced by 5-15
repetitions of tossing meek. The genetic analysis revealed strong evidence of union with a
marker in chromosome 9 after 6 tests but not after 15 tests, considering that another gene in
chromosome 2 were not clear after 6 tests but it showed clear signs of union after 15 tests.
Maxson (1992) [64] he/she informed that the effects of the chromosome of AND in the
behavior of the agonistic in their tensions of the congenic disappeared when the colony
moved to a cleaner atmosphere where the water drinking was acidified to suppress the
bacterias. Certain AND chromosome effects were most marked when the males were raised
in the isolation and they proved against the males of the same genotype, instead of it raised
with a sister and it proved against a normal antagonistic tension (the et of Guillot at the
1995). [43] the Peeler (1995) [75] it directed annulment that trains by day in the different
moments, all during the slight phase of the cycle, and he/she found the substantial effects in
some tensions but not others.
The plan of the apparatus and the protocol proving is crucially important. Roullet and
colleagues (1993) [82] he/she finds that mice of used BALB/c the signs of scent and mice
of C57BL/6 used the space signs to learn a radial labyrinth, considering that the hybrids of
F1 could use any sign. Crusio and coworkers (1993) [27] he/she finds the big changes in
the tension the rude orders ahead space against the versions of the nonspatial of a radial
labyrinth; the space version only revealed the genetic correlations with the hippocampal the
anatomy of mossy fiber. The peeler (1995) [75] the differences named in the tension rude
order that depends ahead if the mice had to cross a hole or rift or to jump a barrier to avoid
the fright. These and other results show clearly that a single configuration of the test and
procedure cannot define a single psychological structure, although two tests that differ in a
specific element can indicate a change in a specific structure.
The growing Necessity for the Standardization of the Test
There are grounds for the concern on the almost universal lack of standardized apparatuses,
protocols, and set of the laboratory in the psychological confirmation of animals in view of
these results. In the contrast, they take construction of the test and standardization more
seriously in the evaluation of human. The revisions among the laboratories of the more-
labyrinth, a popular means to evaluate the anxiety, reveal numerous idiosyncratic variations
that are potentially important (Hogg 1996; Rodgers & Dalvi 1997). [46,80] they are often
used inappropriately Tests acquaintances to be valid for the rats with the mice. The Morris
the pool that anything is particularly problematic when it used with the mice (Whishaw &
Tomie 1996). [105] Some common innate tensions (BALB/c, 129) he/she responds quite
bad in this device (Francis the et at the 1995) [36] and often he/she goes to float after
becoming exhausted (the et of Wolfer at the 1997). [108] When the mice can locate a
submerged platform, they should be using the space signs, but the failure to learn it doesn't
necessarily point out by heart a lack space (unless the signs are only manipulated in the
versions different from the task, and a tension can learn a sign but not the other one). the
Additional difficulties are present when investigators subject an individual animal to a
battery of tests each one of which were designed and they validated for the alone use: The
order of proving can alter the results notably when they combine the such tests.
The validity of Animal Models
Considering that the homology among the flies, mice, and human at the molecular genetic
level it is undeniable, homology-and even analogy-to the level of the organism behaving is
not so clear. Certain important genes for the memory in the flies (it Figures 2) it is wrapped
in the memory in the mammals (for example the rutabaga of fly gene, the barrelless of
mouse gene, and the human gene ADCY1 all put in code a cyclase of the adenylate), still
the complex nature of metabolic systems and of development (it characterized for the
pleiotropic and epistatic (1995) [75] the differences named in the tension rude order that
depends ahead if the mice had to cross to hole or rift or to jump to barrier to avoid the
fright. These and other results show clearly that to it sails configuration of the test and
procedure cannot it defines to it sails psychological structure, although two tests that differ
in to specific element dog you indicate yourself to change in to specific structure.
The growing Necessity for the Standardization of the Test
There plows grounds for the concern on the almost universal lack of standardized
apparatuses, protocols, and Sep of the laboratory in the psychological confirmation of
animals in view of these results. In the contrast, they take construction of the test and
standardization lives seriously in the evaluation of human. The revisions among the
laboratories of the live-labyrinth, to popular means to you evaluate yourself the anxiety,
reveal numerous idiosyncratic variations that plows potentially important (Hogg 1996;
Rodgers & Dalvi 1997). [46,80] they plows often used inappropriately Tests acquaintances
to be valid for the rats with the mice. The Morris the pool that anything is particularly
problematic when it used with the mice (Whishaw & Tomie 1996). [105] Some common
innate tensions (BALB/c, 129) he/she responds removes bad in this device (Francis the et at
the 1995) [36] and often he/she goes to float after becoming exhausted (the et of Wolfer at
the 1997). [108] When the mice dog locate to submerged platform, they should be using the
space signs, but the failure to learn it doesn't necessarily point out by heart to lack space
(unless the signs plows only manipulated in the versions different from the task, and to
tension dog learn to sign but not the other one). the Additional difficulties plows present
when investigators subject an individual animal to battery of tests each one of which were
designed and they validated for the alone it uses: The order of proving dog alter the results
notably when they combines the such tests.
The validity Animal of Models
Considering that the homology among the flies, mice, and human at the molecular genetic
level it is undeniable, homology-and even analogy-to the level of the organism behaving is
not so clear. Certain important genes for the memory in the flies (it Figures 2) it is wrapped
in the memory in the mammals (for example the rutabaga of fly gene, the barrelless of
mouse gene, and the human gene ADCY1 all put in code to cyclase of the adenylate), still
the complex nature of metabolic systems and of development (it characterized for the
pleiotropic and epistatic