NONMENDELIAN INHERITANCE

Chapter 7
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NON-MENDELIAN INHERITANCE
Mendelian inheritance patterns
Involve genes directly influencing traits Obey Mendels laws
Law of segregation Law of independent assortment

Include
Dominant / recessive relationships Gene interactions Phenotype-influencing roles of sex and environment

Most genes of eukaryotes follow a Mendelian inheritance pattern

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NON-MENDELIAN INHERITANCE
Many genes do not follow a Mendelian inheritance pattern
e.g., Closely linked genes do not follow Mendels law of independent assortment This chapter will discuss additional and more bizarre non-Mendelian inheritance patterns
Maternal effect Epigenetic inheritance Extranuclear inheritance

MATERNAL EFFECT
Maternal effect
Inheritance pattern for certain nuclear genes Genotype of mother directly determines phenotype of offspring
Genotype of father and offspring are irrelevant

Explained by the accumulation of gene products mother provides to developing eggs

MATERNAL EFFECT
A. E. Boycott (1920s) First to study an example of maternal effect Involved morphological features of water snail
Limnea peregra Shell and internal organs can be either right- or lefthanded
Dextral or sinistral, respectively Determined by cleavage pattern of egg after fertilization

Dextral orientation is more common and dominant

MATERNAL EFFECT
A. E. Boycott (1920s) Began with two different true-breeding strains
One dextral, one sinistral

Dextral x sinistral dextral offspring Reciprocal cross sinistral offspring Contradict a Mendelian pattern of inheritance

MATERNAL EFFECT
A. E. Boycott (1920s); Alfred Sturtevant (1923) Sturtevant proposed that Boycotts results could be explained by a maternal effect gene
Conclusions drawn from F2 and F3 generations Dextral (D) is dominant to sinistral (d) Phenotype of offspring is determined by genotype of mother
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MATERNAL EFFECT
Oogenesis in female animals
Oocyte is formed
Will ultimately become haploid

Nourished by surrounding diploid maternal nurse cells

MATERNAL EFFECT
Oogenesis in female animals
Oocyte is formed
Will ultimately become haploid

Nourished by surrounding diploid maternal nurse cells

Receives gene products from nurse cells Genotype of nurse cells determines gene products in oocyte

MATERNAL EFFECT
Maternal effect genes
Encode RNA and proteins that play important roles in early steps of embryogenesis
e.g., Cell division, cleavage pattern, body axis orientation

Defective alleles tend to have dramatic phenotypic effects

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MATERNAL EFFECT
Maternal effect genes
Identified in Drosophila melanogaster (and other organisms)
Profound effects on early stages of development Gene products important in proper development along axes
Anterio-posterior axis Dorso-ventral axis

Discussed further in chapter 23

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EPIGENETIC INHERITANCE
Epigenetic inheritance
Modification occurs to a nuclear gene or chromosome Occur during spermatogenesis, oogenesis, and early stages of embryogenesis Gene expression is altered
May be fixed during an individuals lifetime

Expression is not permanently changed over multiple generations

DNA sequence is not altered

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EPIGENETIC INHERITANCE
Two types of epigenetic inheritance will be discussed
Dosage compensation
Offsets differences in the number of sex chromosomes One sex chromosome is altered

Genomic imprinting
Occurs during gamete formation Involves a single gene or chromosome Governs whether offspring express maternally- or paternallyderived gene
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DOSAGE COMPENSATION
Males and females of many species have different numbers of certain sex chromosomes
e.g., X chromosomes The level of expression of many genes on sex chromosomes is similar in both sexes

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DOSAGE COMPENSATION
Apricot eye color in Drosophila
Conferred by an X-linked gene Homozygous females resemble hemizygous males Females heterozygous for the apricot allele and a deletion have paler eye color Two copies of the allele in a female produce a phenotype similar to one copy in a male The difference in gene dosage is being compensated at the level of gene expression

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DOSAGE COMPENSATION
Dosage compensation does not occur for all eye color alleles in Drosophila
e.g., Eosin eye color
Conferred by an X-linked gene Homozygous eosin females have darker eye color than hemizygous eosin males
Dark eosin and light eosin

Females heterozygous for the eosin allele and the while allele have light eosin eye color Two copies of the allele in a female produce a phenotype different than one copy in a male
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DOSAGE COMPENSATION
Most X-linked genes show dosage compensation Some X-linked genes do not Reasons for the difference are not understood

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DOSAGE COMPENSATION
Mechanisms of dosage compensation
Mammals
One X chromosome is inactivated in females
X inactivation Paternally derived in marsupial mammals Paternal or random, depending on species of placental mammal

Drosophila melanogaster
Twofold increase in expression of genes on the X chromosome of males

The nematode Caenorhabditis elegans

50% reduction in expression of X-linked genes in XX individuals
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DOSAGE COMPENSATION

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DOSAGE COMPENSATION
Dosage compensation is poorly understood in certain species
e.g., Birds and fish

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DOSAGE COMPENSATION
Sex in birds is determined by Z and W sex chromosomes
Males are ZZ, females are ZW The Z chromosome is large
Contains most sex-linked genes

The W chromosome is a smaller microchromosome

Contains a large amount of non-coding repetitive DNA

Dosage compensation usually occurs, but not for all genes

Molecular mechanism is not understood
Highly compacted chromosomes are not seen in males Perhaps genes on both Zs are downregulated Perhaps genes on females Z are upregulated

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DOSAGE COMPENSATION
Murray Barr and Ewart Bertram (1949) Identified a highly condensed structure in interphase nuclei of somatic cells of female cats
This structure was absent in male cats Barr body Later identified as a highly condensed X chromosome

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DOSAGE COMPENSATION
Mary Lyon (1961) Aware of Barr and Bertram cytological evidence Also aware of mammalian mutations producing a variegated coat color pattern
e.g., Calico cats are heterozygous for X-linked alleles determining coat color
Possess randomly distributed patches of black and orange White underside due to dominant mutation of another gene

Lyon hypothesis: A single X chromosome was inactivated in the cells of females

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DOSAGE COMPENSATION
X chromosome inactivation
Both coat color alleles are originally active One X chromosome is randomly inactivated in each cell during early embryonic development X inactivation is passed along to all future somatic cells during cell division Patches of cells with different coloration result
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DOSAGE COMPENSATION
X chromosome inactivation
DNA in inactivated X chromosomes becomes highly compacted
A Barr body is formed

Most genes cannot be expressed

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DOSAGE COMPENSATION
Davidson, Nitowsky, and Childs (1963) Tested the Lyon hypothesis at the cellular level Analyzed expression of a human X-linked gene
Encoded the enzyme glucose-6-phosphate dehydrogenase (G-6-PD) Individuals vary with respect to this enzyme Different alleles produce different yet functional enzymes

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DOSAGE COMPENSATION
Davidson, Nitowsky, and Childs (1963) Variation in G-6-PD can be detected via gel electrophoresis
Electric current forces proteins through a gel Different proteins different movement rates Can discriminate between fast enzyme and slow enzyme

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DOSAGE COMPENSATION
Davidson, Nitowsky, and Childs (1963) Hypothesis
Heterozygous adult females should express only one enzyme in any particular somatic cell and its descendents

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DOSAGE COMPENSATION
Davidson, et al. (1963) Experimental design
Isolate tissue from adult heterozygote Separate individual cells Grow these cells in culture Isolate proteins from various clones Subject proteins to electrophoresis
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DOSAGE COMPENSATION
Davidson, et al. (1963) The data
A single form of the enzyme was detected in each clone
Some clones produced the fast enzyme Some clones produced the slow enzyme

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DOSAGE COMPENSATION
Davidson, Nitowsky, and Childs (1963) Interpreting the data
Lane 1 contains a mixture of cells from a heterozygous woman Each clone produced only a single form of the enzyme The allele encoding the other form resides upon the inactivated X chromosome Consistent with the hypothesis
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DOSAGE COMPENSATION
Genetic control of X inactivation
Human cells (and those of other mammals) possess the ability to count their X chromosomes Only one is allowed to remain active
XX females 1 Barr body XY males 0 Barr bodies XO females 0 Barr bodies (Turner syndrome) XXX females 2 Barr bodies (Triple X syndrome) XXY males 1 Barr body (Kleinfelter syndrome)

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DOSAGE COMPENSATION
Genetic control of X inactivation
Not entirely understood X-inactivation center (Xic) is involved
Short region of the X chromosome

Skip details

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DOSAGE COMPENSATION
Genomic imprinting involves the physical marking of a segment of DNA
Mark is retained and recognized throughout the life of the organism inheriting the marked DNA Resulting phenotypes display non-Mendelian inheritance patterns Offspring expresses one allele, not both Monoallelic expression

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DOSAGE COMPENSATION
Genomic imprinting
The Igf-2 gene encodes an insulin-like growth factor
Functional allele required for normal size Igf-2m allele encodes a non-functional protein

Imprinting results in the expression of the paternal allele only

Paternal allele is transcribed Maternal allele is transcriptionally silent

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DOSAGE COMPENSATION
Genomic imprinting
The Igf-2 gene encodes an insulin-like growth factor
Functional allele required for normal size Igf-2m allele encodes a non-functional protein

Igf-2m Igf-2m x Igf-2 Igf-2

Normal offspring

Igf-2m Igf-2m x Igf-2 Igf-2

Dwarf offspring

Different results in reciprocal crosses generally indicate sex-linked traits

In this case, it indicates genomic imprinting of autosomal alleles
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DOSAGE COMPENSATION
Genomic imprinting
The imprint of the Igf-2 gene is erased during gametogenesis A new imprint is then imparted
Oocytes possess an imprinted gene that is silenced Sperm possess a gene that is not silenced

The phenotypes of offspring are determined by the paternally derived allele

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DOSAGE COMPENSATION
Genomic imprinting
Permanent in the somatic cells of an animal Can be altered from generation to generation

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DOSAGE COMPENSATION
Genomic imprinting
Occurs in several species
Numerous insects, plants, and mammals

Effects can include

A single gene A part of a chromosome An entire chromosome All the chromosomes from one parent

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DOSAGE COMPENSATION
Genomic imprinting
First discovered in the housefly Sciara coprophilia These flies normally inherit three sex chromosomes
One X chromosome from the female Two X chromosomes from the male

Male flies lose both paternal X chromosomes during embryogenesis Female flies lose one paternal X chromosome during embryogenesis

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DOSAGE COMPENSATION
Genomic imprinting
First discovered in the housefly Sciara coprophilia The maternal X chromosome is never lost
The maternal X chromosome is marked to promote its retention, or The paternal X chromosome is marked to promote its loss

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DOSAGE COMPENSATION
Genomic imprinting
Can also be correlated with the process of X inactivation In some species, imprinting determines which X chromosome will be inactivated
e.g., The paternal X chromosome is always inactivated in marsupials e.g., The paternal X chromosome is inactivated in extraembryonic tissue (e.g., the placenta) of placental mammals
X inactivation is random in the placental embryo itself
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DOSAGE COMPENSATION
Genomic imprinting
Involves the physical marking of DNA Involves differentially methylated regions (DMRs) located near imprinted genes
Maternal or paternal copy is methylated, not both

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DOSAGE COMPENSATION
Genomic imprinting
Methylation occurs during gametogenesis
Methylated in oocyte or sperm, not both

This pattern of imprinting is maintained in the somatic cells of the offspring Imprinting is erased during gametogenesis in these offspring
New imprinting established
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DOSAGE COMPENSATION
Genomic imprinting
Methylation generally inhibits expression
Can enhance binding of transcription-inhibiting proteins and/or inhibit binding of transcription-enhancing proteins

Methylation can increase expression of some genes

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DOSAGE COMPENSATION
Genomic imprinting
Identified in several mammalian genes Biological significance is unclear Plays a role in the inheritance of some human diseases

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EXTRANUCLEAR INHERITANCE
Most genes are found in the cells nucleus Some genes are found outside of the nucleus
Some organelles possess genetic material Resulting phenotypes display non-Mendelian inheritance patterns
Extranuclear inheritance Cytoplasmic inheritance

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EXTRANUCLEAR INHERITANCE
Mitochondria and chloroplasts possess DNA
Circular chromosomes resemble smaller versions of bacterial chromosomes Located in the nucleoid region of the organelles
Multiple nucleoids often present Each can contain multiple copies of the chromosome

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EXTRANUCLEAR INHERITANCE
Mitochondrial genome size varies greatly among different species
400-fold variation in mitochondrial chromosome size
Mitochondrial genomes of animals tend to be fairly small Mitochondrial genomes of fungi, algae, and protists tend to be intermediate in size Mitochondrial genomes of plants tend to be fairly large

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EXTRANUCLEAR INHERITANCE
Human mitochondrial DNA is called mtDNA
Circular chromosome 17,000 base pairs in length
Less than 1% of a typical bacterial chromosome

Carries relatively few genes

Genes encoding rRNA and tRNA 13 genes encoding proteins functioning in ATP generation via oxidative phosphorylation

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EXTRANUCLEAR INHERITANCE
Most mitochondrial proteins are encoded by genes in the cells nucleus
Proteins are synthesized in the cytosol and transported into the mitochondria

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EXTRANUCLEAR INHERITANCE
Chloroplast genomes tend to be larger than mitochondrial genomes
Correspondingly greater number of genes ~100,000 200,000 bp in length Ten times larger than the mitochondrial genome of animal cells

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EXTRANUCLEAR INHERITANCE
Chloroplast DNA (cpDNA) of the tobacco plant
156,000 bp circular DNA molecule 110 120 different genes
rRNAs, tRNAs, and many proteins required for photosynthesis Many chloroplast proteins are encoded in the nucleus

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EXTRANUCLEAR INHERITANCE
Most nuclear genes in diploid eukaryotes display Mendelian inheritance patterns
Homologous chromosomes segregate during gamete production Offspring inherit one copy of each gene from each parent

The inheritance pattern of extranuclear genetic material displays non-Mendelian inheritance

Mitochondria and plastids do not segregate into gametes as do nuclear chromosomes
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EXTRANUCLEAR INHERITANCE
Pigmentation in Mirabilis jalapa
The four-oclock plant Pigmentation is determined by chloroplast genes
Green phenotype is the wild-type condition
Green pigment is formed

White phenotype is due to a mutation in a chloroplast gene

Synthesis of green pigment is diminished

Cells containing both types of chloroplasts display green coloration

Normal chloroplasts produce pigment Heterotroplasmy
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EXTRANUCLEAR INHERITANCE
Pigmentation in Mirabilis jalapa
Pigmentation in the offspring depends solely on the maternal parent
Maternal inheritance Chloroplasts are inherited only through the cytoplasm of the egg

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EXTRANUCLEAR INHERITANCE
Pigmentation in Mirabilis jalapa
Cells can contain both types of chloroplasts
Coloration is green because pigment is produced

Chloroplasts are irregularly distributed to daughter cells during cell division

Some cells may receive only chloroplasts defective in pigment synthesis
The sector of the plant arising from such a cell will be white

Variegated phenotype
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EXTRANUCLEAR INHERITANCE
Studies in yeast and unicellular algae provided genetic evidence for extranuclear inheritance of mitochondria and chloroplasts
e.g., Saccharomyces cerevisiae e.g., Chlamydomonas reinhardtii

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EXTRANUCLEAR INHERITANCE
Many organisms are heterogametic
Two kinds of gametes are made
Female gamete tends to be large and provides most of the cytoplasm to the zygote Male gamete is small and often provides little more than a nucleus

Mitochondria and plastids are most often inherited from the maternal parent

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EXTRANUCLEAR INHERITANCE
Many organisms are heterogametic
Two kinds of gametes are made
Female gamete tends to be large and provides most of the cytoplasm to the zygote Male gamete is small and often provides little more than a nucleus

Mitochondria and plastids are most often inherited from the maternal parent
Rarely, mitochondria are provided via the sperm
Paternal leakage
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EXTRANUCLEAR INHERITANCE
The inheritance pattern of mitochondria and plastids varies among different species

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EXTRANUCLEAR INHERITANCE
A few rare human diseases are caused by mitochondrial mutations
Display a strict maternal inheritance pattern

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EXTRANUCLEAR INHERITANCE
Symbiosis involves a close relationship between two species where at least one member benefits
Endosymbiosis involves such a relationship where one organism lives inside the other

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EXTRANUCLEAR INHERITANCE
Mitochondria and chloroplasts were once freeliving bacteria
Engulfed and retained by early eukaryotes Endosymbiosis

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EXTRANUCLEAR INHERITANCE
Endosymbiosis
Origin of chloroplasts proposed in 1883 Origin of mitochondria proposed in 1922 DNA was discovered in these organelles in the 1950s Hotly debated topic when Lynn Margulis published Origin of Eukaryotic Cells in 1970 Molecular analysis in the 1970s and 1980s provided additional evidence Endosymbiotic theory is currently virtually universally accepted
Perhaps not among flat-earthers
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EXTRANUCLEAR INHERITANCE
Plastids were derived from cyanobacteria
Photosynthetic bacteria Relationship allows plants and algae to obtain energy from the sun Benefit to the bacterium is less clear

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EXTRANUCLEAR INHERITANCE
Mitochondria were likely derived from gramnegative nonsulfur purple bacteria
Relationship enabled eukaryotes to produce larger amounts of ATP

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EXTRANUCLEAR INHERITANCE
Endosymbiosis
Most genes originally found in these bacterial genomes have been lost of transferred to the nucleus
The DNA sequence of some nuclear genes indicates horizontal gene transfer from bacteria

Biological benefits are unclear

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EXTRANUCLEAR INHERITANCE
Endosymbiosis
Transfer of mitochondrial genes to the nucleus has apparently ceased in animals Gene transfer from mitochondria and chloroplasts continues in plants at a low rate Transfer from the nucleus to the organelles has apparently almost never occurred
One example in plants of transfer to the mitochondrion is known

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EXTRANUCLEAR INHERITANCE
Endosymbiosis
Horizontal gene transfer can also occur between organelles
Between mitochondria Between chloroplasts Between a mitochondrion and a chloroplast

Biological benefits are unclear

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EXTRANUCLEAR INHERITANCE
Eukaryotic cells occasionally contain symbiotic infective particles
Some individuals of the protozoan Paramecia aurelia possess the killer trait
Secrete the toxin paramecin Many strains of paramecia are killed

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EXTRANUCLEAR INHERITANCE
Killer strains contain cytoplasmic particles
Kappa particles 0.4 m long Contain their own DNA
Gene encodes paramecin toxin Genes encode resistance to this toxin

Kappa particles are infectious

Particles in extract from killer strains can infect nonkiller strains Converted to killer strains
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EXTRANUCLEAR INHERITANCE
The protozoan Paramecia aurelia
Some individuals possess the killer trait
Secrete the toxin paramecin Many strains of paramecia are killed

Killer strains contain cytoplasmic particles

Kappa particles 0.4 m long Contain their own DNA
Gene encodes paramecin toxin Genes encode resistance to this toxin

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EXTRANUCLEAR INHERITANCE
Eukaryotic cells occasionally contain symbiotic infective particles
Certain strains of Drosophila possess a trait known as sex ratio
Most of the offspring are female
Most of the male offspring died Surviving males do not transmit the trait to their offspring

Transmitted maternally Transmitted infective agent is a symbiotic microorganism

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