44200_06_p185-226 3/1/04 3:15 PM Page 185

6
FROM GENE
TO PHENOTYPE

KEY QUESTIONS
How do individual genes exert their effect
on an organisms makeup?
In the cell, do genes act directly
or through some sort of gene product?
What is the nature of gene products?
What do gene products do?
Is it correct to say that an allele of a gene
determines a specific phenotype?
In what way or ways do genes interact
at the cellular level?
How is it possible to dissect complex gene
interaction using a mutational approach?
The colors of peppers are determined by the interaction of
several genes. An allele Y promotes early elimination of
chlorophyll (a green pigment), whereas y does not. R OUTLINE
determines red and r yellow carotenoid pigments. Alleles c1
and c2 of two different genes down-regulate the amounts of 6.1 Genes and gene products
carotenoids, causing the lighter shades. Orange is down- 6.2 Interactions between the alleles of one gene
regulated red. Brown is green plus red. Pale yellow is down-
regulated yellow. [Anthony Griffiths.] 6.3 Interacting genes and proteins
6.4 Applications of chi-square (  2) test
to gene interaction ratios

185
44200_06_p185-226 3/4/04 10:58 AM Page 186
186
CHAPTER OVERVIEW
uch of the early success of genetics can be attrib-
M uted to the correlation of phenotypes and alleles,
as when Mendel equated Y with yellow peas and y with
green. However, from this logic there arises a natural
tendency to view alleles as somehow determining pheno-
types. Although this is a useful mental shorthand, we
must now examine the relationship between genes and
phenotypes more carefully. The fact is that there is no
way a gene can do anything alone. (Imagine a gene a
single segment of DNA alone in a test tube.) For a
gene to have any influence on a phenotype it must act in
concert with many other genes and with the external
and internal environment. So an allele like Y cannot pro-
duce yellow color without the participation of many
other genes and environmental inputs. In this chapter
we examine the ways in which these interactions take
place.
Even though such interactions represent a higher
level of complexity, there are standard approaches that
can be used to help elucidate the type of interaction oc-
CHAPTER OVERVIEW Figure
Environmental signal
Gene for protein modification
Gene for regulatory protein
Gene of interest
Gene for binding protein
Figure 6-1 Genetic and environmental elements affect gene action. P  phosphate group.
Chapter 6 From Gene to Phenotype
curring in any one case. The main ones used in genetics
are as follows:
1. Genetic analysis is the focus of this chapter. The
genes interacting in a specific phenotype are
identified by going on a hunt for all the different
kinds of mutants that affect that phenotype.
2. Functional genomics (Chapter 12) provides powerful
ways of defining the set of genes that participate in
any defined system. For example, the genes that
collaborate in some specific process can be deduced
from finding the set of RNA transcripts present
when that process is going on.
3. Proteomics (also Chapter 12) assays protein
interaction directly. The essence of the technique is
to use one protein as bait and find out which other
cellular proteins attach to it, suggesting the
components of a multiprotein cellular machine.
How does the genetic analysis approach work? The
mutants collected in the mutant hunt identify a set of
genes that represent the individual components of the
Environmental supply
P
P
P
P P
Substrate
Environmental supply
44200_06_p185-226 3/2/04 2:56 PM Page 187

6.1 Genes and gene products 187

biological system that underlies the specific phenotype
under scrutiny. The ways in which they interact can of-
ten be deduced by crossing different mutants to create
double mutants. The phenotype of a double mutant, and
the phenotypic ratios produced when it is crossed, sug-
gests certain types of known interactions. In the cell,
gene interaction is manifested by physical interaction
between proteins or between proteins and DNA or
RNA.
The physical ways in which genes interact with one
another and with the environment are summarized by
the model in Figure 6-1. Some of the interactions shown
in the figure are as follows:
Transcription of one gene may be turned on or off by
other genes called regulatory genes. The regulatory
proteins they encode generally bind to a region in
front of the regulated gene.
Proteins encoded by one gene may bind to proteins
from other genes to form an active complex that
performs some function. These complexes, which can
be much larger than that shown in the figure, have
become known as molecular machines because they
have several interacting functional parts just like a
machine.
Proteins encoded by one gene may modify the
proteins encoded by a second gene in order to
activate or deactivate protein function. For example,
proteins may be modified through the addition of
phosphate groups.
The environment engages with the system in several
ways. In the case of an enzyme, its activity may
depend on the availability of a substrate supplied by
the environment. Signals from the environment can
also set in motion a chain of consecutive gene-
controlled steps that follow one another like a
cascade of falling dominoes. The chain of events
initiated by an environmental signal is called signal
transduction.
lead to malfunction because it now cannot bind to its
partner protein. However, a mutation in the gene for the
partner protein might cause a shape change that would
now permit binding to the abnormal protein of the first
gene, hence restoring an active complex.
6.1 Genes and gene products
The first clues about how genes function came from
studies of humans. Early in the twentieth century,
Archibald Garrod, an English physician (Figure 6-2),
noted that several recessive human diseases show meta-
bolic defects harmful alterations in basic body chem-
istry. This observation led to the notion that such genetic
diseases are inborn errors of metabolism. For example,
phenylketonuria (PKU), which is caused by an autoso-
mal recessive allele, results from an inability to convert
phenylalanine into tyrosine. Consequently, phenylala-
nine accumulates and is spontaneously converted into a
toxic compound, phenylpyruvic acid. In another exam-
ple, introduced in Chapter 1, the inability to convert
tyrosine into the pigment melanin produces an albino.
Garrods observations focused attention on metabolic
control by genes.
One-gene one-enzyme hypothesis
A landmark study by George Beadle and Edward Tatum
in the 1940s clarified the role of genes. They later re-
ceived a Nobel prize for their study, which marks the
beginning of molecular biology. Beadle and Tatum did
their work on the haploid fungus Neurospora, which we
have met in our discussions of octad analysis. They first
irradiated Neurospora to produce mutations and then

Formal names have been given to certain commonly

encountered types of interactions between mutations of
different genes: Figure 6-1 can be used to illustrate some
of those covered in this chapter. If mutation of one gene
prevents expression of alleles of another, the former is
said to be epistatic. An example would be a mutation of
the regulatory gene because, if its protein is defective,
any allele of a gene that it regulates could not be tran-
scribed. Sometimes mutation in one gene can restore
wild-type expression to a mutation in another gene; in
this case the restoring mutation is said to be a suppressor.
An example is seen in proteins that bind to each other: a
mutation causing shape change in one protein might Figure 6-2 Archibald Garrod.
44200_06_p185-226 3/2/04 2:56 PM Page 188

188 Chapter 6 From Gene to Phenotype

X rays

(a)
Mutagenized Fruiting bodies Microscopic ascospores are
conidia dissected and transferred
one by one to culture tubes
Wild type Crossed with wild type
of opposite mating type

Hundreds of tubes of
complete medium are Complete
(b)
inoculated with single medium
ascospores

Conidia (asexual spores)

Minimal
(c) from each culture are then
medium
tested on minimal medium

No growth on minimal medium

identifies nutritional mutant

Conidia from the cultures that

(d) fail to grow on minimal medium Minimal Minimal Minimal Complete
are then tested on a variety (control) + amino + vitamins (control)
of supplemented media acids

(e)
Glycine

Alanine

Leucine

Isoleucine

Valine

Methionine

Phenylalanine

Tyrosine

Tryptophan

Proline

Arginine

Lysine

Histidine

Glutamic acid

Aspartic acid

Glutamine

Asparagine

Serine

Threonine

Cysteine

Addition of arginine to minimal medium restores growth

Figure 6-3 Experimental approach used by Beadle and Tatum for generating large numbers of
mutants in Neurospora. Shown is the isolation of an arg- mutant. [After Peter J. Russell,
Genetics, 2d ed. Scott, Foresman.]
44200_06_p185-226 3/1/04 3:16 PM Page 189

6.1 Genes and gene products 189

tested cultures from ascospores for interesting mutant Table 6-1 Growth of arg Mutants
phenotypes. They found numerous auxotrophic mu- in Response to Supplements
tants, of the type we have learned about in bacteria.
Beadle and Tatum deduced that each mutation that gen- Supplement
erated the auxotrophic requirement was inherited as a Mutant Ornithine Citrulline Arginine
single-gene mutation because each gave a 1 : 1 ratio
when crossed with a wild type. Letting aux represent an arg-1   
auxotrophic mutation, arg-2   
arg-3   
  aux Note: A plus sign means growth; a minus sign means no
s growth.
p
1
progeny 2  This pathway nicely explains the three classes of mu-
1
aux tants shown in Table 6-1. Under the model, the arg-1
2
mutants have a defective enzyme X, so they are unable
to convert the precursor into ornithine as the first step
Figure 6-3 depicts the experimental procedure that
in producing arginine. However, they have normal en-
Beadle and Tatum used. One particular group of mutant
zymes Y and Z, and so the arg-1 mutants are able to
strains specifically required the amino acid arginine to
produce arginine if supplied with either ornithine or
grow, and these arginine auxotrophs formed the basis of
citrulline. Similarly, the arg-2 mutants lack enzyme Y,
their subsequent analysis. They found that the arginine-
and the arg-3 mutants lack enzyme Z. Thus, a mutation
requiring auxotrophic mutations mapped to three differ-
at a particular gene is assumed to interfere with the
ent loci on separate chromosomes. Lets call the genes at
production of a single enzyme. The defective enzyme
the three loci the arg-1, arg-2, and arg-3 genes. A key
creates a block in some biosynthetic pathway. The
breakthrough was their discovery that the auxotrophs
block can be circumvented by supplying to the cells
for each of the three loci differed in their response to
any compound that normally comes after the block in
the structurally related compounds ornithine and citrul-
the pathway.
line (Figure 6-4). The arg-1 mutants grew when supplied
We can now diagram a more complete biochemical
with any one of the chemicals, ornithine, citrulline, or
model:
arginine. The arg-2 mutants grew when given arginine or
citrulline but not ornithine. The arg-3 mutants grew only arg-1 arg-2
when arginine was supplied. We can see this more easily
by looking at Table 6-1. precursor
enzyme X
ornithine
enzyme Y

NH2 NH2 arg-3

C"O C " NH enzyme Z

citrulline arginine
NH2 NH NH
(CH2)3 (CH2)3 (CH2)3 This brilliant model, which has become known as the
CHNH2 CHNH2 CHNH2 one-gene one-enzyme hypothesis, was the source of the
first exciting insight into the functions of genes: genes
COOH COOH COOH
somehow were responsible for the function of en-
Ornithine Citrulline Arginine
zymes, and each gene apparently controlled one spe-
Figure 6-4 Chemical structures of arginine and the related cific enzyme. Other researchers obtained similar results
compounds citrulline and ornithine. for other biosynthetic pathways, and the hypothesis
soon achieved general acceptance. It was also found
It was already known that cellular enzymes inter- that all proteins, whether or not they are enzymes, are
convert related compounds such as these. On the basis encoded by genes, so the phrase was refined to become
of the properties of the arg mutants, Beadle and Tatum one-gene one-protein, or more accurately one-gene
and their colleagues proposed a biochemical pathway one-polypeptide. (Recall that a polypeptide is the sim-
for such conversions in Neurospora: plest type of protein, a single chain of amino acids.) It
soon became clear that a gene encodes the physical
enzyme X enzyme Y
precursor ornithine structure of a protein, which in turn dictates its func-
enzyme Z
tion. Beadle and Tatums hypothesis became one of the
citrulline arginine great unifying concepts in biology, because it provided a
44200_06_p185-226 3/1/04 3:16 PM Page 190

190 Chapter 6 From Gene to Phenotype

bridge that brought together the two major research ar-

eas of genetics and biochemistry.
We must add that although the great majority of
genes encode proteins, it is now known that some en-
code RNAs that have special functions. All genes are
transcribed to make RNA. Protein-coding genes are tran-
scribed to messenger RNA (mRNA), which is then
translated into protein. However, for a minority of genes
their RNA is never translated to protein because the
RNA itself has a unique function. We shall call these
functional RNAs. Some examples are transfer RNAs,
ribosomal RNAs, and small cytoplasmic RNAs more
of these in later chapters.
MESSAGE The majority of genes exert their influence on
biological properties at a purely chemical level, by coding
for the structures of cellular proteins. Each gene of this type
encodes one polypeptide, the simplest protein (a single chain
of amino acids). A few genes encode functional RNAs that are
destined never to become proteins.
Mutant genes and proteins
If genes code for proteins, how does a mutant allele of a
gene affect the protein product? Let us explore the
topic using phenylketonuria (PKU), the human disease
that we first encountered in Chapter 2. Recall that PKU

Dietary protein

Phenylalanine
(Phe) If [Phe] high

Phenylpyruvic
Phe hyroxylase PKU acid

Albinism Cretinism
Tyrosine
(Tyr)
Melanin Thyroxine

Tyr aminotransferase

Hydroxyphenylpyruvic acid
(HPA)

HPA oxidase Tyrosinosis

Homogentisic acid
(HA)

HA oxidase Alkaptonuria

Maleylacetoacetic
acid

CO2 + H2O

Figure 6-5 A section of the phenylalanine metabolic pathway, including

diseases associated with enzyme blockages. The disease PKU is produced
when the enzyme phenylalanine hydroxylase malfunctions. Accumulation
of phenylalanine results in an increase in phenylpyruvic acid, which
interferes with the development of the nervous system. [After I. M. Lerner
and W. J. Libby, Heredity, Evolution, and Society, 2d ed. Copyright 1976 by
W. H. Freeman and Company.]
44200_06_p185-226 3/1/04 3:16 PM Page 191

6.1 Genes and gene products 191

is an autosomal recessive disease caused by a defective
allele of the gene coding for the liver enzyme phenylala-
nine hydroxylase (PAH). In the absence of normal PAH
the phenylalanine entering the body in food is not bro-
ken down and hence accumulates. Under such condi-
tions, phenylalanine is converted into phenylpyruvic
acid, which is transported to the brain via the blood-
stream and there impedes normal development, leading
to mental retardation. The section of the metabolic
pathway responsible for PKU symptoms is shown in Fig-
ure 6-5. (This figure also shows other inborn errors of
metabolism caused by blocks at other steps in the reac-
tion sequence.)
The PAH enzyme is a single polypeptide. Recent se-
quencing of the mutant alleles from many patients has
revealed a plethora of mutations at different sites along
the gene, summarized in Figure 6-6. What these alleles
have in common is that each encodes a defective PAH.
They all inactivate some essential part of the protein en-
coded by the gene. The positions in an enzyme at which
function can be adversely affected in general are shown
in Figure 6-7. These are likely to fall in the sequences
coding for the proteins active site, the region of the pro-
tein that catalyzes the chemical reaction breaking down
phenylalanine. Mutations may fall anywhere in the gene,
but those away from the active site are more likely to be

fs G352(delG)
Figure 6-6 Structure of the human phenylalanine hydroxylase S349P[H1]
gene and a summary of mutations resulting in enzyme L348V[H9]
malfunction. Mutations in the exons, or protein-coding regions fs G346
A345T[H7]
(black), are listed above the gene. Mutations in the intron Q304Q A322G[H12]
Y343C
A300S[H1] A322T[H1]
regions (green, numbered 1 13) that alter splicing are listed F299C[H8] P314H
A342T
below the gene. The various symbols represent different D338Y
P281L[H1,4] R297H L311P[H1,7,10]
Q336X
types of mutational changes. [Modified from C. R. Scriver, E280K[H1,2,4,28,38] D282N A309V
L333F
del1043-1056/fs/278X A309D
Ann. Rev. Genet. 28, 1994, 141 165.] 1306V[H4]
F331L[H1]
T278N W326X[H4]
T278A
Q232Q[H3,4,#]
Y277D
S231P fs R400
M276V MspI
V230I V399V[H4]
M276I
P225T A395P
S273F[H7]
I224M[H4] A395G
G272X[H7]
E221D222 fs D394H
R270S[H1]
E221G[H3] D394A
R270K
G218V E390G
H264L
L213P fs delAGx1(1389-1394)
R261X[H3]
P211 fs V388M
R261P
P211T V388L
R261Q[H1,2,4,28]
Y204X Y386C
A259V[H42]
Y204C[H4] L385L[H3,?]
A259T[H3]
del198 204 T380M
G257C
L194P fs Y377
L255V[H18,21]
V190A[H3] fs A373(delGC)[H1,12]
L255S[H36,5]
W187X 364 .368(LLPLE)
R252W[H1,6,7,11]
E178G P366H
R252Q
D143G[H11] R176X L364[H5]
R252G[H7]
T124I R176L fs K363
L249F[H1]
W120X I174T S359X
G247V[H4]
P173T[H4] Y356X[H3,4,7,9]
E1,2del V245V[H3,4,6,17,28,#]
Q172X
V245E
T63PH64N R111X[H4] G171A
V245A T418P[H4]
E56D[H10] A104D[H1]
P244L[H12] D415N[H1]
fs F55[H1] I94[H2]
R243X[H4] Y414Y
L48S[H4,3] T92I H170R
R243Q[H4] Y414C[H4]
A47V S87R I164T
L242F R413P[H4]
G46S D84Y[H4] F161S[H4]
R241H[H5] R408Q[H4,12, #]
Q20X L41F R68S[H1] R158W[4]
R241C[H4] R408W[H1,2,5,34,41,44]
S16 fs S40L S67P[H4] R158Q[H4,16,28]
G239S fs P407(delC)
M1I[H7] F39 I65T[H1,5,9,21,B] Y154N
T238P[H4] A403V
11V[H2] F39L E3 del G148S[H1]
A447D

1 2 3 4 5 6 7 8 9 10 11 12 13

IVS1nt5 IVS2nt19 IVS4SA-1 IVS5nt1 IVS12nt1[H3]

IVS2nt6 IVS4SA-5 IVS6SA-2[H1?] IVS11nt1
IVS2nt5
IVS2nt1(delE2)[H7,42] IVS7nt5 IVS10nt556[H4]
IVS7nt2[H7] IVS10nt546[H6,10,34,36
IVS7nt1 IVS10nt3
IVS8nt1 IVS10nt1
44200_06_p185-226 3/1/04 3:16 PM Page 192
192
Figure 6-7
Representative
Components of protein active site
positions of mutant sites
and their functional Promoter
consequences. 5 3 Wild type
Exon
m2
Protein
m3
= mutant site
silent mutations that do not result in a defective protein,
and therefore produce the wild-type phenotype.
Many of the mutant alleles are of a type generally
called nulls: the proteins they encode completely lack PAH
function. Either there is no protein product or one exists
but is nonfunctional. Other mutant alleles produce pro-
teins showing some low residual function: these are called
leaky mutations. Hence it is a very powerful insight that
the reason people express disease symptoms (the disease
phenotype) is that they lack some key function that fits
into a crucial slot in the overall chemistry of the cell. The
same is true for mutations generally in any organismal-
tering the structure of a gene alters the function of its
product, generally producing a decreased or zero function.
The absence of a properly functioning protein disturbs cell
chemistry, ultimately yielding a mutant phenotype.
The PKU case also makes the point that multiple
alleles are possible at one locus. However, generally they
can be grouped into two main categories: the normally
functioning wild type, represented P or p, and all the
defective recessive mutations, null and leaky, repre-
sented as p. The complete set of known alleles of one
gene is called an allelic series.
6.2 Interactions between
the alleles of one gene
What happens when two different alleles are present in a
heterozygote? In many cases, one is expressed and the
other isnt. Formally, these responses are a type of interac-
tion we call dominance and recessiveness. We saw that
Chapter 6 From Gene to Phenotype
DNA
Intron
Exon
m1: null
m2: null
m3: null
m4: leaky
m5: silent
m6: null
Active site
m4
m5
PKU and many other single-gene diseases are recessive.
Some single-gene diseases such as achondroplasia are
dominant. What is the general explanation for dominance
and recessiveness in terms of gene products?
PKU is a good general model for recessive mutations.
The reason that a defective PAH allele is recessive is that
one dose of the wild-type allele P is sufficient to produce
wild-type phenotype. The PAH gene is said to be haplo-
sufficient. Hence both P/P (two doses) and P/p (one dose)
have enough PAH activity to result in the normal cellular
chemistry. Of course p/p individuals have zero doses of
PAH activity. Figure 6-8 illustrates this general notion.
How can we explain dominant mutations? There are
several molecular mechanisms for dominance, but a
common one is that the wild-type allele of a gene is
haploinsufficient. This means that one wild-type dose is
not enough to achieve normal levels of function. Assume
that 16 units of a genes product are needed for normal
chemistry, and that each wild-type allele can make 10
units. Two wild-type alleles will produce 20 units of
product, well over the minimum. A null mutation in
combination with a single wild-type allele would pro-
duce 10  0  10 units, well below the minimum.
Hence the heterozygote (wild type/null) is mutant, and
the mutation is by definition dominant.
MESSAGE Recessiveness of a mutant allele is generally
a result of haplosufficiency of the wild-type allele of that
gene. Dominance of a mutant allele is often a result of
haploinsufficiency of the wild-type allele of that particular
gene.
44200_06_p185-226 3/1/04 3:16 PM Page 193

6.2 Interactions between the alleles of one gene 193

Homozygous Heterozygote Homozygous

wild type recessive mutant
+ /+ + /m m /m

Protein Functional Functional Nonfunctional

mRNA

Chromosome
+ + m
+ m m
Chromosome

mRNA

Protein

Functional Nonfunctional Nonfunctional

Figure 6-8 Recessiveness of a mutant allele of a haplosufficient gene. In the heterozygote,

even though the mutated copy of the gene produces nonfunctional protein, the wild-type
copy generates enough functional protein to produce the wild-type phenotype.

The type of dominance we have just described is

Molecular allele interactions

called full, or complete, dominance. In cases of full

dominance, the homozygous dominant cannot be distin-
guished from the heterozygote; that is, A/A  A/a.
However, there are variations on this theme, as shown in
the next sections.
Incomplete dominance
Four-oclocks are plants native to tropical America. Their
name comes from the fact that their flowers open in the
late afternoon. When a pure-breeding wild-type four-o
www. ANIMATED ART

clock line with red petals is crossed with a pure line

with white petals, the F1 has pink petals. If an F2 is pro-
duced by selfing the F1, the result is
1
4 of the plants have red petals
1
2 of the plants have pink petals
1
4 of the plants have white petals
Figure 6-9 shows these phenotypes. From this 1 : 2 : 1 ra-
tio in the F2, we can deduce that the inheritance pattern
is based on two alleles of a single gene. However, the
heterozygotes (the F1 and half the F2) are intermediate
in phenotype. By inventing allele symbols, we can list Figure 6-9 Red, pink, and white phenotypes of four oclock
the genotypes of the four-oclocks in this experiment as plants. The pink heterozygote demonstrates incomplete
c/c(red), c/c (white), and c/c (pink). The occurrence dominance. [R. Calentine/Visuals Unlimited.]
44200_06_p185-226 3/1/04 3:16 PM Page 194

194 Chapter 6 From Gene to Phenotype

of the intermediate phenotype suggests an incomplete

dominance, the term used to describe the general case in
which the phenotype of a heterozygote is intermediate
between those of the two homozygotes, on some quanti-
tative scale of measurement.
How do we explain incomplete dominance at the
molecular level? In cases of incomplete dominance, each
wild-type allele generally produces a set dose of its protein
product. The number of doses of a wild-type allele deter-
mines the concentration of some chemical made by the
protein (such as pigment). Two doses produce the most
copies of transcript, hence the greatest amount of protein,
and hence the greatest amount of chemical. One dose pro-
duces less chemical, and a zero dose produces none.

Codominance
The human ABO blood groups are determined by three
alleles of one gene. These three alleles interact in several
ways to produce the four blood types of the ABO system.
The three major alleles are i, IA, and IB, but one person
can have only two of the three alleles or two copies of
one of them. The combinations result in six different
genotypes: the three homozygotes and three different
types of heterozygotes.
Genotype Blood type
A A A
I /I , I /i A cells including some sickled cells. In regard to the pres-
IB/IB, IB/i B ence or absence of anemia, the HbA allele is dominant.
IA/IB AB
i/i O to prevent anemia. In regard to blood-cell shape, how-
In this allelic series, the alleles determine the presence
and form of an antigen, a cell-surface molecule that can
be recognized by the immune system. The alleles IA and
IB determine two different forms of this antigen, which is
deposited on the surface of the red blood cells. However,
the allele i results in no antigenic protein of this type (it is
a null allele). In the genotypes IA/i and IB/i, the alleles IA
and IB are fully dominant to i. However, in the genotype
IA/IB, each of the alleles produces its own form of antigen,
so they are said to be codominant. Formally, codominance
is defined as the expression in a heterozygote of both the
phenotypes normally shown by the two alleles.
The human disease sickle-cell anemia is a source of an-
other interesting insight into dominance. The gene con-
cerned affects the molecule hemoglobin, which transports
oxygen and is the major constituent of red blood cells. The
three genotypes have different phenotypes, as follows:
HbA/HbA: Normal; red blood cells never sickle
HbS/HbS: Severe, often fatal anemia; abnormal
hemoglobin causes red blood cells to have
sickle shape
HBA/HbS: No anemia; red blood cells sickle only under
low oxygen concentrations
Figure 6-10 An electron micrograph of a sickle-shaped red
blood cell. Other, more rounded cells appear almost normal.
[Meckes/Ottawa/Photo Researchers.]
Figure 6-10 shows an electron micrograph of blood
A single HbA produces enough functioning hemoglobin
ever, there is incomplete dominance, as shown by the
fact that many of the cells have a slight sickle shape.
Finally, in regard to hemoglobin itself, there is codomi-
nance. The alleles HbA and HbS code for two different
forms of hemoglobin differing by a single amino acid,
and both these forms are synthesized in the heterozy-
gote. The A and S forms of hemoglobin can be sepa-
rated by electrophoresis, because it happens that they
have different charges (Figure 6-11). We see that ho-
mozygous normal people have one type of hemoglobin
(A) and anemics have another (type S), which moves
more slowly in the electric field. The heterozygotes
have both types, A and S. In other words, there is
codominance at the molecular level. The fascinating
population genetics of the HbA and HbS alleles will be
considered in Chapter 19.
Sickle-cell anemia illustrates that the terms domi-
nance, incomplete dominance, and codominance are some-
what arbitrary. The type of dominance inferred depends
on the phenotypic level at which the assay is made
organismal, cellular, or molecular. Indeed the same cau-
tion can be applied to many of the categories that scien-
tists use to classify structures and processes; these
categories are devised by humans for convenience of
analysis.
44200_06_p185-226 3/1/04 3:16 PM Page 195

6.2 Interactions between the alleles of one gene 195

Positions to
which hemo-
globins have Hemoglobin types
migrated present
Phenotype Genotype Origin
vv

Sickle-cell HbS / HbA S and A

trait
V lV l
Sickle-cell S S
Hb / Hb S
anemia

Normal HbA / HbA A

V hV h V lV h
Migration

Figure 6-11 Electrophoresis of normal and mutant

hemoglobins. Shown are hemoglobin from a heterozygote (with V fV f V lV f V hV f
sickle-cell trait), a person with sickle-cell anemia, and a
normal person. The smudges show the positions to which the
hemoglobins migrate on the starch gel.
V ba V ba V l V ba V h V ba V f V ba

MESSAGE The type of dominance is determined by

the molecular functions of the alleles of a gene and
by the investigative level of analysis. V bV b V lV b V hV b V fV b V ba V b

The leaves of clover plants show several variations

on the dominance theme. Clover is the common name
for plants of the genus Trifolium. There are many species.
Some are native to North America, whereas others grow
there as introduced weeds. Much genetic research has
been done with white clover, which shows considerable
variation among individuals in the curious V, or chevron,
pattern on the leaves. The different chevron forms (and
the absence of chevrons) are determined by a series of
alleles of one gene, as seen in Figure 6-12. The figure
shows the many different types of interactions that are
possible, even for one allele.
Recessive lethal alleles
Many mutant alleles are capable of causing the death of
an organism; such alleles are called lethal alleles. The
human disease alleles provide examples. A gene whose
mutations may be lethal is clearly an essential gene. The
ability to determine whether a gene is essential is an im-
portant aid to research on experimental organisms, espe-
cially when working on a gene of unknown function.
However, maintaining stocks bearing lethal alleles for
laboratory use is a challenge. In diploids, recessive lethal
alleles can be maintained as heterozygotes. In haploids,
heat-sensitive lethal alleles are useful. These are mem-
bers of a general class of temperature-sensitive (ts) mu-
tations. Their phenotype is wild type at the permissive
temperature (often room temperature), but mutant at
the restrictive temperature. Temperature-sensitive alleles
V by V by V l V by V h V by V f V by V ba V by V b V by
Figure 6-12 Multiple alleles determine the chevron pattern on
the leaves of white clover. The genotype of each plant is shown
below it. [After photograph by W. Ellis Davies.]
are thought to be caused by mutations that make the
protein prone to twist or bend its shape to an inactive
conformation at the restrictive temperature. Research
stocks can be maintained easily under permissive condi-
tions, and the mutant phenotype assayed by a switch to
the restrictive conditions.
A good example of a recessive lethal allele is an allele
of a coat color gene in mice (see Model Organism box on
page 196). Normal wild-type mice have coats with a
rather dark overall pigmentation. A mutation called
yellow (a lighter coat color) shows a curious inheritance
pattern. If any yellow mouse is mated to a homozygous
wild-type mouse, a 1 : 1 ratio of yellow to wild-type mice
is always observed in the progeny. This result suggests
that a yellow mouse is always heterozygous for the yel-
low allele and that the yellow allele is dominant to wild
type. However, if any two yellow mice are crossed with
each other, the result is always as follows:
2
yellow  yellow 9: 3 yellow, 13 wild type
44200_06_p185-226 3/1/04 3:16 PM Page 196

196 Chapter 6 From Gene to Phenotype

Figure 6-13 shows a typical litter from a cross between

yellow mice.
How can the 2 : 1 ratio be explained? The results
make sense if it is assumed that the yellow allele is lethal
when homozygous. It is known that the yellow allele is
of a coat-color gene called A. Lets call it AY. Hence the
results of crossing two yellow mice are

AY/A  AY/A
1
Progeny 4 AY/AY lethal
1
AY/A yellow Figure 6-13 A litter from a cross between two mice
2
heterozygous for the yellow coat-color allele. The allele is lethal
1
4 A/A wild type in a double dose. Not all progeny are visible. [Anthony Griffiths.]

MODEL ORGANISM Mouse

The laboratory mouse is descended from the house factory-sized building. Furthermore, although mice do
mouse Mus musculus. The pure lines used today as breed rapidly (compared with humans), they cannot
standards are derived from mice bred in past centuries compete with microorganisms for speedy life cycle.
by mouse fanciers. Among model organisms it is the Hence, the large-scale selections and screens necessary
one whose genome most closely resembles the human to detect rare genetic events are not possible.
genome. Its diploid chromosome number is 40 (com-
pared to 46 in humans), and the genome is slightly
smaller than that of humans (3000 Mb) and approxi-
mately the same number of genes (current estimates
about 30,000). Furthermore, it seems that all mouse
genes have a counterpart in humans. A large propor-
tion of genes are arranged in blocks in exactly the
same positions as those of humans.
Research on the Mendelian genetics of mice began
early in the twentieth century. One of the most im-
portant early contributions was the elucidation of the
genes that control coat color and pattern. Genetic
control of the mouse coat has provided a model for all
mammals, including cats, dogs, horses and cattle. Also
a great deal of work was done on mutations induced
by radiation and chemicals. Mouse genetics has been
of great significance in medicine. A large proportion of
human genetic diseases have a mouse counterpart use-
ful for experimental study (these are called mouse
models). The mouse has played a particularly impor-
tant role in the development of our current under-
standing of the genes underlying cancer.
The genome of mice can be modified by the inser-
tion of specific fragments of DNA into a fertilized egg
or into somatic cells. The mice in the photo at the
right have received a jellyfish gene for green fluores-
cent protein (GFP) that makes them glow green. Gene
knockouts and replacements are also possible. Green-glowing genetically modified mice embryos. The
A major limitation of mouse genetics is its cost. jellyfish gene for green fluorescent protein has been inserted
Whereas working with a million individuals of E. coli or into the chromosomes of the glowing mice. Normal mice are
S. cerevisiae is a trivial matter, a million mice requires a darker in the photo. [Kyodo News.]
44200_06_p185-226 3/1/04 3:16 PM Page 197
6.3 Interacting genes and proteins
Figure 6-14 Manx cat. A dominant allele causing taillessness
is lethal in the homozygous state. The phenotype of two eye
colors is unrelated to taillessness. [Gerard Lacz/NHPA.]
The expected monohybrid ratio of 1 : 2 : 1 would be
found among the zygotes, but it is altered to a 2 : 1 ratio
in the progeny actually seen at birth because zygotes
with a lethal AY/AY genotype do not survive to be
counted. This hypothesis is supported by the removal of
uteri from pregnant females of the yellow  yellow
cross; one-fourth of the embryos are found to be dead.
The AY allele produces effects on two characters:
coat color and survival. It is entirely possible, however,
that both effects of the AY allele result from the same
basic cause, which promotes yellowness of coat in a sin-
gle dose and death in a double dose.
The tailless Manx phenotype in cats (Figure 6-14)
also is produced by an allele that is lethal in the homo-
zygous state. A single dose of the Manx allele, ML, se-
verely interferes with normal spinal development, result-
ing in the absence of a tail in the ML/M heterozygote.
But in the ML/ML homozygote, the double dose of the
gene produces such an extreme abnormality in spinal
development that the embryo does not survive.
Whether an allele is lethal or not often depends on
the environment in which the organism develops.
Whereas certain alleles are lethal in virtually any envi-
ronment, others are viable in one environment but lethal
in another. Human hereditary diseases provide some ex-
amples. Cystic fibrosis and sickle-cell anemia are diseases
that would be lethal without treatment. Furthermore,
many of the alleles favored and selected by animal and
plant breeders would almost certainly be eliminated in
nature as a result of competition with the members of
the natural population. The dwarf mutant varieties of
grain, which are very high-yielding, provide good exam-
ples; only careful nurturing by farmers has maintained
such alleles for our benefit.
197
Geneticists commonly encounter situations in
which expected phenotypic ratios are consistently
skewed in one direction because one allele of a gene re-
duces viability. For example, in the cross A/a  a/a,
we predict a progeny ratio of 50 percent A/a and
50 percent a/a, but we might consistently observe a
ratio such as 55 percent : 45 percent or 60 percent :
40 percent. In such a case, the recessive allele is said to
be sublethal because the lethality is expressed in only
some of and not all the homozygous individuals. Thus,
lethality may range from 0 to 100 percent, depending
on the gene itself, the rest of the genome, and the
environment.
MESSAGE A gene can have several different states or
forms called multiple alleles. The alleles are said to
constitute an allelic series, and the members of a series can
show various degrees of dominance to one another.
6.3 Interacting genes
and proteins
One of the first indications that individual genes do not
act alone was the observation in the early 1900s that a
single gene mutation may have multiple effects. Even
though the impact of a mutation is seen mainly in the
character under investigation, many mutations produce
effects in other characters. (We just saw an example in
the yellow coat allele of mice. The allele affected both
coast color and chances of survival.) Such multiple ef-
fects are called pleiotropic effects. Some pleiotropic
effects can be subtle, but others quite strong. The inter-
pretation is that pleiotropy is based on the complexity
of gene interactions in the cell.
Lets reexamine PKU in light of the complexity of
genes interacting to produce a particular phenotype. The
simple model of PKU as a single-gene disease was ex-
tremely useful medically. Notably, it provided a success-
ful treatment and therapy for the disease simply re-
strict the dietary intake of phenylalanine. Many PKU
patients have benefited from this treatment. However,
there are some interesting complications that draw at-
tention to the underlying complexity of the genetic sys-
tem involved. For example, some cases of elevated
phenylalanine level and its symptoms are associated not
with the PAH locus, but with other genes. Also, some
people who have PKU and its associated elevated
phenylalanine level do not show abnormal cognitive de-
velopment. These apparent exceptions to the model
show that the expression of the symptoms of PKU de-
pends not only on the PAH locus, but also on many
other genes, and on the environment.
44200_06_p185-226 3/1/04 3:16 PM Page 198
198
This complex situation is summarized in simple
form in Figure 6-15. The figure shows that there are
many steps in the pathway leading from the ingestion of
phenylalanine to impaired cognitive development, and
any one of them can show variation. First, the amount of
phenylalanine in the diet is obviously of key importance.
Then the phenylalanine must be transported into the
appropriate sites in the liver, the chemical factory of
the body. In the liver, PAH must act in concert with its
cofactor, tetrahydrobiopterin. If excess phenylpyruvic
acid is produced, to affect cognitive development it
must be transported to the brain in the bloodstream, and
then pass through the blood-brain barrier. Inside the
brain, developmental processes must be susceptible to
the detrimental action of phenylpyruvic acid. Each of
these multiple steps is a possible site at which genetic or
environmental variation may be found. Hence what
seems to be a simple monogenic disease is actually de-
Phenylalanine
Food protein
Phenylalanine
hydroxylase
"PKU gene"
Figure 6-15 The determination of the disease PKU involves a complex series of steps.
The red rectangles indicate those steps where variation or blockage is possible.
Chapter 6 From Gene to Phenotype
pendent on a complex set of processes. The example
well illustrates the idea that individual genes do not de-
termine phenotype. We also see how exceptions to the
simple PKU model can be explained. For example, we
see how mutations in genes other than PAH can cause
elevated levels of phenylalanine a gene needed for
tetrahydrobiopterin synthesis is one such gene.
How experimental genetics
dissects complexity
There is a standard genetic methodology for identifying
the interacting genes that contribute to a particular bio-
logical property. Briefly, the approach is as follows:
Step 1. Treat cells with mutation-causing agents
(mutagens), such as ultraviolet radiation. This
treatment produces a large set of mutants with an
abnormal expression of the property under study.
Brain
development
Blood-brain
barrier
Phenylpyruvic acid
Liver
Normal
products
Tetrahydrobiopterin
(cofactor)
Genes in biosynthetic
pathways making THB
44200_06_p185-226 3/1/04 3:16 PM Page 199
6.3 Interacting genes and proteins
Step 2. Test these mutants to determine how many
gene loci are involved, and which mutations are
alleles of the same gene.
Step 3. Combine the mutations pairwise by means
of crosses to form double mutants to see if they
interact. Remember, gene interaction implies that
gene products interact in the cell. We will see that
classes of progeny appear in specific ratios, as with
the dihybrid crosses in Chapter 2. These ratios
provide a clue to the type of gene interaction.
Hence there are three steps: the mutant hunt; tests for
allelism; and tests for gene interaction. The techniques of
mutant induction and selection are dealt with in Chap-
ter 16. For the present, lets assume we have assembled a
set of single-gene mutations affecting some biological
property of interest. We now need to determine how
many genes are represented in that set (step 2), and this
is done using the complementation test.
Complementation
Lets illustrate the complementation test with an example
from harebell plants (genus Campanula). The wild-type
flower color of this plant is blue. Lets assume that by ap-
plying mutagenic radiation we have induced three white-
petaled mutants and that they are available as homozy-
gous pure-breeding strains. They all look the same, so we
do not know a priori whether they are genetically identi-
cal or not. We can call the mutant strains $, , and , to
avoid any symbolism using letters, which might imply
dominance. When crossed with wild type, each mutant
gives the same results in the F1 and F2, as follows:
white $  blue 9: F1, all blue 9: F2, 34 blue, 14 white
white  blue 9: F1, all blue 9: F2, 34 blue, 14 white
white  blue 9: F1, all blue 9: F2, 34 blue, 14 white
A harebell plant (Campanula species). [Gregory G. Dimijian/
Photo Researchers.]
199
In each case, the results show that the mutant condition
is determined by the recessive allele of a single gene.
However are they three alleles of one gene, or of two
genes, or of three genes? The question can be answered
by asking if the mutants complement one another. Com-
plementation is defined as the production of a wild-type
phenotype when two recessive mutant alleles are
brought together in the same cell.
MESSAGE Complementation is the production of a wild-
type phenotype when two haploid genomes bearing
different recessive mutations are united in the same cell.
In a diploid organism, the complementation test is
performed by intercrossing two individuals that are ho-
mozygous for different recessive mutants. The next step is
to observe whether the progeny have the wild-type phe-
notype. If recessive mutations are alleles of the same gene,
they will not produce wild-type progeny, because the
progeny are essentially homozygotes. Such alleles can be
thought of generally as a and a, using primes to distin-
guish between two different mutant alleles of a gene
whose wild-type allele is a. These alleles could have dif-
ferent mutant sites within the same gene, but they would
both be nonfunctional. The heterozygote a/a would be
a
a
However, two recessive mutations in different genes
would have wild-type function provided by the respec-
tive wild-type alleles. Here we can name the genes a1
and a2, after their mutant alleles. We can represent the
heterozygotes as follows, depending on whether the
genes are on the same or different chromosomes:
Different chromosomes
a1 1
1 a2
Same chromosome (shown in trans)
a1 1
1 a2
Let us return to the harebell example and intercross
the mutants to test for complementation. Assume that the
results of intercrossing mutants $, , and are as follows:
white $  white 9: F1, all white
white $  white 9: F1, all blue
white  white 9: F1, all blue
44200_06_p185-226 3/1/04 3:16 PM Page 200

200 Chapter 6 From Gene to Phenotype

Figure 6-16 The Wild type

molecular basis of genetic
complementation. Three
phenotypically identical white
mutants $, , and are
intercrossed. Mutations in the
same gene (such as $ and ) + +
cannot complement, because
the F1 has one gene with two
+ +
mutant alleles. The pathway
is blocked and the flowers are w1 w2
gene gene
white. When the mutations
are in different genes (such
as and ), complementation
of the wild-type alleles of Mutant "$" Mutant "" Mutant ""
each gene occurs in the F1
heterozygote. Pigment is
synthesized and the flowers
are blue. (What would you
predict to be the result of
crossing $ and ?) "$" + + + ""

"$" + + + ""
w1 w2 w1 w2 w1 w2
gene gene gene gene gene gene

P White $ White White White

F1

No
complementation Complementation
$ + +

+ +

Enzyme 1 Enzyme 2
No substrate Enzyme 2

Colorless No Colorless Colorless
White Blue
precursor 1 precursor 2 precursor 1 precursor 2

Block (no enzyme 1)

Mutation in the same gene Mutation in different genes

From this set of results, we can conclude that mutants $
and must be caused by alleles of one gene (say, w1)
because they do not complement; but must be caused
by a mutant allele of another gene (w2) because com-
plementation is seen.
How does complementation work at the molecular
level? The normal blue color of the harebell flower is
caused by a blue pigment called anthocyanin. Pigments
are chemicals that absorb certain parts of the visible
spectrum; in the case of the harebell, the anthocyanin
absorbs all wavelengths except blue, which is reflected
into the eye of the observer. However, this anthocyanin
is made from chemical precursors that are not pigments;
that is, they do not absorb light of any specific wave-
length and simply reflect back the white light of the sun
to the observer, giving a white appearance. The blue pig-
ment is the end product of a series of biochemical con-
versions of nonpigments. Each step is catalyzed by a spe-
44200_06_p185-226 3/1/04 3:16 PM Page 201

6.3 Interacting genes and proteins 201

cific enzyme encoded by a specific gene. We can explain take the intermediates to the final blue product. Their
the results with a pathway as follows: genotypes will be
w1/w1 w2/w2
gene w11 gene w21
Hence we see that complementation is actually a re-
sult of the cooperative interaction of the wild-type alleles
enzyme 1 enzyme 2 of the two genes. Figure 6-16 is a summary diagram of
the interaction of the complementing and noncomple-
precursor 1 precursor 2 blue anthocyanin menting white mutants.
In a haploid organism, the complementation test
A homozygous mutation in either of the genes will lead cannot be performed by intercrossing. In fungi, there is
to the accumulation of a precursor that will simply an alternative way to bring mutant alleles together to
make the plant white. Now the mutant designations test complementation: one makes a heterokaryon (Fig-
could be written as follows: ure 6-17). Fungal cells fuse readily. When two different
strains fuse, the haploid nuclei from the different
$ w1$ /w1$ w2/w2 strains occupy one cell, which is called a heterokaryon
w1 /w1 w2/w2 (Greek; different kernels). The nuclei in a hetero-
w1/w1 w2/w2 karyon generally do not fuse. In one sense, this condition
is a mimic diploid.
However, in practice, the subscript symbols would be Assume that in different strains there are mutations
dropped and the genotypes written as follows: in two different genes conferring the same mutant
phenotype for example, an arginine requirement. We
$ w1/w1 w2/w2 can call these genes arg-1 and arg-2. The genotypes of
w1/w1 w2/w2 the two strains can be represented as arg-1 arg-2 and
arg-1 arg-2. These two strains can be fused to form
w1/w1 w2/w2
a heterokaryon with the two nuclei in a common
cytoplasm:
Hence an F1 from $  will be
Nucleus 1 is arg-1 arg-2
w1/w1 w2 /w2  
Nucleus 2 is arg-1 arg-2

These F1 individuals will thus have two defective alleles
for w1 and will therefore be blocked at step 1. Even
though enzyme 2 is fully functional, it has no substrate
to act on, so no blue pigment will be produced and the
phenotype will be white.
The F1s from the other crosses, however, will have
the wild-type alleles for both the enzymes needed to
Because gene products are made in a common cyto-
plasm, the two wild-type alleles can exert their domi-
nant effect and cooperate to produce a heterokaryon of
wild-type phenotype. In other words, the two mutations
complement, just as they would in a diploid. If the mu-
tations had been alleles of the same gene, there would
have been no complementation.

arg-1 cells, defective for arg-2 cells, defective for

one specific enzyme in a different enzyme in
arginine synthetic pathway arginine synthetic pathway

Fusion

Heterokaryon grows
without arginine

Figure 6-17 Formation of a heterokaryon of Neurospora mimics a diploid state. When

vegetative cells fuse, haploid nuclei share the same cytoplasm in a heterokaryon. In this
example, haploid nuclei with mutations in different genes in the arginine synthetic pathway
complement to produce a Neurospora that no longer requires arginine.
44200_06_p185-226 3/1/04 3:16 PM Page 202

202 Chapter 6 From Gene to Phenotype

MESSAGE When two independently derived recessive Regulatory gene Gene for active protein
mutant alleles producing similar recessive phenotypes
fail to complement, the alleles must be of the same gene. r+ a+

(a)
Normal
A modified F2 ratio can be useful in supporting a hy-
pothesis of gene complementation. As an example, lets
consider what F2 ratio will result from crossing the dihy-
(b) r a+
brid F1 harebell plants. The F2 shows both blue and
Mutation in
white plants in a ratio of 9 : 7. How can these results be the gene that
explained? The 9 : 7 ratio is clearly a modification of the codes for the
regulatory Nonfunctional
dihybrid 9 : 3 : 3 : 1 ratio with the 3 : 3 : 1 combined to protein regulatory protein
make 7. The cross of the two white lines and subsequent
generations can be represented as follows: (c) r+ a
Mutation in
the gene that
w1/w1 ; w2/w2 (white)  w1/w1 ; w2/w2 (white) codes for the
s structural
p protein
F1 w1/w1 ; w2/w2 (blue) r a
w1/w1 ; w2/w2  w1/w1 ; w2/w2 (d)
s Mutation in
p both genes
F2 9 w1/ ; w2/ (blue) 9

3 w1 / ; w2/w2 (white)
3 w1/w1 ; w2/ (white)
1 w1/w1 ; w2/w2 (white)
7
 Figure 6-18 Interaction between a regulating gene and its
target. The r  gene codes for a regulatory protein, and the a
gene codes for a structural protein. Both must be normal for a
functional (active) structural protein to be synthesized.
The results show that a plant will have white petals if
it is homozygous for the recessive mutant allele of ei-
ther gene or both genes. To have the blue phenotype, a
plant must have at least one of the dominant allele of Functional a
both genes because both are needed to complement Proportion Genotype protein Ratio
each other and complete the sequential steps in the 9
16 r/ ; a/ Yes 9
pathway. Thus, three of the genotypic classes will pro-


3
duce the same phenotype, so overall only two pheno- 16 r/ ; a/a No
3
types result. 16 r/r ; a/ No 7
1
The example of complementation in harebells in- 16 r/r ; a/a No
volved different steps in a biochemical pathway. Simi-
lar results can come from gene regulation. A regulatory
gene often functions by producing a protein that binds An example of interacting genes from different
to a regulatory site upstream of the target gene, facili- pathways is the inheritance of skin coloration in corn
tating the transcription of the gene by RNA poly- snakes. The snakes natural color is a repeating black-
merase (Figure 6-18). In the absence of the regulatory and-orange camouflage pattern, as shown in Figure
protein, the target gene would be transcribed at very 6-19a. The phenotype is produced by two separate pig-
low levels, inadequate for cellular needs. Lets cross a ments, both of which are under genetic control. One
pure line r/r defective for the regulatory protein to a gene determines the orange pigment, and the alleles that
pure line a/a defective for the target protein. The cross we shall consider are o (presence of orange pigment)
is r/r ; a/a  r/r ; a/a. The r/r ; a/a dihybrid and o (absence of orange pigment). Another gene deter-
will show complementation between the mutant geno- mines the black pigment, with alleles b (presence of
types because both r and a are present, permitting black pigment) and b (absence of black pigment). These
normal transcription of the wild-type allele. When two genes are unlinked. The natural pattern is produced
selfed the F1 dihybrid will also result in a 9 : 7 pheno- by the genotype o/ ; b/. A snake that is o/o ; b/ is
typic ratio in the F2: black because it lacks orange pigment (Figure 6-19b),
44200_06_p185-226 3/2/04 2:57 PM Page 203

6.3 Interacting genes and proteins 203

Here, however, an F2 shows a standard 9 : 3 : 3 : 1 ratio:

female o/o ; b/b  male o/o ; b/b

(camouflaged) s (camouflaged)
p
F2 9 o/ ; b/ (camouflaged)
3 o/ ; b/b (orange)
3 o/o ; b/ (black)
1 o/o ; b/b (albino)

The 9 : 3 : 3 : 1 ratio is produced because of the indepen-

(a) (b)
dence of the interacting genes at the level of cellular
action:

b
precursor black pigment
o
camouflaged
precursor orange pigment

(c) (d)
Figure 6-19 Skin pigmentation patterns in the corn snake.
Combinations of orange and black pigments determine the four
phenotypes shown. (a) A wild-type black and orange camouflaged
snake synthesizes both black and orange pigments. (b) A black
snake does not synthesize orange pigment. (c) An orange snake
does not synthesize black pigment. (d) An albino snake
synthesizes neither black nor orange pigments.
[Anthony Griffiths.]
and a snake that is o/ ; b/b is orange because it lacks
the black pigment (Figure 6-19c). The double homozy-
gous recessive o/o ; b/b is albino (Figure 6-19d). Notice,
however, that the faint pink color of the albino is from
yet another pigment, the hemoglobin of the blood that
is visible through this snakes skin when the other pig-
ments are absent. The albino snake also clearly shows
that there is another element to the skin-pigmentation
pattern in addition to pigment: the repeating motif in
and around which pigment is deposited.
If a homozygous orange and a homozygous black
snake are crossed, the F1 is wild type (camouflaged),
demonstrating complementation:
female o/o ; b/b  male o/o ; b/b
(orange) s (black)
p
F1 o/o ; b/b
(camouflaged)
Epistasis
In trying to find evidence of gene interaction, one ap-
proach is to look for cases of a type of gene interaction
called epistasis. This word means stand upon, referring
to the ability of a mutation at one locus to override a
mutation at another in a double mutant. The overriding
mutation is called epistatic, whereas the overridden one
is hypostatic. Epistasis results from genes being in the
same cellular pathway. In the case of a simple biochemi-
cal pathway, the epistatic mutation is of a gene that is
farther upstream (earlier in the pathway) than that of
the hypostatic. The mutant phenotype of the upstream
gene takes precedence, no matter what is going on later
in the pathway.
Epistasis is difficult to screen for in any way other
than combining candidate mutations pairwise to form
double mutants. How is the double mutant identified?
In fungi, tetrad analysis is useful. For example an ascus
containing half its products as wild type must contain
double mutants. Consider the cross
a  b  a  b
A tetrad showing chance cosegregation of a and b (a
nonparental ditype ascus) would show the following
phenotypes:
wild type a b
wild type a  b
double mutant a  b
double mutant a  b
Hence the double mutant must be the non-wild-type
genotype.
44200_06_p185-226 3/1/04 3:16 PM Page 204

204 Chapter 6 From Gene to Phenotype

In diploids, the double mutant is more difficult to

identify, but ratios can help us identify epistasis. Lets
look at an example using petal pigment synthesis in the
plant blue-eyed Mary (Collinsia parviflora). From the
blue wild type, well start with two pure mutant lines,
one with white (w/w) and one with magenta petals Dihybrid w +/ w ; m + /m
(m/m). The w and m genes are not linked. The F1 and F2
are as follows:
Selfed

w/w ; m/m (white)  w/w ; m/m (magenta)

F1 w/w ; m/m (blue) 9
w + / ; m + / Both enzymes active
s 16
p w+ m+
w/w ; m/m  w/w ; m/m Enzyme 1 Enzyme 2 9
s
p
F2 9 w/ ; m/ (blue) 9
3 w/ ; m/m (magenta) 3 3
16
w + / ; m/m Blocked at second enzyme
3 w/w ; m/ (white)
1 w/w ; m/m (white)
4  w+
Enzyme 1 3

Complementation results in a wild-type F1. However, in

the F2, a 9 : 3 : 4 phenotypic ratio is produced. This ratio
is the mark of epistasis: the ratio tells us that the double 3
w/w ; m + / Blocked at first enzyme
16
mutant must be white, so white must be epistatic to ma- m+
genta. To find the double mutant for subsequent study,
Enzyme 2
white F2 individuals would have to be testcrossed.
At the cellular level, we can account for the epistasis No substrate
by the following type of pathway (see also Figure 6-20). 4
1
16
w/w ; m/m Blocked at first enzyme
gene w gene m
colorless magenta blue

MESSAGE Epistasis is inferred when a mutant allele
of one gene masks expression of alleles of another gene
and expresses its own phenotype instead.
Another case of recessive epistasis is the yellow
coat color of some Labrador retriever dogs. Two alleles,
B and b, stand for black and brown coats, respectively.
The two alleles produce black and brown melanin. The
allele e of another gene is epistatic on these alleles, giv-
ing a yellow coat (Figure 6-21). Therefore the geno-
types B/ ; e/e and b/b ; e/e both produce a yellow
phenotype, whereas B/ ; E/ and b/b ; E/ are black
and brown, respectively. This case of epistasis is not
caused by an upstream block in a pathway leading to
dark pigment. Yellow dogs can make black or brown
pigment, as can be seen in their noses and lips. The
action of the allele e is to prevent deposition of the pig-
ment in hairs. In this case, the epistatic gene is develop-
mentally downstream; it represents a kind of devel-
opmental target that has to be of E genotype before
pigment can be deposited.
Figure 6-20 A molecular mechanism for recessive epistasis.
Wild-type alleles of two genes (w  and m) encode enzymes
catalyzing successive steps in the synthesis of a blue petal
pigment. Homozygous m /m plants produce magenta flowers
and homozygous w/w plants produce white flowers. The
double mutant w /w ; m /m also produces white flowers,
indicating that white is epistatic to magenta.
MESSAGE Epistasis points to interaction of genes in
some biochemical or developmental sequence.
Suppressors
A type of gene interaction that can be detected more
easily is suppression. A suppressor is a mutant allele of
one gene that reverses the effect of a mutation of an-
other gene, resulting in a wild-type or near wild-type
phenotype. For example, assume that an allele a pro-
duces the normal phenotype, whereas a recessive mu-
tant allele a results in abnormality. A recessive mutant
44200_06_p185-226 3/1/04 3:16 PM Page 205
6.3 Interacting genes and proteins
(a) (b)
Figure 6-21 Coat-color inheritance in Labrador retrievers. Two alleles B and b of a pigment
gene determine (a) black and (b) brown, respectively. At a separate gene, E allows color
deposition in the coat, and e/e prevents deposition, resulting in (c) the gold phenotype.
This is a case of recessive epistasis. [Anthony Griffiths.]
allele s at another gene suppresses the effect of a, so that
the genotype a/a s/s will have wild-type (a-like) phe-
notype. Suppressor alleles sometimes have no effect in
the absence of the other mutation; in such a case, the
phenotype of a/a s/s would be wild type. In other
cases, the suppressor allele produces its own abnormal
phenotype.
Again, a genetic interaction (suppression) implies
that gene products interact somehow, as well, so sup-
pressors are useful in revealing such interactions.
Screening for suppressors is quite straightforward. Start
with a mutant in some process of interest, expose this
mutant to mutation-causing agents such as high-energy
radiation, and screen the descendants for wild types. In
haploids such as fungi, screening is accomplished by
simply plating mutagenized cells and looking for
colonies with wild-type phenotypes. Many wild types
arising in this way are merely reversals of the original
mutational event; these are called revertants. However,
many will be double mutants, in which one of the mu-
tations is a suppressor. Revertant and suppressed states
can be distinguished by appropriate crossing. For exam-
ple in yeast, the two results would be distinguished as
follows:
Revertant a  standard wild type a
Progeny all a
Suppressed mutant a s  standard wild type a s
Progeny a s wild type
a s wild type
a s original mutant
a s wild type (suppressed)
The appearance of the original mutant phenotype iden-
tifies the parent as a suppressed mutant.
205
(c)
In diploids, suppressors produce specific F2 ratios,
which are useful in confirming suppression. Lets look at
a real-life example from Drosophila. The recessive allele
pd will result in purple eye color when unsuppressed.
A recessive allele su has no detectable phenotype itself,
but suppresses the unlinked recessive allele pd. Hence
pd/pd ; su/su is wildtype in appearance and has red
eyes. The following analysis illustrates the inheritance
pattern. A homozygous purple-eyed fly is crossed to a
homozygous red-eyed stock carrying the suppressor.
pd/pd ; su/su (purple)  pd/pd ; su/su (red)
s
p
F1 all pd/pd ; su/su (red)
pd/pd ; su/su (red)  pd/pd ; su/su (red)
s
p

F2 9 pd/ ; su/ red
3 pd/ ; su/su red 13
1 pd/pd ; su/su red
3 pd/pd ; su/ purple 3
The overall ratio in the F2 is 13 red : 3 purple. This ratio
is characteristic of a recessive suppressor acting on a
recessive mutation. Both recessive and dominant sup-
pressors are found, and they can act on recessive or
dominant mutations. These possibilities result in a vari-
ety of different phenotypic ratios.
Suppression is sometimes confused with epistasis.
However, the key difference is that a suppressor cancels
the expression of a mutant allele and restores the corre-
sponding wild-type phenotype. The modified ratio is an
indicator of this type of interaction. Furthermore, often
only two phenotypes segregate (as in the preceding ex-
amples), not three, as in epistasis.
44200_06_p185-226 3/1/04 3:16 PM Page 206

206 Chapter 6 From Gene to Phenotype

m+ s+ Modifiers
Wild As the name suggests, a modifier mutation at a second
type Active protein locus changes the expression of a mutated gene at a first.
complex Regulatory genes provide a simple illustration. As we
saw in an earlier example, regulatory proteins bind to
m s+ the sequence of the DNA upstream to the start site for
First transcription. These proteins regulate the level of tran-
mutation scription. In the discussion of complementation we con-
Inactive
sidered a null mutation of a regulatory gene that almost
completely prevented transcription. However, some reg-
m s ulatory mutations change the level of transcription of
Second
mutation
the target gene so that more or less protein is produced.
acting as Active protein In other words, a mutation in a regulatory protein can
suppressor complex downregulate or upregulate the transcribed gene.
Lets look at an example using a downregulating regula-
m+ s tory mutation b, affecting a gene A in a fungus such as
Suppressor yeast. We make a cross of a leaky mutation a, to the reg-
mutation ulatory mutation b:
alone Inactive
leaky mutant a b  inefficient regulator a b

Figure 6-22 A molecular mechanism for suppression. Progeny Phenotype

How do suppressors work at the molecular level?
There are many possible mechanisms. A particularly use-
ful type of suppression is based on the physical binding
of gene products in the cell, for example protein-protein
binding, as in the case of protein machines. Two proteins
normally fit together to provide some type of cellular
function. When a mutation causes a shape change in one
protein, it no longer fits together with the other, and
hence the function is lost (Figure 6-22). However, a sup-
pressor mutation that causes a compensatory shape
change in the second protein can restore fit and hence
normal function. In this way, the interacting proteins of
cellular machines can be pieced together.
Alternatively, in situations in which a mutation
causes a block in a metabolic pathway, the suppressor
finds some way of bypassing the block for example, by
rerouting into the blocked pathway intermediates simi-
lar to those beyond the block. In the following example,
the suppressor provides an intermediate B to circumvent
the block.
No suppressor
A B product
With suppressor
A B product
B leaky mutation in a different step, the whole pathway
MESSAGE Suppressors cancel the expression of a
mutant allele of another gene, resulting in normal wild-
type phenotype.
a b wildtype
a b defective (low transcription)
a b defective (defective protein A)
a b extremely defective (low transcription of
defective protein)
Hence the action of the modifier is seen in the appear-
ance of two grades of mutant phenotypes within the a
progeny.
Synthetic lethals
In some cases, when two viable single mutants are inter-
crossed, the resulting double mutants are lethal. These
synthetic lethals can be considered a special category of
gene interaction. They can point to specific types of in-
teractions of gene products. For instance, genome analy-
sis has revealed that evolution has produced many du-
plicate systems within the cell. One advantage of these
duplicates might be to provide backups. If there are
null mutations in genes in both duplicate systems, then a
faulty system will have no backup, and the individual
will lack essential function and die. In another instance, a
leaky mutation in one step of a pathway may cause the
pathway to slow down, but leave enough function for
life. However, if double mutants combine, each with a
grinds to a halt. One version of the latter interaction is
two mutations in a protein machine, as shown in
Figure 6-23.
Building a protein machine is partly a matter of con-
stituent proteins finding each other by random molecu-
44200_06_p185-226 3/1/04 3:16 PM Page 207

6.3 Interacting genes and proteins 207

may show a range of phenotypes depending on the

A+ B+ Wild type environment. It is possible that the range of pheno-
full binding; types for mutant and wild-type individuals will
fully functioned overlap: the phenotype of a mutant individual raised
DNA in one set of circumstances may match the pheno-
type of a wild-type individual raised in a separate set
of circumstances. Should this happen, it becomes
A B+ Mutant A impossible to distinguish mutant from wild type.
partial binding;
functional 2. The influence of other genes. Modifiers, epistatic
genes, or suppressors in the rest of the genome may
act to prevent the expression of the typical
phenotype.
Mutant B
A+ B partial binding;
functional
Catalytic
assembly factor

Membrane,
Double mutant protein filament,
A B binding impossible; or nucleic acid
nonfunctional

ATP

Figure 6-23 One genetic mechanism for the origin of synthetic

lethality. Two interacting proteins perform some essential P
function on some substrate such as DNA, but must first bind
to it. Reduced binding of either protein allows some functions
to remain, but reduced binding of both is lethal.

lar motion and binding through complementary shape. P

However, some steps in assembly require energy and en-
zymes. Such an example is shown in Figure 6-24. Any of
these interacting components, whether machine compo-
nents or associated enzymes, can be dissected by analysis
of synthetic lethals.

Penetrance and expressivity

P Very tight
In the preceding examples, the dependence of one gene complex
on another is deduced from clear genetic ratios. In such
cases, we can use the phenotype to distinguish mutant
and wild-type genotypes with 100 percent certainty. In
these cases, we say that the mutation is 100 percent P1
penetrant. However, many mutations show incomplete
penetrance: not every individual with the genotype ex-
presses the corresponding phenotype. Thus penetrance is
defined as the percentage of individuals with a given allele
who exhibit the phenotype associated with that allele.
Why would an organism have a particular genotype
and yet not express the corresponding phenotype? There Figure 6-24 Building a protein machine. Phosphorylation
are several possible reasons: activates an assembly factor, enabling protein machines to be
assembled in situ on a membrane, filament, or nucleic acid.
1. The influence of the environment. We saw in [B. Alberts, The Cell as a Collection of Protein Machines, Cell, 92,
Chapter 1 that individuals with the same genotype 1998, 291 294.]
44200_06_p185-226 3/1/04 3:16 PM Page 208

208 Chapter 6 From Gene to Phenotype

Phenotypic expression
(each oval represents an individual)

Variable penetrance

1 2

Variable expressivity

Variable penetrance and expressivity

Figure 6-25 Pigment intensity as an example of penetrance 3 4

and expressivity. Assume that all the individuals shown have
the same pigment allele (P ) and possess the same potential
to produce pigment. Effects from the rest of the genome
and the environment may suppress or modify pigment
production in any one individual. The color reflects the level
of expression.

3. The subtlety of the mutant phenotype. The subtle 5 6

effects brought about by the absence of a gene
function may be difficult to measure in a laboratory
situation.

Another measure for describing the range of pheno-

typic expression is called expressivity. Expressivity mea-
sures the degree to which a given allele is expressed at
7 8
the phenotypic level; that is, expressivity measures the
intensity of the phenotype. For example, brown ani-
mals (genotype b/b) from different stocks might show
very different intensities of brown pigment from light to
dark. Different degrees of expression in different indi-
viduals may be due to variation in the allelic constitu-
tion of the rest of the genome or to environmental fac-
tors. Figure 6-25 illustrates the distinction between 9 10
penetrance and expressivity. Like penetrance, expressiv-
ity is integral to the concept of the norm of reaction. An
example of variable expressivity in dogs is found in Fig- Figure 6-26 Variable expressivity shown by 10 grades of piebald
ure 6-26. spotting in beagles. Each of these dogs has S P, the allele
The phenomena of incomplete penetrance and responsible for piebald spots in dogs. [After Clarence C. Little,
variable expressivity can make any kind of genetic The Inheritance of Coat Color in Dogs. Cornell University Press, 1957;
analysis substantially more difficult, including human and Giorgio Schreiber, Journal of Heredity 9, 1930, 403.]
pedigree analysis and predictions in genetic counseling.
For example, it is often the case that a disease-causing
allele is not fully penetrant. Thus someone could have Figure 6-27 Pedigree for a
dominant allele that is not fully
the allele but not show any signs of the disease. If that
penetrant. Individual Q does not
is the case, it is difficult to give a clean genetic bill of display the phenotype but passed
health to any individual in a disease pedigree (for ex- the dominant allele to at least two
Q
ample, individual R in Figure 6-27). On the other hand, progeny. Since the allele is not fully
pedigree analysis can sometimes identify individuals who penetrant, the other progeny (for
do not express but almost certainly do have a disease R example, R) may or may not have
genotype (for example, individual Q in Figure 6-27). inherited the dominant allele.
44200_06_p185-226 3/1/04 3:16 PM Page 209

6.4 Applications of chi-square ( 2) test to gene interaction ratios 209

Similarly, variable expressivity can complicate counsel- Recall that the general formula for calculating  2 is
ing because individuals with low expressivity might be
misdiagnosed.  2  (O  E)2/E for all classes

MESSAGE The terms penetrance and expressivity For hypothesis 1, the calculation is as follows:
quantify the modification of gene expression by varying
environment and genetic background; they measure, O E (O  E)2 (O  E)2/E
respectively, the percentage of cases in which the gene is
expressed and the level of expression. orange 182 160 484 3.0
yellow 61 80 361 4.5
red 77 80 9 0.1
6.4 Applications of chi-square  2  7.6
( 2) test to gene interaction ratios
To convert the  2 value into a probability, we use Table
Often, the observed ratios of some specific gene interac-
2-2, page 000, which shows  2 values for different de-
tion dont conform precisely to those expected. The ge-
grees of freedom (df ). In this case, there are two degrees
neticist uses the  2 test to decide if the ratios are close
of freedom. Looking along the 2-df line, we find that the
enough to the expected results to indicate the presence
 2 value places the probability at less than .025, or 2.5
of the suspected interaction. Lets look at an example.
percent. This means that, if the hypothesis is true, then
We cross two pure lines of plants, one with yellow petals
deviations from expectations this large or larger are ex-
and one with red. The F1 are all orange. When the F1 is
pected approximately 2.5 percent of the time. As men-
selfed to give an F2, we find the following result:
tioned earlier, by convention the 5 percent level is used
orange 182 as the cutoff line. When values of less than 5 percent are
yellow 61 obtained, the hypothesis is rejected as being too un-
red 77 likely. Hence the incomplete dominance hypothesis
Total 320 must be rejected.
For hypothesis 2, the calculation is set up as follows:
What hypothesis can we invent to explain the results?
There are at least two possibilities: O E (O  E)2 (O  E)2/E
Hypothesis 1: Incomplete dominance orange 182 180 4 0.02
G1/G1 (yellow)  G2/G2 (red) yellow 61 60 1 0.02
s red 77 80 9 0.11
p  2  0.15
F1 G1/G2 (orange)

Expected numbers The probability value (for 2 df) this time is greater than
1 1 1
F2 4 G /G (yellow) 80 .9, or 90 percent. Hence a deviation this large or larger is
1 expected approximately 90 percent of the time in
2 G1/G2 (orange) 160 other words, very frequently. Formally, because 90 per-
1
G2/G2 (red) 80 cent is greater than 5 percent, we conclude that the re-
4
sults uphold the hypothesis of recessive epistasis.
Hypothesis 2: Recessive epistasis of r (red)
on Y (orange) and y (yellow)
y/y ; R/R (yellow)  Y/Y ; r/r (red)
s
p
F1 Y/y ; R/r (orange)

Expected numbers
9
F2 16 Y/ ; R/ (yellow) 180
3
16 y/y ; R/ (orange) 60


3
16 Y/ ; r/r (red)
80
1
16 y/y ; r/r (red)
44200_06_p185-226 3/1/04 3:16 PM Page 210
210
KEY QUESTIONS REVISITED
How do individual genes exert their effect on an
organisms makeup?
Each gene is part of a set of genes needed to produce a
certain property during development. These genes inter-
act with the environment, which provides signals, nutri-
ents, and various other necessary conditions.
In the cell, do genes act directly or through some sort
of gene product?
Through their gene products.
What is the nature of gene products?
For most genes the product is a polypeptide (a single-
chain protein), but some genes have functional RNA as
their final product, and this RNA is never translated into
protein.
What do gene products do?
They control cellular chemistry. The best example is en-
zymes, which catalyze reactions that would otherwise
occur far too slowly.
Is it correct to say that an allele of a gene determines
a specific phenotype?
No, a gene is but a single part of the set of genes neces-
SUMMARY
Genes act through their products, in most cases proteins,
but in some cases functional (and untranslated) RNA.
Mutations in genes may alter the function of these prod-
ucts, producing a change in phenotype. Mutations are
changes in the DNA sequence of a gene. These can be of
a variety of types and occupy many different positions, re-
sulting in multiple alleles. Recessive mutations are often a
result of haplosufficiency of the wild-type allele, whereas
dominant mutations are often the result of the haploin-
sufficiency of the wild type. Some homozygous mutations
cause severe effects or even death (lethal mutations).
Although it is possible by genetic analysis to isolate a
single gene whose alleles dictate two alternative pheno-
types for one character, this gene does not control that
character by itself; the gene must interact with many
other genes in the genome and the environment. Genetic
dissection of complexity begins by amassing mutants af-
fecting a character of interest. The complementation test
decides if two separate recessive mutations are of one
gene or of two different genes. The mutant genotypes are
brought together in an F1 individual, and if the phenotype
is mutant, then no complementation has occurred and
the two alleles must be of the same gene. If complemen-
tation is observed, the alleles must be of different genes.
Chapter 6 From Gene to Phenotype
sary to produce a particular phenotype. Variants of a
single gene can produce phenotypic variants, but even
here they rely on all the other genes and on the envi-
ronment.
In what way or ways do genes interact at the cellular
level?
Some important ways are by producing separate compo-
nents for the same pathway, by regulating one another,
and by producing components of multimolecular assem-
blies (machines).
How is it possible to dissect complex gene interaction
using a mutational approach?
Mutants affecting one specific character of interest are
assembled, grouped into genes using the complementa-
tion test, and then paired to produce double mutation,
which might reveal interactive effects. Suppressors can
be screened directly.
The interaction of different genes can be detected
by testing double mutants, because allele interaction
implies interaction of gene products at the functional
level. Some key types of interaction are epistasis, sup-
pression, and synthetic lethality. Epistasis is the re-
placement of a mutant phenotype produced by one
mutation with a mutant phenotype produced by muta-
tion of another gene. The observation of epistasis sug-
gests a common pathway. A suppressor is a mutation of
one gene that can restore wild-type phenotype to a
mutation at another gene. Suppressors often reveal
physically interacting proteins or nucleic acids. Some
combinations of viable mutants are lethal, a result
known as synthetic lethality. Synthetic lethals can reveal
a variety of interactions, depending on the nature of
the mutations.
The different types of gene interactions produce F2
dihybrid ratios that are modifications of the standard
9 : 3 : 3 : 1. For example, recessive epistasis results in a
9 : 3 : 4 ratio.
An observed modified phenotypic ratio can be as-
sessed against that expected from a specific hypothesis
of gene interaction by using the chi-square test.
44200_06_p185-226 3/1/04 3:16 PM Page 211

Solved problems 211

KEY TERMS
allelic series (p. 000) haploinsufficient (p. 000) one-gene one protein
haplosufficient (p. 000) hypothesis (p. 000)
codominant (p. 000)
heterokaryon (p. 000) penetrance (p. 000)
complementation test (p. 000)
incomplete dominance (p. 000) permissive temperature (p. 000)
double mutants (p. 000)
leaky (p. 000) pleiotropic effects (p. 000)
epistasis (p. 000)
lethal allele (p. 000) restrictive temperature (p. 000)
expressivity (p. 000) revertants (p. 000)
multiple alleles (p. 000)
full, or complete, dominance nulls (p. 000) synthetic lethal (p. 000)
(p. 000)
one-gene one-polypeptide temperature-sensitive (ts)
functional RNAs (p. 000) hypothesis (p. 000) mutations (p. 000)

SOLVED PROBLEMS
1. Most pedigrees show polydactyly (see Figure 2-18)
to be inherited as a rare autosomal dominant, but
the pedigrees of some families do not fully conform
to the patterns expected for such inheritance. Such
a pedigree is shown below. (The unshaded diamonds
stand for the specified number of unaffected persons
of unknown sex.)

I
1 2

II
1 2 3 4 5 6 7 8 9 10 11

III 4
5 6 7 8 9 10 11 12 13 14 15 16 17

IV 4
5 6 7 8 9

a. What irregularity does this pedigree show?
b. What genetic phenomenon does this pedigree
illustrate?
c. Suggest a specific gene interaction mechanism
that could produce such a pedigree, showing geno-
types of pertinent family members.
Solution
a. The normal expectation for an autosomal dominant is
for each affected individual to have an affected parent,
but this expectation is not seen in this pedigree, which
constitutes the irregularity. What are some possible
explanations?
Could some cases of polydactyly be caused by a
different gene, one that is an X-linked dominant? This
suggestion is not useful, because we still have to explain
the absence of the condition in persons II-6 and II-10.
Furthermore, postulating recessive inheritance, whether
autosomal or sex-linked, requires many people in the pedi-
gree to be heterozygotes, which is inappropriate because
polydactyly is a rare condition.
b. Thus we are left with the conclusion that poly-
dactyly must sometimes be incompletely penetrant.
We have learned in this chapter that some individuals
who have the genotype for a particular phenotype do
not express it. In this pedigree, II-6 and II-10 seem to
44200_06_p185-226 3/1/04 3:16 PM Page 212

212 Chapter 6 From Gene to Phenotype

belong in this category; they must carry the polydactyly Cross Parents Progeny
gene inherited from I-1 because they transmit it to
1 blue  green all blue
their progeny. 3 1
c. We have seen in the chapter that environmental 2 blue  blue 4 blue : 4 turquoise
3 1
suppression of gene expression can cause incomplete 3 green  green 4 green : 4 turquoise
1 1
penetrance, as can suppression by another gene. To give 4 blue  turquoise 2 blue : 2 turquoise
the requested genetic explanation, we must come up 5 blue  blue 3 1
4 blue : 4 green
with a genetic hypothesis. What do we need to ex- 6 blue  green 1 1
2 blue : 2 green
plain? The key is that I-1 passes the gene on to two 1 1
7 blue  green 2 blue : 4 green
types of progeny, represented by II-1, who expresses 1
the gene, and by II-6 and II-10, who do not. (From the 4 turquoise

pedigree, we cannot tell whether the other children of 8 turquoise  turquoise all turquoise
I-1 have the gene.) Is genetic suppression at work? I-1
does not have a suppressor allele, because he expresses
polydactyly. So the only person from whom a suppres- a. Deduce the genetic basis of wing-cover color in
sor could come is I-2. Furthermore, I-2 must be het- this species.
erozygous for the suppressor gene because at least one
b. Write the genotypes of all parents and progeny as
of her children does express polydactyly. We have thus
completely as possible.
formulated the hypothesis that the mating in genera-
tion I must have been
Solution
(I-1) P/p s/s  (I-2) p/p S/s a. These data seem complex at first, but the inheritance
pattern becomes clear if we consider the crosses one at a
where S is the suppressor and P is the allele responsible time. A general principle of solving such problems, as we
for polydactyly. From this hypothesis, we predict that have seen, is to begin by looking over all the crosses and
the progeny will comprise the following four types if the by grouping the data to bring out the patterns.
genes assort: One clue that emerges from an overview of the data
is that all the ratios are one-gene ratios: there is no evi-
Genotype Phenotype Example dence of two separate genes taking part at all. How can
such variation be explained with a single gene? The an-
P/p S/s normal (suppressed) II-6, II-10 swer is that there is variation for the single gene itself
P/p s/s polydactylous II-1 that is, multiple allelism. Perhaps there are three alleles
p/p S/s normal of one gene; lets call the gene w (for wing-cover color)
p/p s/s normal and represent the alleles as w g, w b, and w t. Now we have
an additional problem, which is to determine the domi-
nance of these alleles.
If S is rare, the matings of II-6 and II-10 are probably
Cross 1 tells us something about dominance because
giving
the progeny of a blue  green cross are all blue; hence,
Progeny genotype Example blue appears to be dominant to green. This conclusion is
supported by cross 5, because the green determinant
P/p S/s III-13 must have been present in the parental stock to appear
P/p s/s III-8 in the progeny. Cross 3 informs us about the turquoise
p/p S/s determinants, which must have been present, although
p/p s/s unexpressed, in the parental stock because there are
turquoise wing covers in the progeny. So green must be
dominant to turquoise. Hence, we have formed a model
We cannot rule out the possibilities that II-2 and II-4
in which the dominance is w b
w g
w t. Indeed, the
have the genotype P/p S/s and that by chance none of
inferred position of the w t allele at the bottom of the
their descendants are affected.
dominance series is supported by the results of cross 7,
2. Beetles of a certain species may have green, blue, or where turquoise shows up in the progeny of a
turquoise wing covers. Virgin beetles were selected blue  green cross.
from a polymorphic laboratory population and mated b. Now it is just a matter of deducing the specific geno-
to determine the inheritance of wing-cover color. types. Notice that the question states that the parents
The crosses and results were as given in the follow- were taken from a polymorphic population; this means
ing table: that they could be either homozygous or heterozygous.
44200_06_p185-226 3/1/04 3:16 PM Page 213

Solved problems 213

A parent with blue wing covers, for example, might be
homozygous (w b/w b) or heterozygous (w b/w g or w b/w t).
Here, a little trial and error and common sense are called
for, but by this stage the question has essentially been
answered, and all that remains is to cross the ts and dot
the is. The following genotypes explain the results. A
dash indicates that the genotype may be either homozy-
gous or heterozygous in having a second allele farther
down the allelic series.
gives F2 numbers appropriate for a modified dihybrid
Mendelian ratio, so it looks as if we are dealing with a
two-gene interaction. This seems the most promising
place to start; we can go back to crosses 1 and 2 and try
to fit them in later.
Any dihybrid ratio is based on the phenotypic pro-
portions 9 : 3 : 3 : 1. Our observed modification groups
them as follows:

Cross Parents Progeny

9 A/ ; B/
3 A/ ; b/b  12 piping
1 w b/w b  wg/ wb/wg or wb/ 3 a/a ; B/ 3 spiny tip
3 b 1 1 a/a ; b/b 1 spiny
2 w b/w t  wb/wt t
4 w /: 4 w /w
t
3 g 1
3 w g/w t  wg/wt t
4 w /: 4 w /w
t
1 b
So without worrying about the name of the type of gene
t 1
4 w b/w t  wt/wt t
2 w /w : 2 w /w
t
interaction (we are not asked to supply this anyway), we
3 b 1
5 w b/w g  wb/wg g
4 w /: 4 w /w
g
can already define our three pineapple-leaf phenotypes
1 b g 1
6 w b/w g  wg/wg 2 w /w : 2 w /w
g g in relation to the proposed allelic pairs A/a and B/b:
1 b 1 t 1
7 w b/w t  wg/wt g t
2 w /: 4 w /w : 4 w /w
t
piping  A/ (B/b irrelevant)
8 w t/w t  wt/wt all wt/wt
spiny tip  a/a ; B/
spiny  a/a ; b/b
3. The leaves of pineapples can be classified into three
types: spiny (S), spiny tip (ST), and piping (non- What about the parents of cross 3? The spiny parent
spiny; P). In crosses between pure strains followed by must be a/a ; b/b, and because the B gene is needed to
intercrosses of the F1, the following results appeared: produce F2 spiny-tip individuals, the piping parent must
be A/A ; B/B. (Note that we are told that all parents are
Phenotypes pure, or homozygous.) The F1 must therefore be
A/a ; B/b.
Cross Parental F1 F2
Without further thought, we can write out cross 1
1 ST  S ST 99 ST: 34 S as follows:
2 P  ST P 120 P : 39 ST
3 P  S P 95 P : 25 ST: 8 S a/a ; B/B  a/a ; b/b
3
4 a/a ; B/
a/a ; B/b
a. Assign gene symbols. Explain these results in re- 1
a/a ; b/b
4
gard to the genotypes produced and their ratios.
b. Using the model from part a, give the phenotypic Cross 2 can be partly written out without further
ratios that you would expect if you crossed (1) the thought by using our arbitrary gene symbols:
F1 progeny from piping  spiny with the spiny
parental stock and (2) the F1 progeny of pipin  A/A ; /  a/a ; B/B
spiny with the F1 progeny of spin  spiny tip. 3
4 A/ ; /
A/a ; B/
1
Solution 4 a/a ; B/
a. First, lets look at the F2 ratios. We have clear 3 : 1 ra-
tios in crosses 1 and 2, indicating single-gene segrega- We know that the F2 of cross 2 shows single-gene segre-
tions. Cross 3, however, shows a ratio that is almost cer- gation, and it seems certain now that the A/a allelic pair
tainly a 12 : 3 : 1 ratio. How do we know this? Well, there has a role. But the B allele is needed to produce the
are simply not that many complex ratios in genetics, and spiny tip phenotype, so all individuals must be homozy-
trial and error brings us to the 12 : 3 : 1 quite quickly. In gous B/B:
the 128 progeny total, the numbers of 96 : 24 : 8 are ex-
pected, but the actual numbers fit these expectations re- A/A ; B/B  a/a ; B/B
3
markably well. 4 A/ ; B/B
One of the principles of this chapter is that modi- A/a ; B/B
1
fied Mendelian ratios reveal gene interactions. Cross 3 4 a/a ; B/B
44200_06_p185-226 3/1/04 3:16 PM Page 214

214 Chapter 6 From Gene to Phenotype

Notice that the two single-gene segregations in crosses 1 (2) A/a ; B/b  a/a ; B/b
and 2 do not show that the genes are not interacting. 3
B/
3
4 8
What is shown is that the two-gene interaction is not re- 1
A/a
1
piping
2 2
vealed by these crosses only by cross 3, in which the F1 1
b/b
1
4 8
is heterozygous for both genes.
3 3
b. Now it is simply a matter of using Mendels laws to 4 B/ 8 spiny tip
1
predict cross outcomes: 2
a/a
1 1
4 b/b 8 spiny
(1) A/a ; B/b  a/a ; b/b
(independent 1
A/a ; B/b
4
assortment in 1
piping
a standard 4 A/a ; b/b
testcross) 1
4 a/a ; B/b spiny tip
1
4 a/a ; b/b spiny

PROBLEMS
BASIC PROBLEMS in the biosynthetic pathway to G are known but
1. In humans, the disease galactosemia causes mental their order in the pathway is not known. Each com-
retardation at an early age because lactose in milk pound is tested for its ability to support the growth
cannot be broken down, and this failure affects brain of each mutant (1 to 5). In the following table, a
function. How would you provide a secondary cure plus sign indicates growth and a minus sign indicates
for galactosemia? Would you expect this phenotype no growth:
to be dominant or recessive? Compound tested
2. In humans, PKU (phenylketonuria) is a disease A B C D E G
caused by an enzyme inefficiency at step A in the
following simplified reaction sequence, and AKU Mutant 1      
(alkaptonuria) is due to an enzyme inefficiency in 2      
one of the steps summarized as step B here: 3      
4      
phenylalanine
A
tyrosine
B
CO2  H2O 5      

A person with PKU marries a person with AKU.
What phenotypes do you expect for their children?
All normal, all having PKU only, all having AKU
only, all having both PKU and AKU, or some having
AKU and some having PKU?
3. In Drosophila, the autosomal recessive bw causes a
dark-brown eye, and the unlinked autosomal recessive
st causes a bright scarlet eye. A homozygote for both
genes has a white eye. Thus, we have the following
correspondences between genotypes and phenotypes:
st/st ; bw/bw  red eye (wild type)
st/st ; bw/bw  brown eye
st/st ; bw/bw  scarlet eye
st/st ; bw/bw  white eye
Construct a hypothetical biosynthetic pathway show-
ing how the gene products interact and why the differ-
ent mutant combinations have different phenotypes.
4. Several mutants are isolated, all of which require
compound G for growth. The compounds (A to E)
a. What is the order of compounds A to E in the
pathway?
b. At which point in the pathway is each mutant
blocked?
c. Would a heterokaryon composed of double mu-
tants 1,3 and 2,4 grow on a minimal medium? 1,3
and 3,4? 1,2 and 2,4 and 1,4?
5. In a certain plant, the flower petals are normally
purple. Two recessive mutations arise in separate
plants and are found to be on different chromo-
somes. Mutation 1 (m1) gives blue petals when ho-
mozygous (m1/m1). Mutation 2 (m2) gives red petals
when homozygous (m2/m2). Biochemists working on
the synthesis of flower pigments in this species have
already described the following pathway:
enzym
eA blue pigment
colorless (white)
compound enzym
eB red pigment
44200_06_p185-226 3/1/04 3:16 PM Page 215

Problems 215

a. Which mutant would you expect to be deficient 11. Black, sepia, cream, and albino are all coat colors of
in enzyme A activity? guinea pigs. Individual animals (not necessarily from
b. A plant has the genotype M1/m1 ; M2/m2. What pure lines) showing these colors were intercrossed;
would you expect its phenotype to be? the results are tabulated as follows, where the abbre-
c. If the plant in part b is selfed, what colors of prog- viations A (albino), B (black), C (cream), and S
eny would you expect, and in what proportions? (sepia) represent the phenotypes:
d. Why are these mutants recessive? Phenotypes of progeny
Parental
6. In sweet peas, the synthesis of purple anthocyanin Cross phenotypes B S C A
pigment in the petals is controlled by two genes, B
and D. The pathway is 1 BB 22 0 0 7
2 BA 10 9 0 0
gene B gene D 3 CC 0 0 34 11
white enzyme blue enzyme anthocyanin 4 SC 0 24 11 12
intermediate intermediate (purple) 5 BA 13 0 12 0
a. What color petals would you expect in a pure- 6 BC 19 20 0 0
breeding plant unable to catalyze the first reaction? 7 BS 18 20 0 0
8 BS 14 8 6 0
b. What color petals would you expect in a pure-
9 SS 0 26 9 0
breeding plant unable to catalyze the second reaction?
10 CA 0 0 15 17
c. If the plants in parts a and b are crossed, what
color petals will the F1 plants have? a. Deduce the inheritance of these coat colors and
d. What ratio of purple : blue : white plants would use gene symbols of your own choosing. Show all
you expect in the F2? parent and progeny genotypes.
7. If a man of blood group AB marries a woman of b. If the black animals in crosses 7 and 8 are
blood group A whose father was of blood group O, crossed, what progeny proportions can you predict
to what different blood groups can this man and by using your model?
woman expect their children to belong?
12. In a maternity ward, four babies become accidentally
8. Erminette fowls have mostly light-colored feathers mixed up. The ABO types of the four babies are
with an occasional black one, giving a flecked ap- known to be O, A, B, and AB. The ABO types
pearance. A cross of two erminettes produced a total of the four sets of parents are determined. Indi-
of 48 progeny, consisting of 22 erminettes, 14 cate which baby belongs to each set of parents:
blacks, and 12 pure whites. What genetic basis of the (a) AB  O, (b) A  O, (c) A  AB, (d) O  O.
erminette pattern is suggested? How would you test
13. Consider two blood polymorphisms that humans
your hypotheses?
have in addition to the ABO system. Two alleles LM
9. Radishes may be long, round, or oval, and they may and LN determine the M, N, and MN blood groups.
be red, white, or purple. You cross a long, white vari- The dominant allele R of a different gene causes a
ety with a round, red one and obtain an oval, purple person to have the Rh (rhesus positive) phenotype,
F1. The F2 shows nine phenotypic classes as follows: whereas the homozygote for r is Rh (rhesus nega-
9 long, red; 15 long, purple; 19 oval, red; 32 oval, tive). Two men took a paternity dispute to court,
purple; 8 long, white; 16 round, purple; 8 round, each claiming three children to be his own. The
white; 16 oval, white; and 9 round, red. blood groups of the men, the children, and their
a. Provide a genetic explanation of these results. Be mother were as follows:
sure to define the genotypes and show the constitu-
tion of parents, F1, and F2. Person Blood group
b. Predict the genotypic and phenotypic propor- husband O M Rh
tions in the progeny of a cross between a long, pur- wifes lover AB MN Rh
ple radish and an oval, purple one. wife A N Rh
10. In the multiple allele series that determines coat child 1 O MN Rh
color in rabbits, c codes for agouti, c ch for chinchilla child 2 A N Rh
(a beige coat color), and c h for Himalayan. Domi- child 3 A MN Rh
nance is in the order c 
c ch
c h. In a cross of
c /c ch  c ch/c h, what proportion of progeny will From this evidence, can the paternity of the children
be chinchilla? be established?
44200_06_p185-226 3/1/04 3:16 PM Page 216
216
14. On a fox ranch in Wisconsin, a mutation arose that
gave a platinum coat color. The platinum color
proved very popular with buyers of fox coats, but
the breeders could not develop a pure-breeding
platinum strain. Every time two platinums were
crossed, some normal foxes appeared in the progeny.
For example, the repeated matings of the same pair
of platinums produced 82 platinum and 38 normal
progeny. All other such matings gave similar prog-
eny ratios. State a concise genetic hypothesis that
accounts for these results.
15. For a period of several years, Hans Nachtsheim in-
vestigated an inherited anomaly of the white blood
cells of rabbits. This anomaly, termed the Pelger
anomaly, is the arrest of the segmentation of the nu-
clei of certain white cells. This anomaly does not ap-
pear to seriously inconvenience the rabbits.
a. When rabbits showing the typical Pelger anomaly
were mated with rabbits from a true-breeding nor-
mal stock, Nachtsheim counted 217 offspring show-
ing the Pelger anomaly and 237 normal progeny.
What appears to be the genetic basis of the Pelger
anomaly?
b. When rabbits with the Pelger anomaly were
mated to each other, Nachtsheim found 223 normal
progeny, 439 showing the Pelger anomaly, and 39
extremely abnormal progeny. These very abnormal
progeny not only had defective white blood cells,
but also showed severe deformities of the skeletal
system; almost all of them died soon after birth. In
genetic terms, what do you suppose these extremely
defective rabbits represented? Why do you suppose
there were only 39 of them?
c. What additional experimental evidence might
you collect to support or disprove your answers to
part b?
d. In Berlin, about 1 human in 1000 shows a Pelger
anomaly of white blood cells very similar to that de-
scribed in rabbits. The anomaly is inherited as a sim-
ple dominant, but the homozygous type has not
been observed in humans. Can you suggest why, if
you are permitted an analogy with the condition in
rabbits?
e. Again by analogy with rabbits, what phenotypes
and genotypes might be expected among the chil-
dren of a man and woman who both show the Pel-
ger anomaly?
(Problem 15 from A. M. Srb, R. D. Owen, and R. S. Edgar,
General Genetics, 2d ed. W. H. Freeman and Company,
1965.)
16. Two normal-looking fruit flies were crossed, and in
the progeny there were 202 females and 98 males.
Chapter 6 From Gene to Phenotype
a. What is unusual about this result?
b. Provide a genetic explanation for this anomaly.
c. Provide a test of your hypothesis.
17. You have been given a virgin Drosophila female. You
notice that the bristles on her thorax are much
shorter than normal. You mate her with a normal
male (with long bristles) and obtain the following F1
progeny: 31 short-bristled females, 13 long-bristled
females, and 13 long-bristled males. A cross of the
F1 long-bristled females with their brothers gives
only long-bristled F2. A cross of short-bristled
females with their brothers gives 13 short-bristled
females, 31 long-bristled females, and 13 long-bristled
males. Provide a genetic hypothesis to account for
all these results, showing genotypes in every cross.
18. A dominant allele H reduces the number of body
bristles that Drosophila flies have, giving rise to a
hairless phenotype. In the homozygous condition,
H is lethal. An independently assorting dominant al-
lele S has no effect on bristle number except in the
presence of H, in which case a single dose of S sup-
presses the hairless phenotype, thus restoring the
hairy phenotype. However, S also is lethal in the
homozygous (S/S) condition.
a. What ratio of hairy to hairless flies would you
find in the live progeny of a cross between two hairy
flies both carrying H in the suppressed condition?
b. When the hairless progeny are backcrossed with a
parental hairy fly, what phenotypic ratio would you
expect to find among their live progeny?
19. After irradiating wild-type cells of Neurospora (a
haploid fungus), a geneticist finds two leucine-
requiring auxotrophic mutants. He combines the
two mutants in a heterokaryon and discovers that
the heterokaryon is prototrophic.
a. Were the mutations in the two auxotrophs in
the same gene in the pathway for synthesizing
leucine, or in two different genes in that pathway?
Explain.
b. Write the genotype of the two strains according
to your model.
c. What progeny and in what proportions would
you predict from crossing the two auxotrophic mu-
tants? (Assume independent assortment.)
20. A yeast geneticist irradiates haploid cells of a strain
that is an adenine-requiring auxotrophic mutant,
caused by mutation of the gene ade1. Millions of
the irradiated cells are plated on minimal medium,
and a small number of cells divide and produce pro-
totrophic colonies. These colonies are crossed indi-
44200_06_p185-226 3/1/04 3:16 PM Page 217
Problems
vidually to a wild-type strain. Two types of results
are obtained:
prototroph  wild type progeny all prototrophic
prototroph  wild type progeny 75% prototrophic,
25% adenine-requiring auxotrophs
a. Explain the difference between these two types
of results.
b. Write the genotypes of the prototrophs in each
case.
c. What progeny phenotypes and ratios do you pre-
dict from crossing a prototroph of type 2 by the
original ade1 auxotroph?
21. It is known that in roses the synthesis of red pig-
ment is by two steps in a pathway, as follows:
gene P
colorless intermediate
gene Q
magenta intermediate red pigment
a. What would the phenotype be of a plant ho-
mozygous for a null mutation of gene P?
b. What would the phenotype be of a plant ho-
mozygous for a null mutation of gene Q?
c. What would the phenotype be of a plant ho-
mozygous for null mutations of genes P and Q?
d. Write the genotypes of the three strains in a, b,
and c.
e. What F2 ratio is expected from crossing plants
from a and b? (Assume independent assortment.)
22. Because snapdragons (Antirrhinum) possess the
pigment anthocyanin, they have reddish-purple
petals. Two pure anthocyanin-less lines of Antir-
rhinum were developed, one in California and one
in Holland. They looked identical in having no red
pigment at all, manifested as white (albino) flow-
ers. However, when petals from the two lines were
ground up together in buffer in the same test tube,
the solution, which appeared colorless at first,
gradually turned red.
a. What control experiments should an investigator
conduct before proceeding with further analysis?
b. What could account for the production of the red
color in the test tube?
c. According to your explanation for part b, what
would be the genotypes of the two lines?
d. If the two white lines were crossed, what
would you predict the phenotypes of the F1 and
F2 to be?
217
23. The frizzle fowl is much admired by poultry
fanciers. It gets its name from the unusual way that
its feathers curl up, giving the impression that it has
been (in the memorable words of animal geneticist
F. B. Hutt) pulled backwards through a knothole.
Unfortunately, frizzle fowls do not breed true; when
two frizzles are intercrossed, they always produce
50 percent frizzles, 25 percent normal, and 25 per-
cent with peculiar woolly feathers that soon fall out,
leaving the birds naked.
a. Give a genetic explanation for these results,
showing genotypes of all phenotypes, and provide a
statement of how your explanation works.
b. If you wanted to mass-produce frizzle fowls for sale,
which types would be best to use as a breeding pair?
24. The petals of the plant Collinsia parviflora are nor-
mally blue, giving the species its common name,
blue-eyed Mary. Two pure-breeding lines were ob-
tained from color variants found in nature; the first
line had pink petals, and the second line had white
petals. The following crosses were made between
pure lines, with the results shown:
Parents F1 F2
blue  white blue 101 blue, 33 white
blue  pink blue 192 blue, 63 pink
pink  white blue 272 blue, 121 white, 89 pink
a. Explain these results genetically. Define the allele
symbols that you use, and show the genetic consti-
tution of parents, F1, and F2.
b. A cross between a certain blue F2 plant and a
certain white F2 plant gave progeny of which 83
were blue, 81 were pink, and 12 were white. What
must the genotypes of these two F2 plants have been?
UNPACKING PROBLEM 24
1. What is the character being studied?
2. What is the wild-type phenotype?
3. What is a variant?
4. What are the variants in this problem?
5. What does in nature mean?
6. In what way would the variants have been found in
nature? (Describe the scene.)
7. At which stages in the experiments would seeds be
used?
8. Would the way of writing a cross blue  white
(for example) mean the same as white  blue?
Would you expect similar results? Why or why not?
44200_06_p185-226 3/1/04 3:16 PM Page 218

218 Chapter 6 From Gene to Phenotype

9. In what way do the first two rows in the table differ b. A white F2 plant was crossed to a solid-purple F2
from the third row? plant, and the progeny were
10. Which phenotypes are dominant? white 50%
11. What is complementation? solid-purple 25%
12. Where does the blueness come from in the progeny spotted-purple 25%
of the pink  white cross? What were the genotypes of the F2 plants crossed?
13. What genetic phenomenon does the production of
27. Most flour beetles are black, but several color vari-
a blue F1 from pink and white parents represent?
ants are known. Crosses of pure-breeding parents
14. List any ratios that you can see. produced the following results in the F1 generation,
15. Are there any monohybrid ratios? and intercrossing the F1 from each cross gave the ra-
16. Are there any dihybrid ratios? tios shown for the F2 generation. The phenotypes
are abbreviated Bl, black; Br, brown; Y, yellow; and
17. What does observing monohybrid and dihybrid
W, white.
ratios tell you?
18. List four modified Mendelian ratios that you can Cross Parents F1 F2
think of.
1 Br  Y Br 3 Br : 1 Y
19. Are there any modified Mendelian ratios in the 2 Bl  Br Bl 3 Bl : 1 Br
problem? 3 Bl  Y Bl 3 Bl : 1 Y
20. What do modified Mendelian ratios indicate 4 W  Y Bl 9 Bl : 3 Y: 4 W
generally? 5 W  Br Bl 9 Bl : 3 Br : 4 W
21. What does the specific modified ratio or ratios in 6 Bl  W Bl 9 Bl : 3 Y: 4 W
this problem indicate?
22. Draw chromosomes representing the meioses inthe a. From these results deduce and explain the inheri-
parents in the cross blue  white and meiosis in the F1. tance of these colors.
23. Repeat for the cross blue  pink. b. Write the genotypes of each of the parents, the
F1, and the F2 in all crosses.
25. A woman who owned a purebred albino poodle (an 28. Two albinos marry and have four normal children.
autosomal recessive phenotype) wanted white pup- How is this possible?
pies, so she took the dog to a breeder, who said he
would mate the female with an albino stud male, 29. Consider production of flower color in the Japanese
also from a pure stock. When six puppies were born, morning glory (Pharbitis nil). Dominant alleles of
they were all black, so the woman sued the breeder, either of two separate genes (A/ b/b or
claiming that he replaced the stud male with a black a/a B/) produce purple petals. A/ B/ pro-
dog, giving her six unwanted puppies. You are called duces blue petals, and a/a b/b produces scarlet
in as an expert witness, and the defense asks you if it petals. Deduce the genotypes of parents and prog-
is possible to produce black offspring from two eny in the following crosses:
pure-breeding recessive albino parents. What testi-
mony do you give? Cross Parents Progeny
1
26. A snapdragon plant that bred true for white petals 1 blue  scarlet 4 blue : 12
purple : 14 scarlet
1
was crossed to a plant that bred true for purple 2 purple  purple 4 blue : 12
purple : 14 scarlet
3
petals, and all the F1 had white petals. The F1 was 3 blue  blue 4 blue : 14
purple
selfed. Among the F2, three phenotypes were ob- 4 blue  purple 3
blue : 48
purple : 18 scarlet
8
served in the following numbers: 5 purple  scarlet 1
purple : 12 scarlet
2
white 240
solid-purple 61
30. Corn breeders obtained pure lines whose kernels
spotted-purple 19
turn sun red, pink, scarlet, or orange when exposed
Total 320
to sunlight (normal kernels remain yellow in sun-
a. Propose an explanation for these results, showing light). Some crosses between these lines produced
genotypes of all generations (make up and explain the following results. The phenotypes are abbrevi-
your symbols). ated O, orange; P, pink; Sc, scarlet; and SR, sun red.
44200_06_p185-226 3/1/04 3:16 PM Page 219
Problems
Phenotypes
Cross Parents F1 F2
1 SR  P all SR 66 SR : 20 P
2 O  SR all SR 998 SR : 314 O
3 O  P all O 1300 O : 429 P
4 O  Sc all Y 182 Y: 80 O : 58 Sc
Analyze the results of each cross, and provide a uni-
fying hypothesis to account for all the results. (Ex-
plain all symbols that you use.)
31. Many kinds of wild animals have the agouti coloring
pattern, in which each hair has a yellow band
around it.
a. Black mice and other black animals do not have
the yellow band; each of their hairs is all black. This
absence of wild agouti pattern is called nonagouti.
When mice of a true-breeding agouti line are
crossed with nonagoutis, the F1 is all agouti and the
F2 has a 3 : 1 ratio of agoutis to nonagoutis. Diagram
this cross, letting A represent the allele responsible
for the agouti phenotype and a, nonagouti. Show
the phenotypes and genotypes of the parents, their
gametes, the F1, their gametes, and the F2.
b. Another inherited color deviation in mice substi-
tutes brown for the black color in the wild-type hair.
Such brown-agouti mice are called cinnamons.
When wild-type mice are crossed with cinnamons,
the F1 is all wild type and the F2 has a 3 : 1 ratio of
wild type to cinnamon. Diagram this cross as in part
a, letting B stand for the wild-type black allele and b
stand for the cinnamon brown allele.
c. When mice of a true-breeding cinnamon line are
crossed with mice of a true-breeding nonagouti
(black) line, the F1 is all wild type. Use a genetic dia-
gram to explain this result.
d. In the F2 of the cross in part c, a fourth color
called chocolate appears in addition to the parental
cinnamon and nonagouti and the wild type of the
F1. Chocolate mice have a solid, rich-brown color.
What is the genetic constitution of the chocolates?
e. Assuming that the A/a and B/b allelic pairs assort
independently of each other, what do you expect to
be the relative frequencies of the four color types in
the F2 described in part d? Diagram the cross of
parts c and d, showing phenotypes and genotypes
(including gametes).
f. What phenotypes would be observed in what
proportions in the progeny of a backcross of F1 mice
from part c to the cinnamon parental stock? To the
nonagouti (black) parental stock? Diagram these
backcrosses.
219
g. Diagram a testcross for the F1 of part c. What col-
ors would result and in what proportions?
h. Albino (pink-eyed white) mice are homozygous
for the recessive member of an allelic pair C/c
which assorts independently of the A/a and B/b
pairs. Suppose that you have four different highly
inbred (and therefore presumably homozygous) al-
bino lines. You cross each of these lines with a true-
breeding wild-type line, and you raise a large F2
progeny from each cross. What genotypes for the al-
bino lines can you deduce from the following F2
phenotypes?
(Problem 31 adapted from A. M. Srb, R. D. Owen, and R.
S. Edgar, General Genetics, 2d ed. W. H. Freeman and
Company, 1965.)
32. An allele A that is not lethal when homozgous
causes rats to have yellow coats. The allele R of a
www.
separate gene that assorts independently produces
a black coat. Together, A and R produce a grayish
coat, whereas a and r produce a white coat. A gray
male is crossed with a yellow female, and the F1 is 38
yellow, 38 gray, 18 black, and 18 white. Determine the
genotypes of the parents.
33. The genotype r/r ; p/p gives fowl a single comb,
R/ ; P/ gives a walnut comb, r/r ; P/ gives a
pea comb, and R/ ; p/p gives a rose comb (see the
illustrations).
Single Walnut Pea Rose
a. What comb types will appear in the F1 and in the
F2 in what proportions if single-combed birds are
crossed with birds of a true-breeding walnut strain?
b. What are the genotypes of the parents in a
walnut  rose mating from which the progeny are
3 3 1 1
8 rose, 8 walnut, 8 pea, and 8 single?
c. What are the genotypes of the parents in a
walnut  rose mating from which all the progeny
are walnut?
d. How many genotypes produce a walnut pheno-
type? Write them out.
34. The production of eye-color pigment in Drosophila
requires the dominant allele A. The dominant allele
P of a second independent gene turns the pigment
to purple, but its recessive allele leaves it red. A fly
44200_06_p185-226 3/1/04 3:16 PM Page 220
220
producing no pigment has white eyes. Two pure
lines were crossed with the following results:
P red-eyed female  white-eyed male
F1 purple-eyed females
red-eyed males
F1  F1
3 this number.
F2 both males and females: 8 purple-eyed
3 d. Why your scheme is the fastest and the most
8 red-eyed
2
8 white-eyed
Explain this mode of inheritance and show the
genotypes of the parents, the F1, and the F2.
35. When true-breeding brown dogs are mated with
certain true-breeding white dogs, all the F1 pups are
white. The F2 progeny from some F1  F1 crosses
were 118 white, 32 black, and 10 brown pups. What
is the genetic basis for these results?
36. Wild-type strains of the haploid fungus Neurospora
can make their own tryptophan. An abnormal allele td
renders the fungus incapable of making its own tryp-
tophan. An individual of genotype td grows only when
its medium supplies tryptophan. The allele su assorts
independently of td; its only known effect is to sup-
press the td phenotype. Therefore, strains carrying
both td and su do not require tryptophan for growth.
a. If a td ; su strain is crossed with a genotypically
wild-type strain, what genotypes are expected in the
progeny, and in what proportions?
b. What will be the ratio of tryptophan-dependent
to tryptophan-independent progeny in the cross of
part a?
37. Mice of the genotypes A/A ; B/B ; C/C ;
D/D ; S/S and a/a ; b/b ; c/c ; d/d ; s/s are
crossed. The progeny are intercrossed. What pheno-
types will be produced in the F2, and in what propor-
tions? (The allele symbols stand for the following:
A  agouti, a  solid (nonagouti); B  black pig-
ment, b  brown; C  pigmented, c  albino; D 
nondilution, d  dilution (milky color); S  unspot-
ted, s  pigmented spots on white background.)
38. Consider the genotypes of two lines of chickens:
the pure-line mottled Honduran is i/i ; D/D ;
M/M ; W/W, and the pure-line leghorn is
I/I ; d/d ; m/m ; w/w, where
I  white feathers, i  colored feathers
D  duplex comb, d  simplex comb
M  bearded, m  beardless
W  white skin, w  yellow skin
Chapter 6 From Gene to Phenotype
These four genes assort independently. Starting with
these two pure lines, what is the fastest and most
convenient way of generating a pure line of birds
that has colored feathers, has a simplex comb, is
beardless, and has yellow skin? Make sure that you
show
a. The breeding pedigree.
b. The genotype of each animal represented.
c. How many eggs to hatch in each cross, and why
convenient.
39. The following pedigree is for a dominant phenotype
governed by an autosomal gene. What does this
pedigree suggest about the phenotype, and what can
you deduce about the genotype of individual A?
A
40. Petal coloration in foxgloves is determined by three
genes. M codes for an enzyme that synthesizes an-
thocyanin, the purple pigment seen in these petals;
m/m produces no pigment, resulting in the pheno-
type albino with yellowish spots. D is an enhancer of
anthocyanin, resulting in a darker pigment; d/d does
not enhance. At the third locus, w/w allows pigment
deposition in petals, but W prevents pigment depo-
sition except in the spots and, so, results in the
white, spotted phenotype. Consider the following
two crosses:
Cross Parents Progeny
1
1 dark-  white with 2 dark-purple :
1
purple yellowish 2 light-purple
spots
1
2 white with  light- 2 white with purple
yellowish purple spots : 41 dark-
spots purple : 14 light-purple
In each case, give the genotypes of parents and prog-
eny with respect to the three genes.
41. In one species of Drosophila, the wings are normally
round in shape, but you have obtained two pure
lines, one of which has oval wings and the other
sickle-shaped wings. Crosses between pure lines re-
veal the following results:
44200_06_p185-226 3/1/04 3:16 PM Page 221

Problems 221

Parents F1 44. In Drosophila, an autosomal gene determines the

shape of the hair, with B giving straight and b bent
Female Male Female Male
hairs. On another autosome, there is a gene of which
sickle round sickle sickle a dominant allele I inhibits hair formation so that
round sickle sickle round the fly is hairless (i has no known phenotypic
sickle oval oval sickle effect).
a. If a straight-haired fly from a pure line is crossed
with a fly from a pure-breeding hairless line known
a. Provide a genetic explanation of these results, to be an inhibited bent genotype, what will the
defining all allele symbols. genotypes and phenotypes of the F1 and the F2 be?
b. If the F1 oval females from cross 3 are crossed to b. What cross would give the ratio 4 hairless : 3
the F1 round males from cross 2, what phenotypic straight : 1 bent?
proportions are expected in each sex of progeny?
45. The following pedigree concerns eye phenotypes in
42. Mice normally have one yellow band on their hairs, Tribolium beetles. The solid symbols represent black
but variants with two or three bands are known. A eyes, the open symbols represent brown eyes, and
female mouse with one band was crossed to a male the cross symbols (X) represent the eyeless pheno-
who had three bands. (Neither animal was from a type, in which eyes are totally absent.
pure line.) The progeny were
1 I
Females 2 one band 1 2 3
1
2 three bands
1
Males 2 one band II
1
1 2 3 4 5
2 two bands
III
a. Provide a clear explanation of the inheritance of 1 2 3 4
these phenotypes. IV
1
b. Under your model, what would be the outcome
of a cross between a three-banded daughter and a a. From these data, deduce the mode of inheritance
one-banded son? of these three phenotypes.
43. In minks, wild types have an almost black coat. b. Using defined gene symbols, show the genotype
Breeders have developed many pure lines of color of individual II-3.
variants for the mink coat industry. Two such pure
46. A plant believed to be heterozygous for a pair of al-
lines are platinum (blue-gray) and aleutian (steel-
leles B/b (where B encodes yellow and b encodes
gray). These lines were used in crosses, with the fol-
bronze) was selfed, and in the progeny there were
lowing results:
280 yellow and 120 bronze individuals. Do these re-
sults support the hypothesis that the plant is B/b?
Cross Parents F1 F2
47. A plant thought to be heterozygous for two inde-
1 wild  platinum wild 18 wild, 5 platinum
pendently assorting genes (P/p ; Q/q) was selfed,
2 wild  aleutian wild 27 wild, 10 aleutian
3 platinum  aleutian wild 133 wild
and the progeny were
41 platinum 88 P/ ; Q/
46 aleutian 32 P/ ; q/q
17 sapphire (new)
25 p/p ; Q/
14 p/p ; q/q

a. Devise a genetic explanation of these three
crosses. Show genotypes for parents, F1, and F2 in
the three crosses, and make sure that you show the
alleles of each gene that you hypothesize in every
individual.
b. Predict the F1 and F2 phenotypic ratios from
crossing sapphire with platinum and aleutian pure
lines.
Do these results support the hypothesis that the
original plant was P/p ; Q/q?
48. A plant of phenotype 1 was selfed, and in the prog-
eny there were 100 individuals of phenotype 1 and
60 of an alternative phenotype 2. Are these numbers
compatible with expected ratios of 9 : 7, 13 : 3, and
3 : 1? Formulate a genetic hypothesis based on your
calculations.
44200_06_p185-226 3/1/04 3:16 PM Page 222
222
49. Four homozygous recessive mutant lines of
Drosophila melanogaster (labeled 1 through 4)
showed abnormal leg coordination, which made
their walking highly erratic. These lines were inter-
crossed; the phenotypes of the F1 flies are shown in
the following grid, in which  represents wild-
type walking and  represents abnormal walking:
1 2 3 4
1    
2    
3    
4    
a. What type of test does this analysis represent?
b. How many different genes were mutated in cre-
ating these four lines?
c. Invent wild-type and mutant symbols and write
out full genotypes for all four lines and for the F1s.
d. Do these data tell us which genes are linked? If
not, how could linkage be tested?
e. Do these data tell us the total number of genes
involved in leg coordination in this animal?
50. Three independently isolated tryptophan-requiring
mutants of haploid yeast are called trpB, trpD, and
trpE. Cell suspensions of each are streaked on a
plate of nutritional medium supplemented with just
enough tryptophan to permit weak growth for a trp
strain. The streaks are arranged in a triangular pat-
tern so that they do not touch one another. Luxuri-
ant growth is noted at both ends of the trpE streak
and at one end of the trpD streak (see the accompa-
nying figure).
a. Do you think complementation is involved?
b. Briefly explain the pattern of luxuriant growth.
c. In what order in the tryptophan-synthesizing
pathway are the enzymatic steps that are defective
in trpB, trpD, and trpE?
d. Why was it necessary to add a small amount of
tryptophan to the medium in order to demonstrate
such a growth pattern?
Chapter 6 From Gene to Phenotype
CHALLENGING PROBLEMS
51. A pure-breeding strain of squash that produced
disk-shaped fruits (see the accompanying illustra-
tion) was crossed with a pure-breeding strain having
long fruits. The F1 had disk fruits, but the F2 showed
a new phenotype, sphere, and was composed of the
following proportions:
Long Sphere Disk
disk 270
sphere 178
long 32
Propose an explanation for these results, and show
the genotypes of the P, F1, and F2 generations.
(Illustration from P. J. Russell, Genetics, 3d ed. Harper-
Collins, 1992.)
52. Marfans syndrome is a disorder of the fibrous con-
nective tissue, characterized by many symptoms, in-
cluding long, thin digits; eye defects; heart disease;
and long limbs. (Flo Hyman, the American volley-
ball star, suffered from Marfans syndrome. She died
soon after a match from a ruptured aorta.)
a. Use the accompanying pedigree (see the top
of page 39) to propose a mode of inheritance for
Marfans syndrome.
b. What genetic phenomenon is shown by this
pedigree?
c. Speculate on a reason for such a phenomenon.
(Illustration from J. V. Neel and W. J. Schull, Human
Heredity. University of Chicago Press, 1954.)
53. In corn, three dominant alleles, called A, C, and R,
must be present to produce colored seeds. Geno-
type A/ ; C/ ; R/ is colored; all others are
colorless. A colored plant is crossed with three
tester plants of known genotype. With tester
a/a ; c/c ; R/R, the colored plant produces 50 per-
cent colored seeds; with a/a ; C/C ; r/r, it pro-
duces 25 percent colored; and with A/A ; c/c ; r/r,
it produces 50 percent colored. What is the geno-
type of the colored plant?
44200_06_p185-226 3/1/04 3:16 PM Page 223

Problems 223

II

III

Symptoms
Unknown, presumed normal
Examined, normal
Eye lens displacement
Pedigree for Problem 52. Congenital heart disease
Long fingers and toes
Very long, thin fingers and toes
Questionably affected

54. The production of pigment in the outer layer of a. What is the name given to the type of gene inter-
seeds of corn requires each of the three indepen- action in this example?
dently assorting genes A, C, and R to be represented b. What are the genotypes of the individuals in the
by at least one dominant allele, as specified in Prob- pedigree? (If there are alternative possibilities, state
lem 53. The dominant allele Pr of a fourth indepen- them.)
dently assorting gene is required to convert the bio-
56. A researcher crosses two white-flowered lines of
chemical precursor into a purple pigment, and
Antirrhinum plants as follows and obtains the fol-
its recessive allele pr makes the pigment red. Plants
lowing results:
that do not produce pigment have yellow seeds.
Consider a cross of a strain of genotype A/A ; pure line 1  pure line 2
C/C ; R/R ; pr/pr with a strain of genotype s
a/a ; c/c ; r/r ; Pr/Pr. p
F1 all white
a. What are the phenotypes of the parents?
F1  F1
b. What will be the phenotype of the F1?
s
c. What phenotypes, and in what proportions, will p
appear in the progeny of a selfed F1? F2 131 white
d. What progeny proportions do you predict from 29 red
the testcross of an F1? a. Deduce the inheritance of these phenotypes,
using clearly defined gene symbols. Give the geno-
55. The allele B gives mice a black coat, and b gives a
types of the parents, F1, and F2.
brown one. The genotype e/e of another, indepen-
dently assorting gene prevents expression of B and b. Predict the outcome of crosses of the F1 to each
b, making the coat color beige, whereas E/ permits parental line.
expression of B and b. Both genes are autosomal. In 57. Assume that two pigments, red and blue, mix to give
the following pedigree, black symbols indicate a the normal purple color of petunia petals. Separate
black coat, pink symbols indicate brown, and white biochemical pathways synthesize the two pigments, as
symbols indicate beige. shown in the top two rows of the accompanying dia-
gram. White refers to compounds that are not pig-
I
ments. (Total lack of pigment results in a white petal.)
1 2 Red pigment forms from a yellow intermediate that
normally is at a concentration too low to color petals.
E
pathway I white1 blue
II A B
1 2 3 4 5 6 pathway II white2 yellow red

III D
1 2 3 4 5 6 7 pathway III white3 white4
44200_06_p185-226 3/1/04 3:16 PM Page 224

224 Chapter 6 From Gene to Phenotype

A third pathway, whose compounds do not con- Y1 Y2 B O

tribute pigment to petals, normally does not affect
F1 all Y all R all R all R
the blue and red pathways, but if one of its interme-
Y1 F2 all Y 9R 9R 9R
diates (white3) should build up in concentration, it
7Y 4Y 4O
can be converted into the yellow intermediate of
3B 3Y
the red pathway.
In the diagram, A to E represent enzymes; their F1 all Y all R all R
corresponding genes, all of which are unlinked, may Y2 F2 all Y 9R 9R
be symbolized by the same letters. 4Y 4Y
Assume that wild-type alleles are dominant and 3B 3O
code for enzyme function and that recessive alleles F1 all B all R
result in lack of enzyme function. Deduce which B F2 all B 9R
combinations of true-breeding parental genotypes 4O
could be crossed to produce F2 progenies in the fol- 3B
lowing ratios: F1 all O
a. 9 purple : 3 green : 4 blue O F2 all O
b. 9 purple : 3 red : 3 blue : 1 white
a. Define your own symbols and show genotypes of
c. 13 purple : 3 blue
all four pure lines.
d. 9 purple : 3 red : 3 green : 1 yellow b. Show how the F1 phenotypes and the F2 ratios
(Note: Blue mixed with yellow makes green; assume are produced.
that no mutations are lethal.) c. Show a biochemical pathway that explains the
58. The flowers of nasturtiums (Tropaeolum majus) may genetic results, indicating which gene controls which
be single (S), double (D), or superdouble (Sd). Su- enzyme.
perdoubles are female sterile; they originated from a 60. In common wheat, Triticum aestivum, kernel color is
double-flowered variety. Crosses between varieties determined by multiply duplicated genes, each with
gave the progenies as listed in the following table, an R and an r allele. Any number of R alleles will
where pure means pure-breeding. give red, and the complete lack of R alleles will give
the white phenotype. In one cross between a red
Cross Parents Progeny pure line and a white pure line, the F2 was 64 63
red
1
1 pure S  pure D All S and 64 white.
2 cross 1 F1  cross 1 F1 78 S : 27 D a. How many R genes are segregating in this system?
3 pure D  Sd 112 Sd : 108 D b. Show genotypes of the parents, the F1, and the F2.
4 pure S  Sd 8 Sd : 7 S
5 pure D  cross 4 Sd progeny 18 Sd : 19 S c. Different F2 plants are backcrossed to the white
6 pure D  cross 4 S progeny 14 D : 16 S parent. Give examples of genotypes that would give
the following progeny ratios in such backcrosses: (1)
1 red : 1 white, (2) 3 red : 1 white, (3) 7 red : 1 white.
Using your own genetic symbols, propose an expla- d. What is the formula that generally relates the
nation for these results, showing number of segregating genes to the proportion of
a. All the genotypes in each of the six rows. red individuals in the F2 in such systems?
b. The proposed origin of the superdouble. 61. The accompanying pedigree shows the inheritance
of deaf-mutism.
59. In a certain species of fly, the normal eye color is
red (R). Four abnormal phenotypes for eye color
I 1 2 3 4
were found: two were yellow (Y1 and Y2), one
was brown (B), and one was orange (O). A pure
line was established for each phenotype, and all
possible combinations of the pure lines were II
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
crossed. Flies of each F1 were intercrossed to pro-
duce an F2. The F1s and F2s are shown within the
following square; the pure lines are given in the III
margins. 1 2 3 4 5 6 7
44200_06_p185-226 3/1/04 3:16 PM Page 225

Problems 225

a. Provide an explanation for the inheritance of this ment of dead pupae was uncapped by the bee-
rare condition in the two families in generations I keeper, about half the individuals removed the dead
and II, showing genotypes of as many individuals as pupae, but the other half did not.
possible, using symbols of your own choosing.
a. Propose a genetic hypothesis to explain these be-
b. Provide an explanation for the production of only havioral patterns.
normal individuals in generation III, making sure
b. Discuss the data in relation to epistasis, domi-
that your explanation is compatible with the answer
nance, and environmental interaction.
to part a.
(Note: Workers are sterile, and all bees from one line
62. The accompanying pedigree is for blue sclera (bluish carry the same alleles.)
thin outer wall to the eye) and brittle bones.
64. The normal color of snapdragons is red. Some pure
lines showing variations of flower color have been
I 3
1 2 found. When these pure lines were crossed, they
gave the following results:
II
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Cross Parents F1 F2
III 1 orange  yellow orange 3 orange : 1 yellow
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 2 red  orange red 3 red : 1 orange
3 red  yellow red 3 red : 1 yellow
IV 4 red  white red 3 red : 1 white
1 2 3 4 5 6 7 8 9 10 11 12 13 5 yellow  white red 9 red : 3 yellow : 4 white
,  blue sclera  brittle bones 6 orange  white red 9 red : 3 orange : 4 white
7 red  white red 9 red : 3 yellow : 4 white

a. Are these two abnormalities caused by the same

gene or separate genes? State your reasons clearly. a. Explain the inheritance of these colors.
b. Is the gene (or genes) autosomal or sex-linked? b. Write the genotypes of the parents, the F1, and
the F2.
c. Does the pedigree show any evidence of incom-
plete penetrance or expressivity? If so, make the best 65. Consider the following F1 individuals in different
calculations that you can of these measures. species and the F2 ratios produced by selfing:
63. Workers of the honeybee line known as Brown
(nothing to do with color) show what is called F1 Phenotypic ratio in the F2
hygienic behavior; that is, they uncap hive com-
12 3 1
partments containing dead pupae and then re- 1 cream 16 cream 16black 16 gray
move the dead pupae. This behavior prevents the 9 7
2 orange 16 orange 16yellow
spread of infectious bacteria through the colony. 3 black 13
black 3
white
16 16
Workers of the Van Scoy line, however, do not 9 3 4
4 solid solid red mottled small red
perform these actions, and therefore this line is 16 16 16

said to be nonhygienic. When a queen from the red red dots

Brown line was mated with Van Scoy drones, the
F1 were all nonhygienic. When drones from this F1
inseminated a queen from the Brown line, the If each F1 were testcrossed, what phenotypic ratios
progeny behaviors were as follows: would result in the progeny of the testcross?

1 66. To understand the genetic basis of locomotion in

4 hygienic the diploid nematode Caenorhabditis elegans, re-
1
uncapping but no removing of pupae cessive mutations were obtained, all making the
4
worm wiggle ineffectually instead of moving
1
2 nonhygienic with its usual smooth gliding motion. These mu-
tations presumably affect the nervous or muscle
However, when the nonhygienic individuals were systems. Twelve homozygous mutants were inter-
examined further, it was found that if the compart- crossed, and the F1 hybrids were examined to see
44200_06_p185-226 3/1/04 3:16 PM Page 226

226 Chapter 6 From Gene to Phenotype

if they wiggled. The results were as follows,

where a plus sign means that the F1 hybrid was
wild type (gliding) and w means that the hybrid
wiggled.

1 2 3 4 5 6 7 8 9 10 11 12
1 w    w       
2 w    w  w  w  
3 w w        
4 w        
5 w       
6 w  w  w  
7 w    w w
8 w  w  
9 w   
10 w  
11 w w
12 w

a. Explain what this experiment was designed to (A, B, C), but two of them contain spores that do
test. not germinate.
b. Use this reasoning to assign genotypes to all 12
mutants. Spore A B C
c. Explain why the F1 hybrids between mutants 1 1 wild type wild type spider
and 2 had a different phenotype from that of the 2 wild type spider spider
hybrids between mutants 1 and 5. 3 no germination mossy mossy
4 no germination no germination mossy
67. A geneticist working on a haploid fungus makes a
cross between two slow-growing mutants call mossy
and spider (referring to abnormal appearance of the Devise a model to explain these genetic results, and
colonies). Tetrads from the cross are of three types propose a molecular basis for your model.

INTERACTIVE GENETICS MegaManual CD-ROM Tutorial

Biochemical Genetics
For additional coverage of the topics in this chapter, refer to the Interactive
Genetics CD-ROM included with the Solutions MegaManual. The
Biochemical Genetics activity contains animated tutorials on the model
organism Neurospora, and how it has been used to determine the relationships
between genes and enzymes. Five interactive problems are also provided for
extra practice.