Ch4 .

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CHAPTER OUTLINE

4.1 Overview of Mendelian Inheritance Patterns


4.2 Dominant and Recessive Alleles
4.3 Environmental Effects on Gene
Expression
4.4 Incomplete Dominance, Heterozygote
Advantage, and Codominance
4.5 Genes on Sex Chromosomes
4.6 Sex-Influenced and Sex-Limited
Inheritance
4.7 Lethal Alleles
4.8 Understanding Complex Phenotypes
Caused by Mutations in Single Genes

4
4.9 Gene Interactions Inheritance patterns and alleles. In petunia plants, multiple alleles re-
sult in flowers with several different colors, such as the ones shown here.
dimitriosp/123RF

EXTENSIONS OF MENDELIAN
INHERITANCE
Many traits in eukaryotic species follow a pattern known as mechanisms by which alleles affect the outcome of traits. Many
Mendelian inheritance. Such traits obey two laws: the law of alleles don’t produce the ratios of offspring that are expected with
segregation and the law of independent assortment. Furthermore, simple Mendelian inheritance. This does not mean that Mendel
the genes that influence such traits are not altered (except by rare was wrong. Rather, the inheritance patterns of many traits are
mutations) as they are passed from parent to offspring. The traits more complex and interesting than Mendel had realized. In this
that are displayed by the offspring depend on the alleles they chapter, we will examine how the outcome of a trait may be influ-
inherit and also on environmental factors. enced by a variety of factors such as the level of protein expres-
Until now, we have mainly considered traits that are affected sion, the sex of the individual, the presence of multiple alleles of a
by a single gene that is found in two different alleles. In these given gene, and environmental effects. We will also explore how
cases, one allele is dominant over the other. This type of inheri- two different genes can contribute to the outcome of a single trait.
tance is called simple Mendelian inheritance because the ob- In Chapters 5 and 6, we will examine eukaryotic inheritance
served ratios of traits in the offspring clearly obey Mendel’s laws. patterns that are not considered Mendelian. For example, some
For example, when true-breeding tall and short pea plants are genes are located in mitochondrial DNA and do not obey the law
crossed and the F1 generation is allowed to self-fertilize, the F2 of segregation. Others are closely linked along the same chromo-
generation shows a 3:1 phenotypic ratio of tall to short offspring. some and violate the law of independent assortment. In addition,
In this chapter, we will extend our understanding of Mende- some genes are altered (by DNA methylation) during gamete for-
lian inheritance by first examining the transmission patterns for mation, which affects their expression in the offspring that inherit
several traits that do not display a simple dominant/recessive rela- them. This results in an epigenetic pattern of inheritance that we
tionship. Geneticists have discovered an amazing diversity of will consider in Chapter 5.

81

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82 C H A P T E R 4 :: EXTENSIONS OF MENDELIAN INHERITANCE

or more alleles in several different ways. Geneticists want to un-


4.1 OVERVIEW OF MENDELIAN derstand Mendelian inheritance for two reasons:
INHERITANCE PATTERNS ∙ One goal is to predict the outcome of crosses. Many of the
Learning Outcomes: inheritance patterns described in Table 4.1 do not produce
a 3:1 phenotypic ratio when two heterozygotes produce
1. Compare and contrast the different types of Mendelian in-
offspring.
heritance patterns.
∙ A second goal is to understand how the molecular expres-
2. Describe the molecular mechanisms that account for Men-
sion of genes can account for an individual’s phenotype. In
delian inheritance patterns involving single genes.
other words, what is the underlying relationship between
molecular genetics—the expression of genes to produce
functional proteins—and the traits of individuals that
Before we delve more deeply into inheritance patterns, let’s first
inherit the genes?
compare a variety of these patterns (Table 4.1). We have already
discussed two of them—simple dominant/recessive inheritance in The remaining sections of this chapter will explore several
Chapter 2 and X-linked inheritance in Chapter 3. The various pat- patterns of inheritance and consider their underlying molecular
terns occur because the outcome of a trait may be governed by two mechanisms.

TAB L E 4.1
Mendelian Inheritance Patterns Involving Single Genes
Type Description
Simple Mendelian Inheritance: This term is commonly applied to the inheritance of alleles that obey Mendel’s laws and follow a strict dominant/recessive
inheritance relationship. In this chapter, we will see that some genes occur as three or more alleles, making the relationship more complex.
Molecular: 50% of the protein, produced by a single copy of the dominant (functional) allele in the heterozygote, is sufficient to produce the
dominant trait.
Incomplete Inheritance: In the case of dominant traits, this pattern occurs when a dominant phenotype is not expressed even though an individual
penetrance carries a dominant allele. An example is an individual who carries the polydactyly allele but has a normal number of fingers and toes. In the
case of recessive traits, this pattern occurs when a homozygote carrying both recessive alleles does not exhibit the trait.
Molecular: Even though a dominant allele is present or two recessive alleles are present, the protein coded by the gene may not exert its
effects. This can be due to environmental influences or due to other genes that may code proteins that counteract the effects of the protein
coded by the dominant allele.
Incomplete Inheritance: This pattern occurs when the heterozygote has a phenotype that is intermediate between either corresponding homozygote. For
dominance example, a cross between homozygous red-flowered and homozygous white-flowered parents produces heterozygous offspring with pink flowers.
Molecular: 50% of the protein, produced by a single copy of the functional allele in the heterozygote, is not sufficient to produce the same
trait as in a homozygote making 100% of that protein.
Heterozygote Inheritance: This pattern occurs when the heterozygote has a trait that confers a greater level of reproductive success than either homozygote has.
advantage Molecular: Three common ways that heterozygotes may gain benefits: (1) Their cells may have increased resistance to infection by
microorganisms; (2) they may produce more forms of protein dimers with enhanced function; or (3) they may produce proteins that function
under a wider range of conditions.
Codominance Inheritance: This pattern occurs when the heterozygote expresses both alleles simultaneously without forming an intermediate phenotype.
For example, with regard to human blood types, an individual carrying the A and B alleles will have an AB blood type.
Molecular: The codominant alleles code proteins that function slightly differently from each other, and the function of each protein in the
heterozygote affects the phenotype uniquely.
X-linked Inheritance: This pattern involves the inheritance of genes that are located on the X chromosome. In mammals and fruit flies, males have
inheritance one copy of X-linked genes, whereas females have two copies.
Molecular: If a pair of X-linked alleles shows a simple dominant/recessive relationship, 50% of the protein, produced by a single copy of the
dominant allele in a heterozygous female, is sufficient to produce the dominant trait. Males have only one copy of X-linked genes and
therefore express the copy they carry.
Sex-influenced Inheritance: This pattern refers to the effect of sex on the phenotype of the individual. Some alleles are recessive in males and dominant in
inheritance females; others are dominant in males and recessive in females.
Molecular: Sex hormones may regulate the molecular expression of genes. This regulation can influence the phenotypic effects of alleles.
Sex-limited Inheritance: In this pattern, a trait occurs in only one sex. It may occur in males or females, but not both. An example is sperm production in
inheritance male animals.
Molecular: Sex hormones may regulate the molecular expression of genes. This regulation can influence the phenotypic effects of alleles. In this
pattern of inheritance, sex hormones that are primarily produced in only one sex are essential for an individual to display a particular phenotype.
Lethal alleles Inheritance: A lethal allele is one that has the potential of causing the death of an organism.
Molecular: Lethal alleles are most commonly loss-of-function alleles that code proteins that are necessary for survival. In some cases, such an
allele may be due to a mutation in a nonessential gene that changes a protein so that it functions with abnormal and detrimental consequences.

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4.2 DOMINANT AND RECESSIVE ALLELES 83

4.1 COMPREHENSION QUESTION


1. Which of the following statements is true?
a. Not all inheritance patterns follow a strict dominant/reces-
sive relationship.
b. Geneticists want to understand both inheritance patterns
and the underlying molecular mechanisms that cause them
to happen.
c. Different inheritance patterns are explained by a variety of
different molecular mechanisms.
d. All of the above are true.

4.2 DOMINANT AND RECESSIVE


ALLELES FIGURE 4.1 An example of genetic polymorphism. Both yel-
low and red flowers are common in natural populations of the elderflower
Learning Outcomes: orchid, Dactylorhiza sambucina, and both are considered wild type.
1. Define wild-type allele and genetic polymorphism. Blickwinkel/Woike/Alamy Stock Photo
2. Explain why loss-of-function alleles often follow a recessive CONCEPT CHECK: Why are both of these colors considered to be wild type?
pattern of inheritance.
3. Describe how traits can exhibit incomplete penetrance and
vary in their expressivity. Among Mendel’s seven characters discussed in Chapter 3,
the wild-type alleles are those that produce tall plants, purple
flowers, axial flowers, yellow seeds, round seeds, green pods, and
In Chapter 2, we examined patterns of inheritance that showed a smooth pods (refer back to Figure 3.4). The mutant alleles result in
simple dominant/recessive relationship. This means that a hetero- short plants, white flowers, terminal flowers, green seeds, wrin-
zygote exhibits the dominant trait. In this section, we will take a kled seeds, yellow pods, and constricted pods. You may have al-
closer look at why an allele may be dominant or recessive and ready noticed that the seven wild-type alleles are dominant over
discuss how dominant alleles may not always exert their effects. the seven mutant alleles. Likewise, red eyes and normal (long)
wings are examples of traits produced by wild-type alleles in Dro-
Wild-Type Alleles Are Common in a Population sophila, and white eyes and miniature wings are due to recessive
For any given gene, geneticists refer to prevalent alleles in a natural mutant alleles.
population as wild-type alleles. In large populations, more than The idea that recessive mutant alleles usually cause a sub-
one wild-type allele may occur—a phenomenon known as genetic stantial decrease in the expression of a functional protein is
polymorphism. For example, Figure 4.1 illustrates a striking supported by the analysis of many human genetic diseases.
example of polymorphism in the elderflower orchid, Dactylorhiza Keep in mind that a genetic disease is usually caused by a mu-
sambucina. Throughout the range of this species in Europe, both tant allele. Table 4.2 lists several examples of human genetic
yellow- and red-flowered individuals are common. Both colors are diseases in which the recessive allele fails to produce a specific
considered wild type. At the molecular level, a wild-type allele cellular protein in its active form. In many cases, molecular
typically codes a protein that is made in the proper amount and techniques have enabled researchers to clone these genes and
functions in a particular way. As discussed in Chapter 27, wild-type determine the differences between the wild-type and mutant al-
alleles tend to promote the reproductive success of organisms in leles. They have found that the recessive allele usually contains
their native environments. a mutation that causes a defect in the synthesis of a fully func-
tional protein.
To understand why many defective mutant alleles are inher-
Recessive Mutant Alleles Often Cause a Reduction
ited recessively, we need to take a quantitative look at protein
in the Amount or Function of the Coded Proteins function. With the exception of sex-linked genes, diploid individu-
Random mutations occur in populations and alter preexisting alleles. als usually have two copies of every gene. In a simple dominant/
Geneticists sometimes refer to these altered alleles as mutant alleles recessive relationship, the recessive allele does not affect the phe-
to distinguish them from the more common wild-type alleles. Be- notype of the heterozygote. In other words, a single copy of the
cause random mutations are more likely to disrupt gene function, dominant allele is sufficient to mask the effects of the recessive
mutant alleles are often defective in their ability to express a func- allele. If the recessive allele cannot produce a functional protein,
tional protein. These defective alleles are called loss-of-function al- how do we explain the wild-type phenotype of the heterozygote?
leles. Such mutant alleles tend to be rare in natural populations. They As shown in Figure 4.2, a common explanation is that 50% of the
are typically, but not always, inherited in a recessive fashion. functional protein is adequate to provide the wild-type phenotype.

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84 C H A P T E R 4 :: EXTENSIONS OF MENDELIAN INHERITANCE

TAB L E 4.2
Examples of Recessive Human Diseases
Protein That Is Produced by
Disease the Functional Gene* Description
Phenylketonuria Phenylalanine hydroxylase Inability to metabolize phenylalanine. The effects of the disease can be prevented by following a
phenylalanine-free diet. If the diet is not followed early in life, the result can be severe mental
impairment and physical degeneration.
Albinism Tyrosinase Lack of pigmentation in the skin, eyes, and hair.
Tay-Sachs disease Hexosaminidase A Defect in lipid metabolism. Leads to paralysis, blindness, and early death.
Sandhoff disease Hexosaminidase B Defect in lipid metabolism. Muscle weakness in infancy, early blindness, and progressive mental and
motor deterioration.
Cystic fibrosis Chloride transporter Inability to regulate ion balance across epithelial cells. Leads to production of thick mucus and results
in chronic lung infections, poor weight gain, and organ malfunctions.
Lesch-Nyhan syndrome Hypoxanthine-guanine Inability to metabolize purines, which are bases found in DNA and RNA. Leads to self-mutilation
phosphoribosyl transferase behavior, poor motor skills, and usually mental impairment and kidney failure.
*Individuals who exhibit the disease are either homozygous for a recessive allele or have only one copy of the gene in the case of X-linked genes in human males. The disease symptoms
result from a defect in the amount or function of the normal protein.

Dominant (functional) allele: P (purple) Dominant Mutant Alleles Usually Exert Their
Recessive (defective) allele: p (white)
Effects in One of Three Ways
Genotype PP Pp pp Though dominant mutant alleles are much less common than re-
Amount of cessive mutant alleles, they do occur in natural populations. How
functional can a mutant allele be dominant over a wild-type allele? One of
protein P 100% 50% 0%
three mechanisms accounts for most dominant mutant alleles:
a gain-of-function mutation, a dominant-negative mutation, or
haploinsufficiency.
Phenotype Purple Purple White
∙ Gain-of-function mutations change the gene or the pro-
Simple dominant/ tein coded by a gene so that it gains a new or abnormal
recessive
relationship function. A mutant gene may be overexpressed or it may
be expressed in the wrong cell type. For example, many
forms of cancer are caused by gain-of-function mutations
FI GURE 4.2 A comparison of protein levels among homozy- in genes that code proteins that promote cell division.
gous (PP or pp) and heterozygous (Pp) genotypes. Such mutations cause the cells to divide in an uncon-
Genes→Traits In a simple dominant/recessive relationship, 50% of the protein trolled way.
coded by one copy of the dominant allele in the heterozygote is sufficient to ∙ Dominant-negative mutations change a protein such that
produce the wild-type phenotype, in this case, purple flowers. A complete lack the mutant protein acts antagonistically to the normal pro-
of the functional protein results in white flowers. tein. In a heterozygote, the mutant protein counteracts the
CONCEPT CHECK: Does a PP individual produce more of the protein coded effects of the normal protein, thereby altering the pheno-
by the P gene than is necessary for the purple color? type. An example is STAT-3 dominant-negative disease.
STAT-3 codes a regulatory protein that is important for the
function of the immune system in humans. In a heterozy-
gote, the dominant-negative mutant protein inhibits the
In this example, the PP homozygote and Pp heterozygote each function of the wild-type protein. The inhibition is thought
make sufficient amounts of the functional protein to yield purple to occur because the mutant STAT-3 protein forms a dimer
flowers. with the wild-type protein. The inhibition of the wild-type
A second possible explanation for other dominant alleles is protein results in defects in immune system function.
that the heterozygote actually produces more than 50% of the ∙ In haploinsufficiency, the dominant mutant allele is a
functional protein. Due to gene regulation, the expression of the loss-of-function allele. Haploinsufficiency is used to de-
normal (functional) gene may be increased, or up-regulated, in scribe patterns of inheritance in which a heterozygote
the heterozygote to compensate for the lack of function of the defec- (with one functional allele and one inactive allele) exhibits
tive allele. The topic of gene regulation is discussed in Chapters 14 an abnormal or disease phenotype. An example in humans
and 15. is polydactyly, which is discussed next.

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4.2 DOMINANT AND RECESSIVE ALLELES 85

Traits May Skip a Generation Due to Incomplete Sometimes, however, individuals carry the dominant allele
Penetrance and Vary in Their Expressivity but do not exhibit the trait. In Figure 4.3a, individual III-2, who
does not have polydactyly, has inherited the polydactyly allele
As we have seen, dominant alleles are expected to influence the from II-4 and passed the allele to a female and male offspring.
outcome of a trait when they are present in heterozygotes. Occa- These observations indicate that III-2 is an unaffected heterozy-
sionally, however, this may not occur. gote. In the case of polydactyly, the dominant allele does not
∙ The phenomenon called incomplete penetrance results in always “penetrate” into the phenotype of the individual. Alterna-
a pattern of inheritance in which an allele that is expected tively, for recessive traits, incomplete penetrance occurs if a ho-
to cause a particular phenotype does not always do so. mozygote carrying the recessive allele does not exhibit the
recessive trait.
Figure 4.3a presents a human pedigree for a dominant trait known The measure of penetrance is described at the population
as polydactyly. This trait causes the affected individual to have level. For example, if 60% of the heterozygotes carrying a domi-
additional fingers or toes (or both) (Figure 4.3b). Polydactyly is nant allele exhibit the trait, we say that this trait is 60% penetrant.
due to an autosomal dominant allele—the allele is found in a gene At the individual level, the trait is either present or not.
located on an autosome (not a sex chromosome) and a single copy Another term used to describe the outcome of traits is the
of this allele is sufficient to cause this condition. degree to which the trait is expressed, or its expressivity. In the
case of polydactyly, the number of extra digits can vary. For
example, one individual may have an extra toe on only one foot,
I -1 I -2 whereas a second individual may have extra digits on both the
hands and feet. Using genetic terminology, a person with sev-
eral extra digits would have high expressivity of this trait,
whereas a person with a single extra digit would have low
II -1 II -2 II -3 II -4 II -5 expressivity.
How do we explain incomplete penetrance and variable ex-
pressivity? Although the answer may not always be understood,
the range of phenotypes is often due to two factors:
III -1 III -2 III -3 III -4 III -5
∙ The environment may affect the outcome of the
phenotype.
∙ One or more modifier genes may also affect the pheno-
IV-1 IV-2 IV-3 type. For example, a modifier gene may affect the expres-
(a) sion of the gene associated with polydactly and thereby
influence the number of fingers or toes.
We will consider the issue of the environment next. The effects of
modifier genes will be discussed later in the chapter.

4.2 COMPREHENSION QUESTIONS


1. Which of the following phenotypes is not an example of a wild-
type phenotype?
a. Yellow-flowered elderflower orchid
b. Red-flowered elderflower orchid
c. A gray elephant
d. An albino (white) elephant
(b)
2. Dominant alleles may result from a mutation that causes
F I G U R E 4 . 3 Polydactyly, a dominant trait that shows in- a. the overexpression of a gene or its protein product.
complete penetrance. (a) A family pedigree. Affected individuals are b. production of a protein that inhibits the function of a normal
shown in black. Notice that offspring IV-1 and IV-3 have inherited the protein.
trait from a parent, III-2, who is heterozygous but does not exhibit
c. a protein to be inactive and 50% of the normal amount of
polydactyly. (b) Antonio Alfonseca, a former baseball player with
polydactyly.
the protein is insufficient for a normal phenotype.
(b): Bob Shanley/Palm Beach Post/ZUMAPRESS/Newscom d. any of the above.
CONCEPT CHECK: Which individual(s) in this pedigree exhibit(s) the effect 3. Polydactyly is a condition in which a person has extra fingers
of incomplete penetrance? and/or toes. It is caused by a dominant allele. If a person carries

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86 C H A P T E R 4 :: EXTENSIONS OF MENDELIAN INHERITANCE

this allele but does not have any extra fingers or toes, this is an changes one amino acid in tyrosinase and this causes the enzyme
example of to work poorly in warmer parts of the body. However, in the cooler
a. haploinsufficiency. extremities, it is able to function and produce darker fur. This is an
b. a dominant-negative mutation. example of a temperature-sensitive allele. The phenotypic ef-
c. incomplete penetrance. fects are dependent on the temperature. As you might expect, if
Siamese cats are raised at a lower temperature, their fur tends to be
d. a gain-of-function mutation.
darker than if they are raised at a higher one. For those cats that
spend time outdoors in seasonal climates, their fur is lighter in the
warm summer and darker in the cold winter.
4.3 ENVIRONMENTAL EFFECTS A dramatic example of the relationship between environment
ON GENE EXPRESSION and phenotype can be seen in the human genetic disease known as
phenylketonuria (PKU). This autosomal recessive disease is caused
Learning Outcomes: by a loss-of-function mutation in a gene that codes the enzyme
1. Discuss the role of the environment with regard to an indi- phenylalanine hydroxylase. Homozygous individuals with this de-
vidual’s traits. fective allele are unable to metabolize the amino acid phenylala-
2. Define norm of reaction. nine properly. When given a standard diet containing phenylalanine,
which is found in most protein-rich foods, PKU individuals mani-
fest a variety of detrimental traits including mental impairment,
Throughout this book, our study of genetics tends to focus on the underdeveloped teeth, and foul-smelling urine. In contrast, when
roles of genes in the outcome of traits. In addition to genetic varia- PKU is diagnosed early and patients follow a restricted diet low in
tion, environmental conditions have a great effect on the pheno- phenylalanine, they develop properly (Figure 4.4b).
type of the individual. An example is the coat color variation Since the 1960s, testing methods have been developed that
found in a Siamese cat (Figure 4.4a). can determine if an individual is lacking the phenylalanine hy-
Dark coloration in the fur is seen at the extremities of the droxylase enzyme. These tests permit the identification of in-
body, such as the ears, tail, and paws. How do we explain this phe- fants who have PKU, and their diets can then be modified before
notype? It is due to a mutation in the gene that codes tyrosinase, the harmful effects of phenylalanine ingestion have occurred. As
which is an enzyme involved in making the pigment melanin. The a result of government legislation, more than 90% of infants
more melanin that there is, the darker the fur will be. The mutation born in the United States are now tested for PKU. This test

F I G URE 4 . 4 Variation in the expression of traits due to environ-


mental effects. (a) A Siamese cat. This coat color pattern is also found in a
breed of rabbit called a Himalayan. (b) A person with PKU who has followed a
restricted diet and developed properly. (c) Norm of reaction. In this experi-
ment, fertilized eggs from a population of genetically identical fruit flies
(Drosophila melanogaster) were allowed to develop into adults at different
environmental temperatures. The graph shows the relationship between tem-
perature (an environmental factor) and facet number in the eyes of the resulting
adult flies. The micrograph shows an eye of D. melanogaster.
(a) axelbueckert/iStock/Getty Images Plus; (b): ©Sally Haugen/Virginia Schuett, www.pkunews.org;
(c) Tomatito/Shutterstock

(a) Siamese cat (b) Healthy person with PKU CONCEPT CHECK: What are the two main factors that determine an organism’s
traits?

1000

Facet
900
Facet number

800

700
182 μm
0
0 15 20 25 30
Temperature (°C)
(c) Norm of reaction

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4.4 INCOMPLETE DOMINANCE, HETEROZYGOTE ADVANTAGE, AND CODOMINANCE 87

prevents a great deal of human suffering and is also cost- Incomplete Dominance Occurs When Two Alleles
effective. In the United States, the annual cost of PKU testing is Produce an Intermediate Phenotype
estimated to be a few million dollars, whereas the cost of treating
severely affected individuals with the disease would be hundreds Although many alleles display a simple dominant/recessive rela-
of millions of dollars. tionship, some do not.
The Siamese cat and individuals with PKU provide exam- ∙ Incomplete dominance is a pattern of inheritance in which
ples of the effects of different environmental conditions. When the phenotype of the heterozygote is intermediate between
considering the environment, geneticists often examine a range of those of the corresponding homozygous individuals.
conditions, rather than simply observing phenotypes under two
different conditions. The term norm of reaction refers to the ef- In 1905, Carl Correns first observed an example of incomplete
fects of environmental variation on a phenotype. Specifically, it is dominance in the colors of the flowers of the four-o’clock plant
the phenotypic range seen in individuals with a particular geno- (Mirabilis jalapa). Figure 4.5 describes Correns’ experiment, in
type. To evaluate the norm of reaction, researchers begin with which a homozygous red-flowered four-o’clock plant was crossed to
true-breeding strains that have the same genotypes and subject a homozygous white-flowered plant. Because neither allele is dom-
them to different environmental conditions. inant, each allele is designated with a superscript. The wild-type
As an example, let’s consider facet number in the eyes of
fruit flies, Drosophila melanogaster. This species has compound Red White
eyes composed of many individual facets. Figure 4.4c shows the P generation
norm of reaction for facet number in genetically identical fruit
flies that developed from fertilized eggs at different tempera-
tures. As shown in the graph, the facet number varies with CRCR x CWCW
changes in temperature. At a lower temperature (15°C), the facet
number is over 1000, whereas at a higher temperature (30°C), it
is approximately 750. Gametes CR CW

4.3 COMPREHENSION QUESTION Pink

1. The outcome of an individual’s traits is controlled by F1 generation


a. genes.
b. the environment. CRCW

c. both genes and the environment.


d. neither genes nor the environment. Gametes CR or CW

Self-fertilization
4.4 INCOMPLETE DOMINANCE,
HETEROZYGOTE ADVANTAGE, Sperm
F2 generation CR CW
AND CODOMINANCE
Learning Outcomes: CR
1. Predict the outcome of crosses involving incomplete domi- CRCR CRCW
Egg
nance, heterozygote advantage, and codominance.
2. Explain the underlying molecular mechanisms of incomplete
dominance, heterozygote advantage, and codominance. CW
CRCW CWCW

Thus far, we have considered inheritance patterns that follow a F I G URE 4 . 5 Incomplete dominance in the
simple dominant/recessive inheritance pattern. In these cases, the four-o’clock plant, Mirabilis jalapa.
Genes→Traits When two different homozygotes (CRCR and
heterozygote exhibits a phenotype that is the same as a homozy-
CWCW) of the four-o’clock plant are crossed, the resulting het-
gote that carries two copies of the dominant allele but different R W
erozygote, C C , has an intermediate phenotype of pink flowers. In the hetero-
from the homozygote carrying two copies of the recessive allele. zygote, 50% of the functional protein coded by the CR allele is not sufficient to
In this section, we will examine three different inheritance pat- produce a red phenotype.
terns in which the heterozygote shows a phenotype that is different CONCEPT CHECK: At the molecular level, what is the explanation for why
from both types of homozygotes. the flowers of the heterozygous four-o’clock plant are pink instead of red?

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88 C H A P T E R 4 :: EXTENSIONS OF MENDELIAN INHERITANCE

allele for red flower color is designated CR and the allele for white Next, you can use the probabilities derived from the Punnett square
flower color is CW. As shown in the figure, the offspring had pink in the multinomial expansion equation.
flowers. When these F1 offspring were allowed to self-fertilize, ANSWER: From the Punnett square, the phenotypic ratio for the off-
the F2 generation consisted of 1/4 red-flowered plants, 1/2 pink- spring is 1 red : 2 pink : 1 white. In other words, 1/4 are expected to be
flowered plants, and 1/4 white-flowered plants. The pink plants in red, 1/2 pink, and 1/4 white.
the F2 generation were heterozygotes with an intermediate pheno-
type. As presented in the Punnett square in Figure 4.5, the F2 gen-
n! paqbrc
eration displayed a 1:2:1 phenotypic ratio, which is different from P=
a!b!c!
the 3:1 ratio observed for simple Mendelian inheritance.
In Figure 4.5, incomplete dominance has occurred because a
where
heterozygote has an intermediate phenotype. At the molecular level,
n = total number of offspring = 6
the allele that causes a white phenotype is expected to result in a lack
of a functional protein required for pigmentation. Depending on the a = number of reds = 3
effects of gene regulation, the heterozygotes may produce only 50% p = probability of red = 1/4
of the functional protein, but this amount is not sufficient to produce b = number of pinks = 1
the same phenotype as the CRCR homozygote, which may make q = probability of pink = 1/2
twice as much of this protein. In this example, a reasonable explana- c = number of whites = 2
tion is that 50% of the functional protein cannot accomplish the same r = probability of white = 1/4
level of pigment synthesis that 100% of the protein can.
You substitute these values into the equation:

GENETIC TIPS THE QUESTION: Two pink-flowered P=


6!
(1/4)3 (1/2)1 (1/4)2
four-o’clocks were crossed to each other. What is the probability that 3!1!2!
a group of six offspring from this cross will be composed of one P = 0.029, or 2.9%
pink-, two white-, and three red-flowered plants?
This means that 2.9% of the time you expect to obtain six offspring plants
of which three have red flowers, one has pink flowers, and two have white
T OPIC: What topic in genetics does this question address? The
flowers.
topic is Mendelian inheritance. More specifically, the question is
about incomplete dominance in four-o’clock plants.

I NFORMATION: What information do you know based on the


question and your understanding of the topic? From the Our Conclusions About Dominance May Depend
question, you know that two pink-flowered four-o’clock plants are on the Level of Examination
crossed to each other. From your understanding of the topic, you
may remember that pink-flowered plants are heterozygous and Our opinion of whether a trait is dominant or incompletely domi-
show an intermediate phenotype. Also, from Chapter 3, you may nant may depend on how closely we examine the trait in individual
recall that the multinomial expansion equation is used to solve organisms. The more closely we look, the more likely we are to
problems involving three or more categories of offspring that are discover that the heterozygote is not quite the same as the wild-type
produced in an unordered fashion. homozygote. For example, Mendel studied the characteristic of pea
seed shape and visually concluded that the RR and Rr genotypes
P ROBLEM-SOLVING S TRATEGY: Predict the outcome. produced round seeds and the rr genotype produced wrinkled
Make a calculation. To begin to solve this problem, you need to seeds. The peculiar morphology of the wrinkled seed is caused by
know the probability of producing pink-, white-, and red-flowered a large decrease in the amount of starch deposition in the seed due
offspring. This can be deduced from a Punnett square, which is to a defective r allele.
shown below. More recently, other scientists have dissected round and
The cross is CR CW × CR CW. wrinkled seeds and examined their contents under a micro-
scope. They have found that round seeds from heterozygotes
CR CW actually contain an intermediate number of starch grains com-
pared with seeds from the corresponding homozygotes (Fig-
C R CR CRCW ure 4.6). Within the seed, an intermediate amount of the
CR functional protein is not enough to produce as many starch
Red Pink grains as in the homozygote carrying two copies of the R al-
lele. Even so, at the level of our unaided eyes, heterozygotes
CR CW CWCW produce seeds that appear to be round. With regard to pheno-
CW types, the R allele is dominant to the r allele at the level of
Pink White visual examination, but the R and r alleles show incomplete
dominance at the level of starch biosynthesis.

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4.4 INCOMPLETE DOMINANCE, HETEROZYGOTE ADVANTAGE, AND CODOMINANCE 89

Dominant (functional) allele: R (round)


Recessive (defective) allele: r (wrinkled)

Genotype RR Rr rr
Amount of functional
(starch-producing)
protein 100% 50% 0%

6.6 μm 6.6 μm

Phenotype Round Round Wrinkled (a) Normal red blood cell (b) Sickled red blood cell

With unaided eye Hb A Hb S × Hb A Hb S


(simple dominant/
recessive relationship)

Sperm
With microscope
(incomplete Hb A Hb S
dominance)
Hb A Hb A Hb A Hb S
(unaffected, (unaffected,
Hb A
not malaria- malaria-
FI GURE 4.6 A comparison of phenotypes at the macroscopic resistant) resistant)
and microscopic levels. Egg
Hb A Hb S Hb S Hb S
Genes→Traits This illustration shows the effects of a heterozygous pea plant
(unaffected, (sickle cell
having only 50% of the functional protein needed for starch production. The Hb S
malaria- disease)
seed from the heterozygote appears to be as round as that from the homozy- resistant)
gote carrying two copies of the R allele, but when examined microscopically, it
has only half the amount of starch as is found in the homozygote’s seed. (c) Example of sickle cell inheritance
CONCEPT CHECK: At which level(s) is incomplete dominance more likely to pattern
be observed—the molecular, cellular, and/or organism level?
FIGURE 4.7 Inheritance of sickle cell disease.
A comparison of (a) a normal red blood cell and (b) one
from a person with sickle cell disease. (c) The outcome of
Heterozygote Advantage Occurs When a cross between two heterozygous individuals.
(a, b): Mary Martin/Science Source
Heterozygotes Have Greater Reproductive Success
CONCEPT CHECK: Why does the heterozygote have an advantage?
As we have seen, the environment plays a key role in the outcome
of traits. For certain genes, heterozygotes may display characteris-
tics that are more beneficial for their survival in a particular envi- with a normal span of 4 months, and therefore, anemia results. In
ronment. Such heterozygotes may be more likely to survive and addition, sickled cells can become clogged in the capillaries
reproduce. For example, a heterozygote may be larger, more dis- throughout the body, leading to localized areas of oxygen deple-
ease-resistant, or better able to withstand harsh environmental tion. Such an event causes pain and sometimes tissue and organ
conditions. damage. For these reasons, the homozygous HbSHbS individual
∙ The phenomenon in which a heterozygote has greater re- usually has a shortened life span relative to an individual produc-
ing hemoglobin A.
productive success compared with either of the corre-
In spite of the harmful consequences to homozygotes, the
sponding homozygotes is called heterozygote advantage.
sickle cell allele is found at a fairly high frequency among human
A well-documented example of heterozygote advantage involves a populations that are exposed to malaria. The protist genus that
human allele that causes sickle cell disease in homozygous indi- causes malaria, Plasmodium, spends part of its life cycle within
viduals. This disease is an autosomal recessive disorder in which the Anopheles mosquito and another part within the red blood
the affected individual produces an altered form of the protein cells of humans who have been bitten by an infected mos-
hemoglobin, which carries oxygen within red blood cells. Most quito. When an HbSHbS homozygote or an HbAHbS heterozygote is
people carry the HbA allele and make hemoglobin A. Individuals infected with Plasmodium, the parasite’s metabolic activity within
affected with sickle cell disease are homozygous for the HbS allele red blood cells causes a lower oxygen concentration and thereby
and produce only hemoglobin S. This causes their red blood cells promotes sickling. The sickled cells are more likely to be phago-
to deform into a sickle shape (see Figure 4.7a, b) under conditions cytized by the immune system, which diminishes the proliferation
of low oxygen concentration as in the deoxygenated part of the of the pathogen.
cardiovascular system. People who are heterozygotes have better resistance to ma-
How does the sickling of red blood cells cause disease laria than do HbAHbA homozygotes, and they do not suffer the ill
symptoms? The sickling phenomenon causes the life span of red effects of sickle cell disease. Therefore, even though the homozy-
blood cells to be greatly shortened to only a few weeks, compared gous HbSHbS condition is detrimental, the higher survival rate of

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90 C H A P T E R 4 :: EXTENSIONS OF MENDELIAN INHERITANCE

heterozygotes has selected for the presence of the HbS allele within within red blood cells. Interestingly, researchers have speculated
populations where malaria is prevalent. When viewing survival in that other alleles in humans may confer disease resistance in the
such a region, heterozygote advantage explains the prevalence of heterozygous condition but are detrimental in the homozygous
the sickle cell allele. In Chapter 27, we will consider the role that state. These include alleles involved in PKU, in which the hetero-
natural selection plays in maintaining alleles that are beneficial to zygous fetus may be resistant to miscarriage caused by a fungal
the heterozygote but harmful to the homozygote. toxin, and in Tay-Sachs disease, in which the heterozygote may be
Figure 4.7c illustrates the predicted outcome when two het- resistant to tuberculosis.
erozygotes have children. In this example, 1/4 of the offspring are
HbAHbA (unaffected, not malaria-resistant), 1/2 are HbAHbS (unaf- Subunit Composition of Proteins. A second way to explain
fected, malaria-resistant), and 1/4 are HbSHbS (have sickle cell heterozygote advantage is related to the subunit composition of
disease). This 1:2:1 ratio deviates from a simple Mendelian 3:1 proteins. In some cases, a protein functions as a complex of mul-
phenotypic ratio. tiple subunits; each subunit is composed of one polypeptide. A
Heterozygote advantage is usually due to two alleles that protein composed of two subunits is called a dimer. When both
produce proteins with slightly different amino acid sequences. subunits are coded by the same gene, the protein is a homodimer.
How can we explain the observation that two protein variants in The prefix homo- means that the subunits come from the same
the HbAHbS heterozygote produce a more favorable phenotype? type of gene although the gene may exist in different alleles. Fig-
Three common explanations are discussed next. ure 4.8b considers a situation in which a gene exists in two alleles
that code polypeptides designated A1 and A2. Homozygous indi-
Disease Resistance. In the case of sickle cell disease, the phe- viduals can produce only A1A1 or A2A2 homodimers, whereas a
notype is related to the infectivity of Plasmodium (Figure 4.8a). heterozygote can also produce an A1A2 homodimer. Thus, hetero-
In the heterozygote, the infectious agent is less likely to propagate zygotes can produce three forms of the homodimer, homozygotes
only one. For some proteins, A1A2 homodimers may have better
functional activity because they are more stable or able to function
under a wider range of conditions. The greater activity of the ho-
Pathogen can Pathogen
successfully cannot modimer protein may be the underlying reason why a heterozy-
propagate. successfully gote has characteristics superior to either homozygote.
propagate.
Differences in Protein Function. A third molecular expla-
A1A1 A1A2
nation of heterozygote advantage is that the proteins coded by
each allele exhibit differences in their functional activity. For ex-
ample, suppose that a gene codes a metabolic enzyme that can be
Normal homozygote Heterozygote found in two forms (corresponding to the two alleles), one that
(sensitive to infection) (resistant to infection) functions better at a lower temperature and another that functions
optimally at a higher temperature (Figure 4.8c). The heterozy-
(a) Disease resistance
gote, which makes a mixture of both enzymes, may be at an ad-
vantage under a wider temperature range than either of the
A1 A1 The homozygotes that are A1A1 or A2A2
will make homodimers that are A1A1 and corresponding homozygotes.
A2A2, respectively. The A1A2 heterozygote
A2 A2
can make A1A1 and A2A2 and can also make
A1A2 homodimers, which may have better Alleles of the ABO Blood Group Can Be Dominant,
A1 A2 functional activity. Recessive, or Codominant
Thus far, we have considered examples in which a gene exists in
(b) Homodimer formation two different alleles. As researchers have probed genes at the
molecular level within natural populations of organisms, they
have discovered that most genes exist in multiple alleles. Within
A heterozygote, E1E2, would
E1 E2
produce both enzymes and a population, genes are typically found in a few or even many
have a broader temperature alleles.
27°–32°C 30°–37°C range (i.e., 27°–37°C) in which The ABO group of antigens, which determine blood type in
(optimum (optimum the enzyme would function.
temperature temperature humans, are produced in the human population under the control
range) range) of multiple alleles; two of these alleles exhibit a relationship called
codominance. To understand this concept, we first need to exam-
(c) Variation in functional activity
ine the molecular characteristics of human blood types. The
FI GURE 4.8 Three possible explanations for heterozygote ad- plasma membranes of red blood cells have groups of intercon-
vantage at the molecular level. nected sugars—oligosaccharides—that act as surface antigens
CONCEPT CHECK: Which of these three scenarios explains heterozygote (Figure 4.9a). Antigens are molecular structures that are recog-
advantage with regard to the sickle cell allele? nized by antibodies produced by the immune system.

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4.4 INCOMPLETE DOMINANCE, HETEROZYGOTE ADVANTAGE, AND CODOMINANCE 91

Antigen A Antigen B Antigen A Antigen B

RBC N-acetyl- RBC Galactose RBC RBC


galactosamine KEY
Blood type: O A B AB N-acetylgalactosamine
Genotype: ii I AI A or I Ai I BI B or I Bi I AI B Galactose
Fucose
Surface antigen: neither A or B A B A and B
N-acetyl-glucosamine
Serum antibodies: against A and B against B against A none
(a) ABO blood types

I Ai × I Bi Antigen A
Glycosyl transferase
coded by IA allele

Active
Sperm site
IB i
RBC RBC
N-acetyl-
IA B
I A
I i galactosamine
IA
Type AB Type A Antigen B
Glycosyl transferase
Egg coded by IB allele

I Bi ii Active
i site
Type B Type O
RBC RBC
(b) Example of the ABO inheritance Galactose
pattern (c) Formation of A and B antigens by glycosyl transferase

FIGURE 4.9 ABO blood types. (a) A schematic representation of human blood types at the cellular level. Note: This is not
drawn to scale; a red blood cell is much larger than any oligosaccharide on its surface. (b) The predicted offspring from parents who are
IAi and IBi. (c) The glycosyl transferase coded by the IA and IB alleles recognizes different sugars due to changes in its active site. The
i allele results in a nonfunctional enzyme. The antigen produced by type O individuals is called H antigen. Humans of all blood types do
not usually produce antibodies against H antigen.
CONCEPT CHECK: Which allele is an example of a loss-of-function allele?

The synthesis of these surface antigens is controlled by three al- Note: The allele designations for the IA and IB alleles are a capi-
leles, designated i, IA, and IB. tal I with a superscript (A or B) because both of them are domi-
nant to the i allele, but they are not dominant to each other.
∙ The i allele is recessive to both IA and IB, which is why the
i allele is designated with a lowercase letter. A person who As an example of the inheritance of blood type, let’s consider
is homozygous ii has type O blood and produces a rela- the possible offspring between two parents who are IAi and IBi
tively short oligosaccharide, which is called H antigen. (Figure 4.9b). The IAi parent makes IA and i gametes, and the IBi
∙ A homozygous IAIA or heterozygous IAi individual has type parent makes IB and i gametes. These combine to produce IAIB, IAi,
A blood. The red blood cells of this individual contain the IBi, and ii offspring in a 1:1:1:1 ratio. The resulting blood types of
surface antigen known as A. the offspring are AB, A, B, and O, respectively.
∙ A homozygous IBIB or heterozygous IBi individual pro- Biochemists have analyzed the oligosaccharides on the sur-
duces surface antigen B. As Figure 4.9a indicates, surface faces of cells of differing blood types. In type O, the oligosaccha-
antigens A and B have different molecular structures. ride is smaller than in type A or type B because a sugar has not
∙ A person who is IAIB has the blood type AB and expresses been attached to a specific site on the oligosaccharide. This idea is
both surface antigens A and B. schematically shown in Figure 4.9a. How do we explain this dif-
∙ The phenomenon in which two alleles are both expressed ference at the molecular level? The gene that determines ABO
in the heterozygous individual is called codominance. In blood type codes a type of enzyme called a glycosyl transferase
this case, the IA and IB alleles are codominant to each other. that attaches a sugar to an oligosaccharide.

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92 C H A P T E R 4 :: EXTENSIONS OF MENDELIAN INHERITANCE

∙ The i allele carries a mutation that renders this enzyme 2. A person with type AB blood has a child with a person with type
inactive, which prevents the attachment of an additional O blood. What are the possible blood types of the child?
sugar. a. A or B
∙ The two types of glycosyl transferase coded by the IA and b. A, B, or O
IB alleles have different structures in their active sites. The c. A, B, AB, or O
glycosyl transferase coded by the IA allele has an active site
d. O only
that recognizes uridine diphosphate N-acetylgalactos-
amine and attaches N-acetylgalactosamine to the oligosac-
charide (Figure 4.9c). This produces the molecular
structure of surface antigen A. 4.5 GENES ON SEX
∙ The glycosyl transferase coded by the IB allele recognizes
CHROMOSOMES
UDP-galactose and attaches galactose to the oligosaccha-
ride. This produces the molecular structure of surface anti- Learning Outcomes:
gen B. 1. Predict the outcome of crosses for X-linked inheritance.
∙ A person with type AB blood makes both types of en- 2. Explain pseudoautosomal inheritance.
zymes and thereby makes oligosaccharides with both types
of sugar attached.
The term sex chromosomes refers to chromosomes that differ
A small difference in the structure of the oligosaccharide, between males and females. In mammals and fruit flies, the sex
namely, a GalNAc in antigen A versus galactose in antigen B, chromosomes are designated X and Y. In Chapter 3, we consid-
explains why the two antigens are different from each other at ered experiments with fruit flies that showed that an eye color
the molecular level. These differences enable them to be recog- gene is located on the X chromosome. In this section, we will
nized by different antibodies. A person who has blood type A further explore the inheritance of traits for which genes are located
makes antibodies to blood type B (refer back to Figure 4.9a). on sex chromosomes.
The antibodies against blood type B require a galactose on the
oligosaccharide for their proper recognition. This person’s anti-
bodies will not recognize and destroy the person’s own blood The Inheritance Pattern of X-Linked Genes Can
cells, but they will recognize and destroy the blood cells from a Be Revealed by Reciprocal Crosses
type B person.
As discussed in Chapter 2, many species have males and females
With this in mind, let’s consider why blood typing is essen-
that differ in their sex chromosome composition. In mammals, for
tial for safe blood transfusions. The donor’s blood must be an ap-
example, females are XX and males are XY. In such species, cer-
propriate match with the recipient’s blood. People with type O
tain traits are governed by genes that are located on a sex chromo-
blood have the potential to produce antibodies against both A and
some. For these traits, the outcome of crosses depends on the
B antigens if they receive type A, type B, or type AB blood. After
genotypes and sexes of the parents and offspring.
the antibodies are produced in the recipient of the transfusion, they
will react with the donated blood cells and cause them to aggluti- ∙ When a gene is located on the X chromosome but not on
nate (clump together). This is a life-threatening situation that the Y chromosome, it follows a pattern of transmission
causes the blood vessels to clog. Other incompatible combinations called X-linked inheritance.
include a type A person receiving type B or type AB blood and a
The inheritance pattern of X-linked genes shows certain distinc-
type B person receiving type A or type AB blood. Because indi-
tive features. In mammals, males transmit X-linked genes only to
viduals with type AB blood do not produce antibodies to either A
their female offspring, and male offspring receive their X-linked
or B antigens, they can receive any type of blood and are known as
genes only from their female parent. The term hemizygous is used
universal recipients. By comparison, type O persons are universal
to indicate that males have a single copy of an X-linked gene.
donors because their blood can be given to recipients with type O,
A male mammal is said to be hemizygous for X-linked genes.
A, B, or AB.
Because males of certain species, such as humans, have a single
X chromosome, another distinctive feature of X-linked inheri-
tance is that males are more likely to be affected by rare, recessive
4.4 COMPREHENSION QUESTIONS X-linked disorders.
As an example, let’s consider a human disease known as
1. A pink-flowered four-o’clock plant is crossed to a red-flowered
Duchenne muscular dystrophy (DMD), which was first described
plant. What is the expected outcome for the offspring’s
by Guillaume Duchenne in the 1860s. Affected individuals show
phenotypes?
signs of muscle weakness as early as age 3. The disease gradually
a. All pink
weakens the skeletal muscles and eventually affects the heart and
b. All red breathing muscles. Survival is rare beyond the early 30s. The gene
c. 1 red : 2 pink : 1 white for DMD, found on the X chromosome, codes a protein called
d. 1 red : 1 pink dystrophin that is required inside muscle cells for structural

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4.5 GENES ON SEX CHROMOSOMES 93

Unaffected, males are affected by DMD, as indicated by filled squares. The


Affected I -1 I -2 presumed heterozygote female parents of these males are presumed to be heterozygous for
with DMD the X-linked recessive allele. This recessive disease is very rare
among females because females would have to inherit a copy of
the mutant allele from their female parent and a copy from an af-
II -1 II -2 II -3 II -4 II -5 II -6 fected male parent.
X-linked muscular dystrophy has also been found in certain
breeds of dogs such as golden retrievers (Figure 4.11a). As in
humans, the mutation occurs in the dystrophin gene, and the
III -1 III -2 III -3 III -4 III -5 III -6 III -7 III -8 symptoms include severe weakness and muscle atrophy that begin
at about 6 to 8 weeks of age. Many dogs that inherit this disorder
die within the first year of life, though some can live 3 to 5 years
and reproduce.
IV-1 IV-2 IV-3 IV-4 IV-5 IV-6 IV-7 Figure 4.11b (left side) considers a cross between an unaf-
FI GURE 4.10 A human pedigree for Duchenne muscular fected female dog with two copies of the wild-type gene and a
dystrophy, an X-linked recessive trait. Affected individuals are shown male dog with muscular dystrophy that carries the mutant allele
with filled symbols. Females who are unaffected with the disease but and has survived to reproductive age. When setting up a Punnett
have affected sons are presumed to be heterozygous carriers, shown with square involving X-linked traits, we must consider the alleles on
half-filled symbols. the X chromosome as well as the observation that males may
CONCEPT CHECK: What features of this pedigree indicate that the allele for transmit a Y chromosome instead of the X chromosome. A male
Duchenne muscular dystrophy is X-linked? makes two types of gametes, one that carries the X chromosome
and one that carries the Y. The Punnett square must also include
the Y chromosome even though this chromosome does not carry
support. Dystrophin is thought to strengthen muscle cells by an- any X-linked genes. The X chromosomes from the female and
choring elements of the internal cytoskeleton to the plasma mem- male are designated with their corresponding alleles. When the
brane. Without it, the plasma membrane becomes permeable and Punnett square is filled in, it predicts the X-linked genotypes and
may rupture. sexes of the offspring.
DMD follows an inheritance pattern called X-linked reces- As seen on the left side of Figure 4.11b, none of the off-
sive—the allele causing the disease is recessive and located on the spring from this cross are affected with the disorder, although all
X chromosome. In the pedigree shown in Figure 4.10, several female offspring are carriers.

Reciprocal cross

XD XD × Xd Y Xd Xd × XD Y

Sperm Sperm
Xd Y XD Y

XD Xd XD Y XD Xd Xd Y
XD (unaffected, (unaffected) Xd (unaffected, (affected
carrier) carrier) with muscular
dystrophy)
Egg
XD Xd XD Y XD Xd Xd Y
(unaffected, (unaffected) (unaffected, (affected
XD Xd
carrier) carrier) with muscular
dystrophy)

(a) Male golden retriever with X-linked (b) Examples of X-linked muscular dystrophy
muscular dystrophy inheritance patterns
FIGURE 4.11 X-linked muscular dystrophy in dogs. (a) The male golden retriever shown here has the disease. (b) The Pun-
nett square on the left shows a cross between an unaffected female and an affected male. The one on the right shows a reciprocal cross
between an affected female and an unaffected male. D represents the common (non-disease-causing) allele for the dystrophin gene, and
d is the mutant allele that causes a defect in dystrophin function.
CONCEPT CHECK: Explain why the reciprocal cross yields a different result from that obtained for the first cross.

Robriquet et al. (2015) Differential Gene Expression Profiling of Dystrophic Dog Muscle after MuStem Cell Transplantation. PLoS ONE 10(5): e0123336. doi:10.1371/journal.pone.0123336

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94 C H A P T E R 4 :: EXTENSIONS OF MENDELIAN INHERITANCE

The right side of Figure 4.11b shows a reciprocal cross—a Mic2


second cross in which the sexes and phenotypes are reversed. In gene
this case, an affected female dog is crossed to an unaffected male. X
This cross produces female offspring that are carriers and male
offspring that are all affected with muscular dystrophy.
By comparing the two Punnett squares, we see that the out- Y
come of the reciprocal cross yielded different results. This is ex- Mic2
pected with X-linked genes, because the male transmits the gene gene
only to female offspring, but the female transmits an X chromo-
some to both male and female offspring. Male offspring receive a
F I G URE 4 . 1 2 A comparison of the homologous and nonho-
mologous regions of the X and Y chromosomes in humans. The
Y chromosome from their male parent. Therefore, a male parent brackets show three regions of homology between the X and Y chromo-
does not contribute to X-linked phenotypes of male offspring. somes. A few pseudoautosomal genes, such as Mic2, are found on both
This explains why X-linked traits do not behave the same way in the X and Y chromosomes in these small regions of homology.
reciprocal crosses. Experimentally, the observation that reciprocal Researchers estimate that the X chromosome has between 800 and 900
crosses do not yield the same results is an important clue that a protein-coding genes and the Y chromosome has between 50 and 60.
trait may be X-linked. CONCEPT CHECK: Why are the homologous regions of the X and Y chromo-
somes important during meiosis?

Genes Located on Mammalian Sex Chromosomes 4.5 COMPREHENSION QUESTIONS


Can Be Transmitted in an X-Linked, a Y-Linked,
1. A cross is made between a white-eyed female fruit fly and a red-
or a Pseudoautosomal Pattern eyed male. What would be the reciprocal cross?
Our discussion of sex chromosomes has focused on genes that are a. Female is XwXw and male is XwY.
located on the X chromosome but not on the Y chromosome. b. Female is Xw+Xw+ and male is Xw+Y.
∙ The term sex-linked gene refers to a gene that is found c. Female is Xw+Xw+ and male is XwY.
on one of the two types of sex chromosomes but not on d. Female is XwXw and male is Xw+Y.
both. 2. Hemophilia is a blood-clotting disorder in humans that follows
∙ X-linked genes are found only on the X chromosome. an X-linked recessive pattern of inheritance. A male with hemo-
∙ Y-linked genes, or holandric genes, are found only on the philia and a female without hemophilia have a female offspring
Y chromosome. An example of a Y-linked gene is the SRY with hemophilia. If you let H represent the common (non-dis-
gene found in mammals. As discussed in Chapter 26, its ease-causing) allele and h the hemophilia-causing allele, what
expression is necessary for proper male development. A are the genotypes of the parents?
Y-linked inheritance pattern is very distinctive—the gene a. Female parent is XHXh and male parent is XhY.
is transmitted only from a male parent to a male
b. Female parent is XhXh and male parent is XhY.
offspring.
c. Female parent is XhXh and male parent is XHY.
In humans, researchers estimate that the X chromosome carries d. Female parent is XHXh and male parent is XHY.
between 800 and 900 protein-coding genes, whereas the Y chro-
mosome has between 50 and 60.
In addition to sex-linked genes, the X and Y chromosomes 4.6 SEX-INFLUENCED AND SEX-
contain short regions of homology where both chromosomes carry LIMITED INHERITANCE
the same genes. Along with several smaller regions, the human sex
chromosomes have three large homologous regions (Figure 4.12). Learning Outcomes:
These regions, which are evolutionarily related, promote the nec- 1. Compare and contrast sex-influenced inheritance and sex-
essary pairing of the X and Y chromosomes that occurs during limited inheritance.
meiosis I of spermatogenesis. Relatively few genes are located in 2. Predict the outcome of crosses involving sex-influenced
these homologous regions. One example is a human gene called inheritance.
Mic2, which codes a cell surface antigen. The Mic2 gene is found
on both the X and Y chromosomes. It follows a pattern of inheri-
As we have just seen, the transmission pattern of sex-linked genes
tance called pseudoautosomal inheritance. The term pseudoau-
depends on whether the gene is on the X or Y chromosome and on
tosomal refers to the idea that the inheritance pattern of the Mic2
the sex of the offspring. Sex can influence traits in other ways as well.
gene is the same as the inheritance pattern of a gene located on an
autosome even though the Mic2 gene is actually located on the sex ∙ The term sex-influenced inheritance refers to the phe-
chromosomes. As in autosomal inheritance, males have two copies nomenon in which an allele is dominant in one sex but re-
of pseudoautosomally inherited genes, and they can transmit the cessive in the other sex. Therefore, sex influence is a
genes to both female and male offspring. phenomenon of heterozygotes.

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4.6 SEX-INFLUENCED AND SEX-LIMITED INHERITANCE 95

Sex-influenced inheritance should not be confused with sex- GENETIC TIPS THE QUESTION: As we have seen,
linked inheritance. The genes that govern sex-influenced traits having scurs is an example of a sex-influenced trait in cattle that is
are autosomal, not on the X or Y chromosome. Researchers once dominant in males and recessive in females. A male and a female,
thought that human pattern baldness, which is characterized by neither of which has scurs, produce a male offspring with scurs.
hair loss on the front and top of the head but not on the sides, is What are the genotypes of the parents?
an example of sex-influenced inheritance. However, recent re-
search indicates that mutations in the androgen receptor gene, T OPIC: What topic in genetics does this question address? The
which is located on the X chromosome, often play a key role in topic is Mendelian inheritance. More specifically, the question is
pattern baldness. Therefore, pattern baldness often follows an about sex-influenced inheritance.
X-linked pattern of inheritance. Even so, variation in other gene(s)
located on chromosome 20 (an autosome) can be a contributing I NFORMATION: What information do you know based on the
factor to baldness. question and your understanding of the topic? From the
An example of sex-influenced inheritance is found in cattle. question, you know that a male and a female without scurs
Certain breeds exhibit scurs, which are small hornlike growths on produced a male offspring with scurs. From your understanding of
the frontal bone in the same locations where horns (in other the topic, you may remember that the unique feature of sex-
influenced inheritance is that the trait is dominant in one sex and
breeds of cattle) would grow (Figure 4.13). This trait appears to
recessive in the other.
be controlled by a single gene that exists in two alleles, ScP and
ScA. The superscript P represents the allele in which scurs are P ROBLEM-SOLVING S TRATEGY: Predict the outcome. One
present, whereas the superscript A represents the allele in which strategy to solve this type of problem is to use a Punnett square to
scurs are absent. The ScP allele is dominant in males and reces- predict the possible outcomes of this cross. Because the ScA allele
sive in females, whereas the ScA allele is dominant in females and is recessive in males, the male parent without scurs must be
recessive in males: homozygous, ScAScA. A female without scurs can be either ScPScA
or ScAScA. Therefore, two Punnett squares are possible, which are
Phenotype shown next.
Genotype Males Females
P P ScA ScA ScA ScA
Sc Sc Scurs Scurs
ScPScA Scurs No scurs
A A ScP ScPScA ScPScA ScA ScAScA ScAScA
Sc Sc No scurs No scurs

ScA ScAScA ScAScA ScA ScAScA ScAScA

ANSWER: From the question, you know that the male offspring has
scurs. When comparing the two Punnett squares, only the one on the
left can produce a male offspring with scurs (see the gray-shaded
boxes). Therefore, the female parent must be ScPScA and the male
parent is ScAScA.

Some Traits Are Limited to One Sex


Another way in which sex affects an organism’s phenotype in-
volves traits that are found in males or females, but not both.
∙ In sex-limited inheritance, a trait occurs in only one sex.
Genes that produce such traits are controlled by sex hormones or
by the pathway that leads to male and female development, which
is described in Chapter 26. The genes that affect sex-limited traits
FIGURE 4.13 Scurs in cattle, an example of a may be autosomal or X-linked. In humans, examples of sex-lim-
sex-influenced trait. ited traits are the presence of ovaries in females and the presence
Courtesy of Sheila M. Schmutz, Ph.D. of testes in males. Due to these two sex-limited traits, fertile fe-
CONCEPT CHECK: What is the phenotype of a female cow that is heterozy- males only produce eggs, whereas fertile males only produce
gous for the scurs alleles? sperm.

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96 C H A P T E R 4 :: EXTENSIONS OF MENDELIAN INHERITANCE

organism. A loss-of-function mutation in a nonessential gene will


not usually cause death. On rare occasions, however, a nonessen-
tial gene may acquire a gain-of-function mutation that causes the
gene product to be abnormally expressed in a way that may inter-
fere with cell function and lead to a lethal phenotype. Therefore,
not all lethal mutations occur in essential genes, although the great
majority do.
Some lethal alleles may kill an organism only when certain
(a) Hen (b) Rooster environmental conditions prevail. Such conditional lethal al-
F I G U R E 4 . 1 4 Differences in morphological features leles have been extensively studied in experimental organisms.
between (a) female and (b) male chickens, an example of sex-limited For example, some conditional lethal alleles cause an organism
inheritance. to die only in a particular temperature range. These alleles, called
(a): Javier Larrea/Pixtal/age fotostock; (b): Image Source/PunchStock/Getty Images temperature-sensitive (ts) lethal alleles, have been observed in
CONCEPT CHECK: What is the molecular explanation for sex-limited many organisms, including Drosophila. A ts lethal allele may be
inheritance? fatal for a developing larva at a high temperature (30°C), but the
larva survives if grown at a lower temperature (22°C). Temperature-
sensitive lethal alleles are typically caused by mutations that alter
the structure of the coded protein so that it does not function cor-
Sex-limited traits are responsible for sexual dimorphism, in rectly at the nonpermissive temperature or becomes unfolded and
which the sexes in a particular species have different morphologi- is rapidly degraded.
cal features. This phenomenon is common among many animal Conditional lethal alleles may also be identified when an
species and is often striking in various species of birds in which individual is exposed to a particular agent in the environment. For
the male has more ornate plumage than the female. As shown in example, people with a defect in the gene that codes the enzyme
Figure 4.14, roosters have a larger comb and wattles and longer glucose-6-phosphate dehydrogenase (G-6-PD) have a negative re-
neck and tail feathers than do hens. These features are limited to action to the ingestion of fava beans. This reaction can lead to an
roosters. acute hemolytic syndrome with 10% mortality if not treated
properly.
Finally, it is surprising that certain lethal alleles act only in
4.6 COMPREHENSION QUESTION some individuals. These are called semilethal alleles. Of course,
any particular individual cannot be semidead. However, within a
1. A cow with scurs and a bull with no scurs have an offspring. This
population, a semilethal allele will cause some individuals to die
offspring could be
but not all of them. The reasons for semilethality are not always
a. a female with scurs or a male with scurs.
understood, but environmental conditions and the actions of
b. a female with no scurs or a male with scurs. other genes within the organism may help to prevent the detri-
c. a female with scurs or a male with no scurs. mental effects of certain semilethal alleles. An example of a
d. a female with no scurs or a male with no scurs. semilethal allele is the X-linked white-eyed allele in fruit flies,
which is described in Chapter 3 (refer back to Figure 3.18).
Depending on the growth conditions, approximately 1/4 to 1/3 of
the flies that carry the white-eyed allele die during early stages
4.7 LETHAL ALLELES of development.
Learning Outcomes: In some cases, a lethal allele may produce ratios that
seemingly deviate from Mendelian ratios. An example is an al-
1. Describe the different types of lethal alleles.
lele in a breed of cats known as Manx, which originated on the
2. Predict how lethal alleles may affect the outcome of a cross.
Isle of Man (Figure 4.15a). The Manx cat is a heterozygote that
carries a dominant mutant allele affecting the spine. This allele
Let’s now turn our attention to alleles that have the most detrimen- shortens the tail, resulting in a range of tail lengths from normal
tal effect on phenotype—those that result in death. An allele that to tailless. When two heterozygous Manx cats are crossed to
has the potential to cause the death of an organism is called a each other, the ratio of offspring is 1 normal to 2 Manx. How do
lethal allele. Such alleles are usually inherited in a recessive man- we explain the 1:2 ratio? The answer is that 1/4 of the offspring
ner. When the absence of a specific protein results in a lethal are homozygous for the dominant mutant allele, and they die
phenotype, the gene that codes the protein is considered an essen- during early embryonic development (Figure 4.15b). In this
tial gene, one that must be present for survival. Though the pro- case, the Manx phenotype is dominant in heterozygotes,
portion varies by species, researchers estimate that approximately whereas the dominant mutant allele is lethal in the homozygous
1/3 of all genes are essential genes. condition.
By comparison, nonessential genes are not absolutely re- The time when a lethal allele exerts its effect can vary. Many
quired for survival, although they are likely to be beneficial to the lethal alleles disrupt proper cell division and thereby cause an

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4.8 UNDERSTANDING COMPLEX PHENOTYPES CAUSED BY MUTATIONS IN SINGLE GENES 97

FIGURE 4.15 Mm × Mm
The Manx cat, which (Manx) (Manx)
carries a lethal allele.
(a) Photo of a Manx Sperm
cat, which typically has a shortened M m
tail. (b) Outcome of a cross between
two Manx cats. Animals that are ho- MM Mm
mozygous for the dominant Manx al- (early (Manx)
M
lele (M) die during early embryonic embryonic
death) 1:2 ratio
development. Egg of kittens
Juniors Bildarchiv/F215/Alamy Stock Photo that are born
Mm mm
CONCEPT CHECK: Why do you think the (Manx) (non-Manx)
Mm heterozygote offspring of two Manx m
cats survives with developmental abnor-
mality, whereas the MM homozygote dies?
(a) A Manx cat (b) Example of a Manx inheritance pattern

organism to die at a very early stage. Others may allow a short Thus far, we have considered a variety of examples in which muta-
period of development before the organism dies. In the case of the tions in a single gene affect the outcome of a single trait. For some
Manx allele, the homozygote dies early in embryonic develop- of these examples, such as ABO blood types, flower color in the
ment. Certain inherited diseases in humans, such as Tay-Sachs four-o’clock plant, and sickle cell disease, the relationship be-
(see Table 4.2), result in death during childhood. However, some tween a mutation in a gene and its effect on a single trait is rela-
lethal alleles may exert their effects later in life, or only under tively easy to understand. However, for other genes, the phenotypic
certain environmental conditions. For example, a human genetic effects may be more complex, and researchers may have to dig
disease known as Huntington disease is caused by a dominant al- deeper to understand how a mutation in a single gene can produce
lele. The disease is characterized by a progressive degeneration of complex effects on phenotype. In this section, we will consider
the nervous system, dementia, and early death. The age when how the expression of a single gene can have multiple effects
these symptoms appear, or the age of onset, is usually between 30 throughout the body and see how an understanding of embryonic
and 50. development can explain certain complex phenotypes.

Pleiotropy Occurs When the Expression of a Single


4.7 COMPREHENSION QUESTION Gene Has Two or More Phenotypic Effects
Although we tend to discuss genes within the context of how they
1. The Manx phenotype in cats is caused by a dominant allele that influence a single trait, most genes actually have multiple effects
is lethal in the homozygous state. A Manx cat is crossed to a throughout a cell or throughout a multicellular organism. The mul-
normal (non-Manx) cat. What is the expected outcome for the tiple effects of a single gene on the phenotype of an organism is
surviving offspring? called pleiotropy. Pleiotropy occurs for several reasons, including
a. All Manx the following:
b. All normal
∙ The expression of a single gene can affect cell function in
c. 1 normal : 1 Manx
more than one way. For example, a defect in a microtubule
d. 1 normal : 2 Manx protein may affect cell division and cell movement.
∙ A gene may be expressed in different cell types in a multi-
cellular organism.
4.8 UNDERSTANDING COMPLEX ∙ A gene may be expressed only at a specific stage of
development.
PHENOTYPES CAUSED BY
MUTATIONS IN SINGLE GENES In all or nearly all cases, the expression of a gene is pleiotropic
with regard to the characteristics of an organism. The expression
Learning Outcomes: of any given gene influences the expression of many other genes in
1. Explain the phenomenon of pleiotropy. the genome, and vice versa. Pleiotropy is revealed when research-
2. Describe how embryonic development determines certain ers study the effects of gene mutations. As an example of a pleio-
coat patterns in animals. tropic mutation, let’s consider cystic fibrosis, which is a recessive
human disorder. In the late 1980s, the gene for cystic fibrosis was

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98 C H A P T E R 4 :: EXTENSIONS OF MENDELIAN INHERITANCE

identified. It codes a protein called the cystic fibrosis transmem- and extreme white spotting (sw)(compare Figure 4.16a,b). In
brane conductance regulator (CFTR), which regulates ionic bal- many breeds, the areas that are white include the legs, belly, neck,
ance by allowing the transport of chloride ions (Cl−) across and the tip of the tail. For decades, researchers were baffled by this
epithelial cell membranes. coat pattern in which some areas are pigmented and others are
The mutation that causes cystic fibrosis diminishes the func- white.
tion of this Cl− transporter, affecting several parts of the body in Fur pigmentation is dependent on melanocytes, which are
different ways: cells located in the bottom layer of the skin’s epidermis and in the
hair follicles. Melanocytes produce the pigment melanin, which is
∙ Because the movement of Cl− affects water transport
found in the skin, eyes, and hair. If melanin is not produced within
across membranes, the most severe symptom of cystic fi-
hair follicles, a dog’s fur remains white. An understanding of me-
brosis is thick mucus in the lungs that occurs because of a
lanocyte development provides insight regarding the intriguing
water imbalance. This thickened mucus results in diffi-
phenotype of white spotting.
culty in breathing and frequent lung infections.
During embryogenesis, melanocyte precursor cells, called
∙ Thick mucus can also block the tubes that carry digestive
melanoblasts, originate in the neural crest, which is a temporary
enzymes from the pancreas to the small intestine. Without
group of cells that are associated with each other only during em-
these enzymes, certain nutrients are not properly absorbed
bryonic development. The neural crest is located dorsal to the
into the body. As a result, persons with cystic fibrosis may
neural tube, which gives rise to the brain and spinal cord. Melano-
show poor weight gain.
blasts originate only in the part of the neural crest that is located
∙ Another effect is seen in the sweat glands. A functional
in the trunk region of the embryo (between the neck and the tail).
Cl− transporter is needed to recycle salt out of these glands
From there, the melanoblasts migrate to other parts of the body
and back into the skin before it can be lost to the outside
(Figure 4.16c). As they migrate, the melanoblasts proliferate,
world. Persons with cystic fibrosis have excessively salty
which allows some of them to travel longer distances and reach
sweat due to their inability to recycle salt back into their
more ventral regions of the embryo. Once the melanoblasts reach
skin cells—a common test for cystic fibrosis is measure-
their final destination, they continue to proliferate and differenti-
ment of salt on the skin.
ate into pigment-producing melanocytes in places such as the epi-
Taken together, these symptoms show that a defect in CFTR has dermis and hair follicles.
multiple effects throughout the body. Researchers speculate that the alleles conferring the white
spotting phenotype cause a decrease in the number of melanocytes
due to failure of melanoblast migration, proliferation, and/or sur-
Certain Coat-Color Patterns in Dogs Are Determined vival during embryonic development. In 2007, a genome-wide
by Events During Embryonic Development association study determined that this coat-color gene codes a pro-
Many breeds of dogs and other mammals have a coat-color pat- tein called microphthalmia-associated transcription factor (MITF).
tern, called white spotting, in which portions of an animal’s fur (Genome-wide association studies are described in Chapter 24.) In
lack pigmentation. The coat-color gene influencing this trait exists mice and humans, MITF expression is needed for proper migra-
in multiple alleles that affect the amount of pigmentation of an tion, proliferation, and survival of melanoblasts. Reduced expres-
animal’s fur. The S+ allele results in full pigmentation (no white sion of MITF is expected to decrease the number of melanocytes
spotting), whereas other alleles vary with regard to the amount of in adult animals. Because the melanoblasts begin their journey
pigmentation produced; possible patterns include Irish spotting (sI) from the neural crest in the trunk, this reduced expression of MITF

(a) Irish spotting (b) Extreme white spotting (c) Migration of melanoblasts during
embryonic development

FI GURE 4.1 6 White spotting phenotype in dogs. (a) This animal shows a typical Irish spotting pattern seen in an sIsI homozygote or an sIsw
heterozygote. (b) The extreme white spotting pattern of an swsw homozygote. (c) During embryonic development, melanoblasts migrate away from the
trunk region of the neural crest. Source (parts a and b): Figure 1 in Annu. Rev. Anim. Biosci. 2013. 1:125–156.
(a, b): Deanna Vout

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4.9 GENE INTERACTIONS 99

causes the regions of the body in the adult that are farthest away TA B L E 4.3
from the spinal cord to contain fewer melanocytes and are there-
fore more likely to be white. Types of Mendelian Inheritance Patterns Involving Two Genes
Type Description
Epistasis An inheritance pattern in which the alleles of one
4.8 COMPREHENSION QUESTION gene mask the phenotypic effects of the alleles of a
different gene.
1. Which of the following is a possible explanation for pleiotropy? Complementation A phenomenon in which two parents that express
a. The expression of a single gene can affect cell function in the same or similar recessive phenotypes produce
more than one way. offspring with a wild-type phenotype.

b. A gene may be expressed in different cell types in a multi- Gene modification A phenomenon in which an allele of one gene
modifies the phenotypic outcome of the alleles of a
cellular organism. different gene.
c. A gene may be expressed at different stages of
Gene redundancy A phenomenon in which the loss of function in a
development. single gene has no phenotypic effect, but the loss of
d. All of the above are possible explanations. function of two genes has an effect. Functionality of
only one of the two genes is necessary for a wild-type
phenotype; the genes are functionally redundant.

4.9 GENE INTERACTIONS


Learning Outcomes: effects of a single gene even though many genes may affect a
1. Define gene interaction. single trait.
2. Predict the outcome of crosses involving epistasis, comple- Researchers now appreciate that essentially all traits are
mentation, gene modifiers, and gene redundancy. affected by the contributions of many genes. Morphological
3. Describe examples that explain the molecular mechanisms features such as height, weight, growth rate, and pigmentation
of epistasis, complementation, gene modification, and gene are all affected by the expression of many different genes in
redundancy. combination with environmental factors. In this section, we
will further our understanding of genetics by considering how
the allelic variants of two different genes affect a single trait.
This phenomenon is known as gene interaction. Table 4.3 de-
Thus far, we have considered the effects of single genes on the scribes several examples of inheritance patterns in which two
outcome of traits. This approach helps us to understand the vari- different genes interact to influence the outcome of particular
ous ways that alleles influence traits. Researchers often examine traits. In this section, we will examine these examples in greater
the effects of a single gene on the outcome of a single trait as a way detail.
to simplify the genetic analysis. For example, Mendel studied one
gene that affected the height of pea plants—a gene with tall and
short alleles. Actually, many other genes in pea plants also affect
Gene Interaction Can Exhibit Epistasis
height, but Mendel did not happen to study variants in those other and Complementation
height genes. How then did Mendel study the effects of a single In the early 1900s, William Bateson and Reginald Punnett discovered
gene? The answer lies in the genotypes of his strains. Although an unexpected gene interaction when studying crosses involving the
many genes affect the height of pea plants, Mendel chose true- sweet pea, Lathyrus odoratus. The wild sweet pea has purple flowers.
breeding strains that differed with regard to only one of those However, these researchers obtained several true-breeding mutant
genes. As a hypothetical example, let’s suppose that pea plants varieties with white flowers. Not surprisingly, when they crossed a
have 10 genes affecting height, which we will call K, L, M, N, O, true-breeding purple-flowered plant to a true-breeding white-
P, Q, R, S, and T. The genotypes of two hypothetical strains of pea flowered plant, the F1 generation had all purple-flowered plants and
plants may be the F2 generation (produced by self-fertilization of the F1 generation)
consisted of purple- and white-flowered plants in a 3:1 ratio. These
Tall strain: KK LL MM NN OO PP QQ RR SS TT results indicated that white flowers are recessive to purple.
Short strain: KK LL MM NN OO PP QQ RR SS tt A surprising result came in an experiment where Bateson
and Punnett crossed two different varieties of white-flowered
In this example, the alleles affecting height differ at only a single plants (Figure 4.17). All of the F1 generation plants had purple
gene. One strain is TT and the other is tt, and this accounts for the flowers! The researchers then allowed the F1 offspring to self-
difference in their height. If we make crosses between these tall fertilize. The F2 generation resulted in purple- and white-flowered
and short strains, the genotypes of the F2 offspring may differ plants in a ratio of 9 purple to 7 white. From this result, Bateson
with regard to only one gene; the other nine genes will be identi- and Punnett deduced that two different genes were involved, with
cal in all of them. This approach allows a researcher to study the the following relationship:

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100 C H A P T E R 4 :: EXTENSIONS OF MENDELIAN INHERITANCE

P generation white allele of one gene masks the expression of the purple-
producing allele of another gene. In other words, the cc genotype
is epistatic to a purple phenotype, and the pp genotype is also
x
epistatic to a purple phenotype. At the level of genotypes, cc is
epistatic to PP or Pp, and pp is epistatic to CC or Cc. This is an
White variety #1 White variety #2
(CCpp ) (ccPP ) example of recessive epistasis. As seen in Figure 4.17, this epi-
static interaction produces only two phenotypes—purple or white
F1 generation Complementation: Each flowers—in a 9:7 ratio.
recessive allele (c and p)
is complemented by a Epistasis often occurs because two (or more) different
wild-type allele (C and P). proteins participate in a common function. For example, two
This phenomenon indicates (or more) proteins may be part of an enzymatic pathway leading
that the recessive alleles
All purple are in different genes. to the formation of a single product. To illustrate this idea, let’s
(CcPp ) consider the formation of a purple pigment in the sweet pea
flower:
Self-fertilization
colorless Enzyme C colorless Enzyme P purple
F2 generation
precursor intermediate pigment
CP Cp cP cp
In this example, a colorless precursor molecule must be
CP
CCPP CCPp CcPP CcPp acted on by two different enzymes to produce the purple pig-
Epistasis: Homozygosity
Purple Purple Purple Purple
for the recessive allele
ment. Gene C codes a functional protein called enzyme C,
of either gene results in which converts the colorless precursor into a colorless interme-
CCPp CCpp CcPp Ccpp
Cp a white phenotype, thereby diate. Gene P codes a functional enzyme P, which converts the
Purple White Purple White masking the purple
(wild-type) phenotype.
colorless intermediate into the purple pigment. If a plant is ho-
CcPP CcPp ccPP ccPp Both gene products mozygous for either recessive allele (cc or pp), it will not make
cP coded by the wild-type any functional enzyme C or enzyme P, respectively. When one
Purple Purple White White alleles (C and P) are
needed for a purple
of these enzymes is missing, purple pigment cannot be made,
CcPp Ccpp ccPp ccpp phenotype. and the flowers remain white.
cp The parental cross shown in Figure 4.17 illustrates another
Purple White White White
genetic phenomenon called complementation. This term refers
to the production of offspring with a wild-type phenotype by par-
FIGURE 4.17 A cross between two different ents that both display the same or similar recessive phenotype. In
white varieties of the sweet pea.
the example shown in the figure, purple-flowered F1 offspring
Genes→Traits The color of the sweet pea flower is controlled
by two genes, which are epistatic to each other and show
were obtained from two white-flowered parents. Complementa-
complementation. Each gene is necessary for the production of an enzyme re- tion typically occurs because the recessive phenotype in the par-
quired for pigment synthesis. The recessive allele of either gene codes a de- ents is due to homozygosity of two different genes. In our sweet
fective enzyme. If an individual is homozygous for the recessive allele of either pea example, one parent is CCpp and the other is ccPP. In the F1
of the two genes, the purple pigment cannot be synthesized. The result is a offspring, the C and P alleles, which are wild-type and dominant,
white phenotype.
complement the c and p alleles, which are recessive. The off-
CONCEPT CHECK: What do the terms epistasis and complementation spring must have one wild-type allele of both genes to display the
mean?
wild-type phenotype. Why is complementation an important ex-
perimental observation? When geneticists observe complementa-
tion in a genetic cross, this outcome suggests that the recessive
phenotype in the two parent strains is caused by mutant alleles in
∙ C (one purple-color-producing) allele is dominant to c two different genes.
(white).
∙ P (another purple-color-producing) allele is dominant to p Feather Coloration in Parakeets Provides
(white). an Example of Gene Modification
∙ cc or pp masks the P or C allele, producing white color.
The Australian parakeet (Melopsittacus undulatus), also called a
When the alleles of one gene mask the phenotypic effects of budgerigar or a “budgie,” is a small, slender parrot that is native to
the alleles of another gene, the phenomenon is called epistasis. Australia. Since the late 1800s, it has become a common house pet
Geneticists describe epistasis relative to a particular phenotype. If worldwide. The wild-type parakeet has a yellow face and a green
possible, geneticists use the wild-type phenotype as their reference underside (see upper left side of Table 4.4). These colors are caused
phenotype when describing an epistatic interaction. In the case of by psittacofulvin and eumelanin—two types of pigments. In para-
sweet peas, purple flowers are wild type. Homozygosity for the keets, psittacofulvin is a yellow pigment and eumelanin is black.

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4.9 GENE INTERACTIONS 101

TA B L E 4.4
Feather Coloration in Parakeets
Phenotype:

Genotype: YYAA (wild type) yyAA YYaa yyaa


Pigment in the psittacofulvin none psittacofulvin none
feathers on the face:
Face color: yellow white yellow white
Pigment(s) in the psittacofulvin and eumelanin eumelanin psittacofulvin none
feathers on the
underside:
Underside color: green blue yellow white
left: Dlb08d/Getty Images; (second from left) Devonyu/Getty Images; (second from right) suppixz/Getty Images; right: Cheryl Bridges/Alamy Stock Photo

Psittacofulvin and eumelanin are distributed in the feathers pigments are made, they are green. If neither pigment is made, the
in varying patterns across the bird’s body. With regard to feather feathers are white.
coloration on the face and underside, wild-type parakeets have a Parakeets have been bred in captivity for over a century.
base body color that is yellow due to psittacofulvin pigmenta- During that time, over 30 new alleles in several different genes
tion. In addition, a secondary coloration occurs on the underside have been identified that have a gene modifying effect on
of the bird, but not on the face. The secondary coloration is due feather color. Some of these alleles have a direct effect on pig-
to eumelanin synthesis. Although eumelanin is a black pigment, ment synthesis. Alternatively, other alleles may affect feather
tiny air pockets and eumelanin crystals reflect only blue light structure in a way that causes light refraction; this refraction
and absorb the other wavelengths. The reflected blue color com- alters the wavelength of light and thereby changes the feather
bined with the yellow color from psittacofulvin results in a green color.
color. The alleles that affect feather color can be dominant or
This green feather coloration provides an example of gene recessive or exhibit incomplete dominance. An interesting ex-
modification—the phenomenon in which an allele of one gene ample of incomplete dominance occurs with an allele called
modifies the phenotypic outcome of the alleles of a different gene. dark. Let’s designate the wild-type allele for this gene as D and
In this case, the blue color modifies yellow to green on the under- the dark allele as D' (D prime). The gene-modifying effect of the
sides of the bird. dark allele on the underside color depends on whether it is pres-
How does allelic variation in these two genes affect the phe- ent in one or two copies, and also on whether psittacofulvin
notypes of parakeets (Table 4.4)? The gene for psittacofulvin syn- synthesis occurs.
thesis is designated Y for yellow. The dominant allele (Y) results in
psittacofulvin synthesis, whereas a loss-of-function recessive allele ∙ YYAADD: green underside (see wild-type parakeet at the
(y) prevents synthesis of that pigment. The eumelanin gene is typi- upper left in Table 4.4)
cally designated A for albino, because its loss of function in many ∙ YYAADD': dark green underside
different species results in an albino phenotype. The dominant al- ∙ YYAAD'D': olive underside
lele (A) results in eumelanin synthesis and the loss-of-function re- ∙ yyAADD: blue underside (as in the image that is second
cessive allele (a) prevents that synthesis. As seen in Table 4.4, in from the left in Table 4.4)
places where only psittacofulvin is synthesized, the feathers are ∙ yyAADD': cobalt underside
yellow. If only eumelanin is made, the feathers are blue. If both ∙ yyAAD'D': mauve underside

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102 C H A P T E R 4 :: EXTENSIONS OF MENDELIAN INHERITANCE

Due to Gene Redundancy, Loss-of-Function Alleles have no effect (Figure 4.18). Geneticists may attribute this change
May Have No Effect on Phenotype to gene redundancy—the phenomenon in which one gene com-
pensates for the loss of function of another gene.
During the past several decades, researchers have discovered new Gene redundancy may be due to different underlying
kinds of gene interactions by studying model organisms such as causes:
Escherichia coli (a bacterium), Saccharomyces cerevisiae (bak-
er’s yeast), Arabidopsis thaliana (a flowering plant), Drosophila ∙ One common reason is gene duplication. Certain genes have
melanogaster (fruit fly), Caenorhabditis elegans (a nematode been duplicated during evolution, so a species may have two
worm), and Mus musculus (the laboratory mouse). The isolation or more copies of similar genes. These copies, which are not
of mutant alleles that alter the phenotypes of these organisms has identical due to the accumulation of random changes during
become a powerful tool for investigating gene function and has evolution, are called paralogs (look ahead to Figures 8.6
provided ways for researchers to identify new kinds of gene inter- and 8.7). When one gene is missing, a paralog may be able
actions. With the advent of modern molecular techniques (de- to carry out the missing function. For example, genes A and
scribed in Chapters 20, 22, and 23), a common approach for B in Figure 4.18 could be paralogs of each other.
investigating gene function is to intentionally produce loss-of- ∙ Alternatively, gene redundancy may involve proteins
function alleles in a gene of interest. When a geneticist abolishes that are involved in a common cellular function. When
gene function by creating an organism that is homozygous for a one of the proteins is missing due to a gene knockout,
loss-of-function allele, the resulting organism is said to have un- the function of another protein may be increased to com-
dergone a gene knockout. pensate for the missing protein and thereby overcome
Why are gene knockouts useful? The primary reason for the defect.
making a gene knockout is to understand how that gene affects the
structure and function of cells or the phenotypes of organisms. For Let’s explore the consequences of gene redundancy in a genetic
example, if a researcher knocked out a particular gene in a mouse cross. George Shull conducted one of the first studies that illus-
and the resulting animal was unable to hear, the researcher would trated the phenomenon of gene redundancy. This work involved a
suspect that the role of the functional gene is to promote the for- weed known as shepherd’s purse, a member of the mustard family.
mation of ear structures that are vital for hearing. The trait Shull followed was the shape of the seed capsule, which
Interestingly, by studying many gene knockouts in a variety is commonly triangular (Figure 4.19). Strains producing smaller
of experimental organisms, geneticists have discovered that many ovate capsules are homozygous for loss-of-function alleles in two
knockouts have no obvious effect on phenotype at the cellular level different genes (ttvv). The ovate strain is an example of a double
or the level of discernible traits. To explore gene function further, gene knockout.
researchers may make two or more gene knockouts in the same When Shull crossed a true-breeding plant with triangular
organism. In some cases, gene knockouts in two different genes capsules to a plant having ovate capsules, the F1 generation all
produce a phenotypic change even though the single knockouts had triangular capsules. When the F1 plants were self-fertilized,

A A A A A A
F I G URE 4 . 1 8 A molecular
explanation for gene redundancy. To
have a normal phenotype, an organism
must have a functional copy of either
gene A or gene B. If both gene A and
B B B B B B gene B are knocked out, an altered phe-
notype occurs.
Knockout CONCEPT CHECK: Explain why a single
Knockout Knockout of both
of gene A of gene B gene knockout does not always have an
gene A
and gene B effect on phenotype.

A A

B B

Normal Normal Altered phenotype–


phenotype phenotype genes A and B are
redundant.

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KEY TERMS 103

P generation F I G URE 4 . 1 9 Inheritance of seed capsule shape in shep-


herd’s purse, an example of gene redundancy. In this case, triangular
seed capsule shape requires a dominant allele in one of two genes, but
x
not both. The T and V alleles are redundant.
TTVV ttvv CONCEPT CHECK: At the molecular level (with regard to loss-of-function al-
Triangular Ovate leles), explain why the ttvv homozygote has an ovate seed capsule.

a surprising result came in the F2 generation. Shull observed a


15:1 ratio of plants having triangular capsules to ovate cap-
sules. The result can be explained by gene redundancy. Having
F1 generation
at least one functional copy of either gene (T or V) is sufficient
to produce the triangular phenotype. T and V are functional al-
TtVv leles of redundant genes. Only one of them is necessary for a
All triangular
F1 (TtVv) x F1 (TtVv) triangular shape. When the functions of both genes are knocked
out, as in the ttvv homozygote, the capsule becomes smaller and
ovate.
F2 generation
TV Tv tV tv
4.9 COMPREHENSION QUESTIONS
TTVV TTVv TtVV TtVv
TV 1. Two different strains of sweet peas are true-breeding and have
white flowers. When plants of these two strains are crossed, the
F1 offspring all have purple flowers. The outcome of purple flow-
TTVv TTvv TtVv Ttvv ers in the F1 generation is due to
Tv a. epistasis.
b. complementation.
c. incomplete dominance.
TtVV TtVv ttVV ttVv d. incomplete penetrance.
tV
2. If the F1 offspring from question 1 are allowed to self-fertilize,
what is the expected outcome for the F2 offspring?
a. All white
TtVv Ttvv ttVv ttvv
tv b. All purple
c. 3 purple : 1 white
d. 9 purple : 7 white

KEY TERMS

Introduction: Mendelian inheritance, simple Mendelian genes, Y-linked genes (holandric genes), pseudoautosomal
inheritance inheritance
4.2: wild-type alleles, genetic polymorphism, mutant alleles, 4.6: sex-influenced inheritance, sex-limited inheritance, sexual
loss-of-function alleles, gain-of-function mutations, dominant- dimorphism
negative mutations, haploinsufficiency, incomplete pene- 4.7: lethal allele, essential gene, nonessential genes, conditional
trance, expressivity lethal alleles, temperature-sensitive (ts) lethal alleles, semi-
4.3: temperature-sensitive allele, norm of reaction lethal alleles, age of onset
4.4: incomplete dominance, heterozygote advantage, multiple al- 4.8: pleiotropy
leles, codominance 4.9: gene interaction, epistasis, recessive epistasis, complemen-
4.5: sex chromosomes, X-linked inheritance, hemizygous, tation, gene modification, gene knockout, gene redundancy,
X-linked recessive, reciprocal cross, sex-linked gene, X-linked paralogs

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104 C H A P T E R 4 :: EXTENSIONS OF MENDELIAN INHERITANCE

CHAPTER SUMMARY

∙ Mendelian inheritance patterns obey Mendel’s laws. 4.5 Genes on Sex Chromosomes
∙ X-linked inheritance patterns show differences between males
4.1 Overview of Mendelian Inheritance Patterns and females and are revealed in reciprocal crosses (see Fig-
∙ Several inheritance patterns involving single genes differ from ures 4.10, 4.11).
those observed by Mendel (see Table 4.1). ∙ The X and Y chromosomes carry different sets of genes, but
they do have short regions of homology that can lead to pseu-
4.2 Dominant and Recessive Alleles doautosomal inheritance (see Figure 4.12).
∙ Wild-type alleles are those that are prevalent in a natural popu-
lation. When a gene exists in two or more wild-type alleles in a 4.6 Sex-Influenced and Sex-Limited Inheritance
population, the phenomenon is called genetic polymorphism ∙ For sex-influenced traits, heterozygous males and females have
(see Figure 4.1). different phenotypes (see Figure 4.13).
∙ Recessive alleles are often due to mutations that result in a re- ∙ Sex-limited traits are expressed in only one sex, thereby result-
duction or loss of function of the coded protein (see Figure 4.2 ing in sexual dimorphism (see Figure 4.14).
and Table 4.2).
∙ Dominant mutant alleles are most commonly caused by gain- 4.7 Lethal Alleles
of-function mutations, dominant-negative mutations, or ∙ Lethal alleles most commonly occur in essential genes.
haploinsufficiency. ∙ Lethal alleles may result in inheritance patterns that yield unex-
∙ Incomplete penetrance occurs when an allele that is expected to pected ratios of phenotypes (see Figure 4.15).
be expressed is not expressed (see Figure 4.3).
∙ Traits may vary in their expressivity. 4.8 Understanding Complex Phenotypes Caused
by Mutations in Single Genes
4.3 Environmental Effects on Gene Expression
∙ Single genes usually exhibit pleiotropy, which means that they
∙ The outcome of traits is influenced by the environment (see
exert multiple phenotypic effects.
Figure 4.4).
∙ Some phenotypes are best understood within the context of
development (see Figure 4.16).
4.4 Incomplete Dominance, Heterozygote Advan-
tage, and Codominance 4.9 Gene Interactions
∙ Incomplete dominance is an inheritance pattern in which the ∙ A gene interaction is the phenomenon in which two or more
heterozygote has an intermediate phenotype (see Figure 4.5). genes affect a single phenotype (see Table 4.3).
∙ Whether we consider an allele to be dominant or incompletely ∙ Epistasis occurs when the alleles of one gene mask the pheno-
dominant may depend on how closely we examine the pheno- typic expression of the alleles of a different gene. Complemen-
type (see Figure 4.6). tation is the phenomenon in which two individuals with similar
∙ Heterozygote advantage is an inheritance pattern in which the recessive phenotypes produce offspring with a wild-type phe-
heterozygote has greater reproductive success than either ho- notype (see Figure 4.17).
mozygote (see Figures 4.7, 4.8). ∙ Feather coloration in parakeets is an example of gene modifica-
∙ Most genes exist in multiple alleles in a population. Some al- tion (see Table 4.4).
leles, such as those that produce A and B blood antigens, are ∙ Two different genes may have redundant functions, which is
codominant (see Figure 4.9). revealed by a double gene knockout (see Figures 4.18, 4.19).

PROBLEM SETS & INSIGHTS

MORE GENETIC TIPS 1. In Ayrshire cattle, the coat Phenotype


can be either red and white or mahogany and white. Both phenotypes Genotype Females Males
are viable and have equal reproductive success. The mahogany and SMS M Mahogany and white Mahogany and white
white phenotype is caused by the allele SM. The red and white S MS R Red and white Mahogany and white
phenotype is controlled by the allele SR. The following table shows
S RS R Red and white Red and white
the relationship between genotype and phenotype for females and
males: Explain the pattern of inheritance.

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