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III. Nucleic Acid Structure
and DNA Replication
17. Complex Patterns of
Inheritance
© The McGraw−Hill
Companies, 2008
COMPLEX PATTERNS
OF I NHERITANCE
CHAPTER OUTLINE
17.1
17.2
Gene Interactions
17.3
17.4
Extranuclear Inheritance: Organelle Genomes
Genes on the Same Chromosome: Linkage,
Recombination, and Mapping
X Inactivation, Genomic Imprinting,
and Maternal Effect
Snail shells (Lymnaea peregra) that coil to the right or left. The direction
of coiling of a snail’s shell is an example of a complex inheritance pattern.
n Chapter 16, we examined inheritance patterns in which
the outcome of a single trait was governed by a single gene.
In the cases we considered, the alleles segregated and
assorted independently, allowing us to predict the phenotypes
of offspring from the genotypes of their parents. These phenotypes occurred in definite ratios and they did not overlap—a
pea plant was either tall or dwarf; a blood type was either A, B,
or O. The inheritance patterns of most traits are more complex,
however, and in this chapter we will examine some of the factors that complicate the prediction of phenotypes.
In the first section of the chapter, we will consider how two
or more different genes may affect the outcome of a single trait.
For example, we examine continuously varying traits like human
skin color, and you will see how the interaction of multiple
genes and environmental influences can produce such a continuum. In the rest of the chapter we will consider inheritance patterns that defy Mendel’s laws of inheritance. First we discuss
genes that are linked on the same chromosome and therefore do
not assort independently. Next we consider the genes found in
chloroplasts and mitochondria, which defy the law of segregation. Don’t worry, Mendel’s laws do describe most inheritance
patterns, and they accurately reflect the behavior of chromosomes during meiosis. However, as you will learn in this chapter, they simply don’t apply to all of the genes that eukaryotic
organisms possess. We will end the chapter with a discussion of
three inheritance patterns, X inactivation, genomic imprinting,
and maternal effect, that were not easily explained until researchers began to unravel genetic events that occur at the cellular and molecular levels. As you will learn, males and females
don’t always regulate their genes in the same way, and this can
lead to seemingly bizarre patterns of inheritance that are distinct from X-linked and sex-influenced inheritance patterns,
I
which we considered in the previous chapter. An exciting advance over the past few decades has been a better understanding of such unusual patterns of inheritance.
Studies of complex inheritance patterns such as those described in this chapter have helped us appreciate more fully how
genes influence phenotypes. These studies have revealed an astounding variety in the ways that inheritance occurs. The picture
that emerges is of a wonderful web of diverse mechanisms by
which genes give rise to phenotypes. Table 17.1 provides a summary of the most common patterns of inheritance.
17.1 Gene Interactions
The study of single genes was pivotal in establishing the science of genetics. This focus allowed Mendel to formulate the
basic laws of inheritance for traits with a simple dominant/
recessive inheritance pattern. Likewise, this approach helped
later researchers understand inheritance patterns involving incomplete dominance and codominance, as well as traits that are
influenced by an individual’s sex. In reality, however, all or
nearly all traits are influenced by many genes. For example, in
both plants and animals, height is affected by genes that encode
proteins involved in the production of growth hormones, cell
division, the uptake of nutrients, metabolism, and many other
functions. A defect in any of these genes is likely to have a negative impact on an individual’s height.
If height is controlled by many genes, you may be wondering how Mendel was able to study the effects of a single gene
that produced tall or dwarf pea plants. The answer lies in the
genotypes of his strains. Although many genes affect the height
of pea plants, Mendel chose true-breeding strains that differed
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17. Complex Patterns of
Inheritance
UNIT III – CHAPTER 17
Table 17.1 Different Types of Inheritance Patterns
Type
Description
Mendelian
Inheritance patterns in which a single gene affects
a single trait, and the alleles segregate and assort
independently. These patterns include simple
dominant/recessive traits, X-linked traits controlled
by a single gene, incomplete dominance, codominance, and sex-influenced traits (refer back to
Table 16.1).
Epistasis
A type of gene interaction in which the alleles of
one gene mask the effects of a dominant allele of
another gene.
Continuous
variation
Inheritance pattern in which the offspring display
a continuous range of phenotypes. This pattern is
produced by the additive interactions of several
genes, together with environmental influences.
Linkage
Inheritance patterns involving two or more genes
that are close together on the same chromosome.
These genes do not assort independently.
Extranuclear
inheritance
Transmission pattern of genes found in the DNA
of mitochondria or chloroplasts, which are
inherited independently of genes in the nucleus
and do not segregate during meiosis. Usually
these genes are inherited from the mother.
X inactivation
Phenomenon of female mammals in which one
X chromosome is inactivated in every somatic cell,
producing a mosaic phenotype. Most genes on the
inactivated X chromosome are not expressed.
Genomic
imprinting
Inheritance pattern in which an allele from one
parent is inactivated in the somatic cells of the
offspring, while the allele from the other parent is
expressed.
Maternal effect
Inheritance pattern in which the genotype of the
mother determines the phenotype of the offspring.
This occurs because maternal effect genes of the
mother provide gene products to developing egg
cells.
or more alleles. This phenomenon is called a gene interaction.
As you will see, allelic variation at two or more loci may affect
the outcome of traits in different ways. First we will look at
interactions in which an allele of one gene prevents the expression of an allele of a different gene. Then we will discuss interactions in which multiple genes have additive effects on a single
trait. These additive effects, together with environmental influences, account for the continuous phenotypic variation that we
see for most traits.
An Epistatic Gene Interaction Occurs When
the Allele of One Gene Masks the Phenotypic
Effects of a Different Gene
In some gene interactions, the alleles of one gene mask the expression of the alleles of another gene. This phenomenon is
called epistasis (Greek ephistanai, stopping). An example is the
unexpected gene interaction discovered by William Bateson
and Reginald Punnett in the early 1900s, when they were studying crosses involving the sweet pea, Lathyrus odoratus. A cross
between a true-breeding purple-flowered plant and a truebreeding white-flowered plant produced an F1 generation with
all purple-flowered plants and an F2 generation with a 3:1 ratio
of purple- to white-flowered plants. Of course, Mendel’s laws
predicted this result. The surprise came when the researchers
crossed two different varieties of white-flowered sweet peas
(Figure 17.1). All of the F1 generation plants had purple flowers! When these plants were allowed to self-fertilize, the F2
generation had purple-flowered and white-flowered plants in
a 9:7 ratio. From these results, Bateson and Punnett deduced
that two different genes were involved. To have purple flowers, a plant must have one or two dominant alleles for each of
these genes. The relationships among the alleles are as follows:
C (one allele for purple) is dominant to c (white)
P (an allele for purple of a different gene) is dominant
to p (white)
with regard to only one of these genes. As a hypothetical example, let’s suppose that pea plants have 10 genes affecting height,
which we will call K, L, M, N, O, P, Q, R, S, and T. The genotypes of two hypothetical strains of pea plants may be:
Tall strain:
KK LL MM NN OO PP QQ RR SS TT
Dwarf strain:
KK LL MM NN OO PP QQ RR SS tt
In this example, the tall and dwarf strains differ at only a
single locus. One strain is TT and the other is tt, and this accounts for the difference in their height. If we make crosses of
tall and dwarf plants, the genotypes of the F2 offspring will differ with regard to only one gene; the other nine genes will be
identical in all of them. This approach allows a researcher to
study the effects of a single gene even though many genes may
affect a single trait.
In this section, we will examine situations in which a single
trait is controlled by two or more genes, each of which has two
cc masks P, or pp masks C, in either case producing
white flowers
A plant that was homozygous for either c or p would have
white flowers even if it had a purple-producing allele at the
other locus.
Epistatic interactions often arise because two or more different proteins are involved in a single cellular function. For
example, two or more proteins may be part of an enzymatic
pathway leading to the formation of a single product. This is
the case for the formation of a purple pigment in the sweet pea
strains we have been discussing:
Enzyme C
Colorless
precursor
Enzyme P
Colorless
intermediate
Purple
pigment
In this example, a colorless precursor molecule must be
acted on by two different enzymes to produce the purple pig-
98
Brooker−Widmaier−Graham−Stiling:
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III. Nucleic Acid Structure
and DNA Replication
17. Complex Patterns of
Inheritance
© The McGraw−Hill
Companies, 2008
COMPLEX PATTERNS OF INHERITANCE
351
or enzyme P. When either of these enzymes is missing, the plant
cannot make the purple pigment and has white flowers.
P
White variety #1
CCpp
White variety #2
ccPP
F1
All purple
CcPp
Self-fertilization
F2
CP
Cp
cP
cp
CP
CCPP
Purple
CCPp
Purple
CcPP
Purple
CcPp
Purple
Cp
CCPp
Purple
CCpp
White
CcPp
Purple
Ccpp
White
cP
CcPP
Purple
CcPp
Purple
ccPP
White
ccPp
White
cp
CcPp
Purple
Ccpp
White
ccPp
White
ccpp
White
Figure 17.1 Epistasis in the sweet pea. The color of
the sweet pea flower is controlled by two genes, each with a
dominant and a recessive allele. Each of the dominant alleles
(C and P) encodes an enzyme required for the synthesis of purple
pigment. A plant that is homozygous recessive for either gene (cc
or pp) cannot synthesize the pigment and will have white flowers.
Biological inquiry: In a Ccpp individual, which functional enzyme
is missing? Is it the enzyme encoded by the C or P gene?
ment. Gene C encodes a functional protein, enzyme C, that converts the colorless precursor into a colorless intermediate. The
recessive c allele results in a lack of production of enzyme C in
the homozygote. Gene P encodes the functional enzyme P,
which converts the colorless intermediate into the purple pigment. Like the c allele, the p allele results in an inability to produce a functional protein. A plant that is homozygous for either
of the recessive alleles will not make any functional enzyme C
Polygenic Inheritance and Environmental
Influences Produce Continuous Phenotypic
Variation
As we have just seen, an epistatic interaction causes the alleles
of one gene to mask the effects of a different gene. Let’s now
turn to another way that the alleles of different genes may affect
the phenotype of a single trait. In many cases, the effects of
alleles may be additive. This has been observed for many traits,
particularly those that are quantitative in nature.
Until now we have discussed the inheritance of traits with
clearly defined phenotypic variants, such as red or white eyes in
fruit flies. These are known as discrete traits, or discontinuous
traits, because the phenotypes do not overlap. For most traits,
however, the phenotypes cannot be sorted into discrete categories. The majority of traits in all organisms are continuous
traits, also called quantitative traits, which show continuous
variation over a range of phenotypes. In humans, quantitative
traits include height, weight, skin color, metabolic rate, and heart
size, to mention a few. In the case of domestic animals and plant
crops, many of the traits that people consider desirable are quantitative in nature, such as the number of eggs a chicken lays, the
amount of milk a cow produces, and the number of apples on
an apple tree. Consequently, much of our modern understanding of quantitative traits comes from agricultural research.
Quantitative traits are polygenic, which means that several
or many genes contribute to the outcome of the trait. For many
polygenic traits, genes contribute to the phenotype in an additive way. Another important factor is the environment. As we
saw in Chapter 16, the environment plays a vital role in the phenotypic expression of genes. Environmental factors often have
a major impact on quantitative traits. For example, an animal’s
diet affects its weight, and the amount of rain and sunlight that
fall on an apple tree affect how many apples it produces.
Because quantitative traits are polygenic and greatly influenced by environmental conditions, the phenotypes among different individuals may vary substantially in any given population. As an example, let’s consider skin pigmentation in people.
This trait is influenced by several genes that tend to interact in
an additive way. As a simplified example, let’s consider a population in which this trait is controlled by three genes, which we
will designate A, B, and C. Each gene has a dark allele, designated AD, BD, or CD, and a light allele, designated AL, BL, or CL,
respectively. All of the alleles encode enzymes that cause the
synthesis of skin pigment, but the enzymes encoded by dark
alleles cause more pigment synthesis than the enzymes encoded by light alleles. Figure 17.2 considers a hypothetical case
in which people who were heterozygous for all three genes produced a large population of offspring. The bar graph shows the
genotypes of the offspring, grouped according to the total number of dark alleles. As shown by the shading of the figure, skin
pigmentation increases as the number of dark alleles increases.
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UNIT III – CHAPTER 17
ADA LB DB LC DC L ADALB DB LC DC L
Fraction of people with same phenotype
20/
15
64
/64
ADALB DB LC DC L
10/
5
Same population
raised in a sunnier
environment
ADADB LB LC LC L
ADADB DB LC LC L
ALALB DB DC DC D
ALALB DB DC LC L
ADADB LB LC DC L
ADADB LB LC DC D
ALALB LB LC DC D
ADALB DB DC LC L
ADADB DB DC LC L
ADALB LB LC LC L
ADALB DB LC LC L
ADALB LB LC DC D
ALADB LB DC DC D
ALADB DB DC DC D
ALALB DB LC LC L
ADALB LB LC DC L
ALALB DB LC DC D
ALADB DB DC LC D
ADADB LB DC DC D
64
/64
0
Number of
light alleles
Number of
dark alleles
ALALB LB LC DC L
ALALB DB LC DC L
ALALB DB DC DC L
ADADB LB DC LC D
ADADB DB DC LC D
ADADB DB DC DC D
6
5
4
3
2
1
0
0
1
2
3
4
5
6
ALALB LB LC LC L
Light
Dark
Pigmentation
Figure 17.2 Continuous variation in a polygenic trait. Skin color is a polygenic trait that can display a continuum of phenotypes.
The bell curve on the left (solid line) shows the range of skin pigmentation in a hypothetical human population. The bar graphs below
the curve show the additive effects of three genes that affect pigment production in this population; each bar shows the fraction of
people with a particular number of dark alleles (AD, BD, and CD ) and light alleles (AL, BL, and CL). The bell curve on the right (dashed line)
represents the expected range of phenotypes if the same population was raised in a sunnier environment.
Offspring who have no dark alleles or no light alleles—that is,
who are homozygous for all three genes—are fewer in number
than those with some combination of dark and light alleles. As
seen in the bell-shaped curve above the bar graph, the phenotypes of the offspring fall along a continuum. This continuous
phenotypic variation, which is typical of quantitative traits, is
produced by genotypic differences together with environmental
effects. A second bell-shaped curve (the dashed line) depicts
the expected phenotypic range if the same population of offspring had been raised in a sunnier environment, which increases pigment production. These two curves illustrate how the
environment can also have a significant influence on the range
of phenotypes.
In our discussion of genetics, we tend to focus on discrete
traits because this makes it easier to relate a specific genotype
with a phenotype. This is usually not possible for continuous
traits. For example, as depicted in the middle bar of Figure 17.2,
seven different genotypes can produce individuals with a medium amount of pigmentation. Nevertheless, it is important to
emphasize that the majority of traits in all organisms are continuous, not discrete. Most traits are influenced by multiple
genes, and the environment has an important impact on the
phenotypic outcome.
17.2
Genes on the Same
Chromosome: Linkage,
Recombination, and Mapping
In all of the inheritance patterns we have studied so far, the
alleles segregate and assort independently as predicted by Mendel’s laws. As we have seen, phenotypes can be influenced by a
variety of factors, including gene interactions and environmental effects, that make it difficult to relate genotype to phenotype.
Even so, if we understand all of these factors and take them into
account, we can see that each of the genes is transmitted according to Mendel’s laws.
In the rest of this chapter, we will consider inheritance patterns in which the outcome of a cross violates one of Mendel’s
laws. In this section, we focus on transmission patterns that do
not conform to the law of independent assortment. We will begin
by examining the first experimental cross that demonstrated this
pattern. You will learn that this pattern was explained by Thomas
Hunt Morgan, who proposed that genes located close to each
other on the same chromosome tend to be inherited as a group.
Finally, we will see how crossing over between such genes provided the first method of mapping genes on chromosomes.
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COMPLEX PATTERNS OF INHERITANCE
Bateson and Punnett’s Crosses of Sweet
Peas Showed That Genes Do Not Always
Assort Independently
In Chapter 16, we learned that the independent assortment of alleles is due to the random alignment of homologous chromosomes
during meiosis (refer back to Figure 16.11). But what happens
when the alleles of different genes are on the same chromosome? A typical chromosome contains many hundreds or even
a few thousand different genes. When two genes are close together on the same chromosome, they tend to be transmitted as a
unit, a phenomenon known as linkage. A group of genes that usu-
Figure 17.3
ally stay together during meiosis is called a linkage group, and
the genes in the group are said to be linked. In a two-factor cross,
linked genes do not follow the law of independent assortment.
The first study showing linkage between two different genes
was a cross of sweet peas carried out by William Bateson and
Reginald Punnett in 1905. A surprising result occurred when
they conducted a cross involving two different traits, flower
color and pollen shape (Figure 17.3). One of the parent plants
had purple flowers (PP) and long pollen (LL); the other had
red flowers (pp) and round pollen (ll). As Bateson and Punnett expected, the F1 plants all had purple flowers and long
pollen (PpLl). The unexpected result came in the F2 generation.
A cross of sweet peas showing that independent assortment does not always occur.
HYPOTHESIS The alleles of different genes assort independently of each other.
STARTING MATERIALS True-breeding sweet pea strains that differ with regard to flower color and pollen shape.
1
Experimental level
Conceptual level
PPLL ppll
Cross a plant with purple
flowers and long pollen to
a plant with red flowers
and round pollen.
Purple flowers,
long pollen
2
Red flowers,
round pollen
Observe the phenotypes
of the F1 offspring.
PpLl
Purple flowers, long pollen
3
Meiosis
Allow the F1 offspring
to self-fertilize.
PL and pl gametes — more frequent
Pl and pL gametes — less frequent
Purple flowers,
long pollen
4
353
Purple flowers,
long pollen
Fertilization
Observe the phenotypes
of the F2 offspring.
Purple flowers, Purple flowers, Red flowers, Red flowers,
long pollen
round pollen
long pollen
round pollen
15.6
:
1.0
:
1.4
:
4.5
F2 offspring having phenotypes of purple
flowers, long pollen or red flowers, round
pollen occurred more frequently than
expected from Mendel’s law of
independent assortment.
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UNIT III – CHAPTER 17
THE DATA
Phenotypes of
F2 offspring
Purple flowers, long pollen
Purple flowers, round pollen
Red flowers, long pollen
Red flowers, round pollen
Observed
number
Observed
ratio
Expected
number
Expected
ratio
296
19
27
85
15.6
1.0
1.4
4.5
240
80
80
27
9
3
3
1
Although the offspring displayed the four phenotypes predicted
by Mendel’s laws, the observed numbers of offspring did not
conform to the predicted 9:3:3:1 ratio. Rather, as seen in the data
in Figure 17.3, the F2 generation had a much higher proportion
of the two phenotypes found in the parental generation: purple
flowers with long pollen, and red flowers with round pollen.
These results did not support the law of independent assortment.
Bateson and Punnett suggested that the transmission of flower
color and pollen shape was somehow coupled, so that these traits
did not always assort independently. Although the law of independent assortment applies to many other genes, in this example, the hypothesis of independent assortment was rejected.
Linkage and Crossing Over Produce Parental
and Recombinant Phenotypes
The chromosomes next to the flies in Figure 17.4 show the
arrangement of these alleles. If the two genes are on the same
chromosome, we know the arrangement of alleles in the P generation flies because these flies are homozygous for both genes
(bbcc or bbcc). In the P generation female on the left, b and
c are linked, while b and c are linked in the male on the right.
Let’s now look at the outcome of the crosses in Figure 17.4.
As expected, the F1 offspring (bbcc) all had gray bodies and
straight wings, confirming that these are the dominant traits. In
the next cross, F1 females were mated to males that were homozygous for both recessive alleles (bbcc). A cross in which an
individual with a dominant phenotype is mated with a homozygous recessive individual is called a testcross, as described in
Chapter 16. In the crosses we are discussing here, the purpose
of the testcross is to determine whether the genes for body color
and wing shape are linked. If the genes were on different chromosomes and assorted independently, this testcross should have
produced equal numbers of F2 offspring with the four possible
phenotypes. The observed numbers, shown above the F2 phenotypes, clearly conflict with this prediction based on independent assortment. The two most abundant phenotypes are those
with the combinations of characteristics in the P generation:
gray bodies and straight wings or black bodies and curved wings.
These offspring are called nonrecombinants because their combination of traits has not changed from the parental generation.
They are also termed parental types. The smaller number of
offspring that have a different combination of traits—gray bodies and curved wings or black bodies and straight wings—are
recombinants or nonparental types.
How do we explain the occurrence of recombinants when
genes are linked on the same chromosome? As shown beside the
flies of the F2 generation in Figure 17.4, each recombinant individual has a chromosome that is the product of a crossover. The
crossover occurred while the F1 female fly was making egg cells.
Although Bateson and Punnett realized their results did not
conform to Mendel’s law of independent assortment, they did
not provide a clear explanation for their data. A few years later,
Thomas Hunt Morgan obtained similar ratios in crosses of fruit
flies while studying the transmission pattern of genes located
on the X chromosome. Like Bateson and Punnett, Morgan observed many more F2 offspring with the parental combination
of traits than would be predicted on the basis of independent
assortment. To explain his data, Morgan proposed these ideas:
1. When different genes are located on the same chromosome,
the traits that are determined by those genes are most
likely to be inherited together.
2. Due to crossing over during meiosis, homologous chromosomes can exchange pieces of chromosomes and create
new combinations of alleles (refer back to Figure 15.17).
3. The likelihood of crossing over depends on the distance
between two genes. Crossovers between homologous
chromosomes are much more likely to occur between two
genes that are farther apart in the chromosome compared
to two genes that are closer together.
To illustrate the first two of these ideas, Figure 17.4 considers a series of crosses involving two genes that are linked on the
same chromosome in Drosophila. The P generation cross is between flies that are homozygous for alleles that affect body color
and wing shape. The female is homozygous for the wild-type
alleles that produce gray body color (bb) and straight wings
(cc); the male is homozygous for mutant alleles that produce
black body color (bb) and curved wings (cc). Note that the symbols for the genes are based on the name of the mutant allele;
the wild-type allele is indicated by a superscript plus sign (+).
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COMPLEX PATTERNS OF INHERITANCE
P
Gray body, straight wings
Black body, curved wings
b
b
c
c
b
b
c
c
Homozygous recessive
bbcc
Homozygous dominant
bbcc
F1
Gray body, straight wings
Black body, curved wings
Testcross
b
b
c
c
b
b
c
c
bbcc
bbcc
F2
Gray body,
straight wings
Black body,
curved wings
Gray body,
curved wings
Black body,
straight wings
Total
Number observed
371
359
133
137
1,000
Number expected based on
independent assortment
250
250
250
250
1,000
b
b
b
b
c
c
c
c
bbcc
b
b
c
c
bbcc
bbcc
Nonrecombinants
b
b
c
c
bbcc
Recombinants
Figure 17.4 Linkage and recombination of alleles. An experimenter crossed bbcc+ and bbcc flies to produce F1 heterozygotes.
F1 females were then testcrossed to bbcc males. The large number of parental phenotypes in the F2 generation suggests that the two
genes are linked on the same chromosome. F2 recombinant phenotypes occur because the alleles can be rearranged by crossing over.
As shown below, four different egg cells are possible:
b
c
Crossover
b
b
b
b
c
c
c
c
Homologs in F1 female
b
c
Meiosis
b
b
c
c
Nonrecombinant
chromosomes
Recombinant
chromosomes
Due to crossing over, two of the four egg cells produced by
meiosis have recombinant chromosomes. What happens when
eggs containing such chromosomes are fertilized in the testcross? Each of the male fly’s sperm cells carries a chromosome
with the two recessive alleles. If the egg contains the recombinant chromosome carrying the b and c alleles, the testcross
will produce an F2 offspring with a gray body and curved
wings. If the egg contains the recombinant chromosome carrying the b and c alleles, F2 offspring will have a black body
and straight wings. Therefore, crossing over in the F1 female
can explain the occurrence of both types of F2 recombinant
offspring.
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17. Complex Patterns of
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UNIT III – CHAPTER 17
Morgan’s ideas about linkage and crossing over were based
on similar data, derived from his studies of genes on the X chromosome. The idea that linked genes tend to be inherited together explained the high frequency of parental combinations of
traits in certain crosses. The suggestion that crossing over produces chromosomes with new allele combinations accounted for
the occurrence of recombinant phenotypes. Morgan’s third idea
regarding linkage was that the frequency of crossing over between linked genes depends on the distance between them. This
suggested a method for determining the relative positions of
genes on a chromosome, as we will see next.
Recombination Frequencies Provide a Method
for Mapping Genes Along Chromosomes
The oldest approach to studying the arrangement of genes in a
species’ genome is called genetic linkage mapping (also known
as gene mapping or chromosome mapping). This experimental
method is used to determine the linear order of genes that are
linked to each other along the same chromosome. As depicted in
Figure 17.5, this linear arrangement is shown in a chart known
as a genetic linkage map. Each gene has its own unique locus
at a particular site within a chromosome. For example, the gene
for black body color (b) that we discussed earlier is located near
the middle of the chromosome, while the gene for curved wings
(c) is closer to one end. The first genetic linkage map, showing
five genes on the Drosophila X chromosome, was constructed in
1911 by Alfred Sturtevant, an undergraduate who spent time in
Morgan’s laboratory.
Genetic linkage mapping allows us to estimate the relative
distances between linked genes based on the likelihood that a
crossover will occur between them. This likelihood is proportional to the distance between the genes, as Morgan first proposed. If the genes are very close together, a crossover is unlikely
to begin in the region between them. However, if the genes are
very far apart, a crossover is more likely to be initiated between
them and thereby recombine their alleles. Therefore, in a cross
involving two genes on the same chromosome, the percentage of
recombinant offspring is correlated with the distance between
the genes. This correlation provides the experimental basis for
gene mapping. If a two-factor testcross produces many recombinant offspring, the experimenter concludes that the genes are far
apart. If very few recombinant offspring are observed, the genes
must be close together.
To find the distance between two genes, the experimenter
must determine the frequency of crossing over between them,
called their recombination frequency. This is accomplished by
conducting a testcross. As an example, let’s refer back to the
Drosophila testcross described in Figure 17.4. As we discussed,
the genes for body color and wing shape are on the same chromosome; the recombinant offspring are the result of crossing
Mutant phenotype
Wild-type phenotype
Aristaless, al
Long aristae
13.0
Dumpy wings, dp
Long wings
48.5
Black body, b
Gray body
54.5
Purple eyes, pr
Red eyes
67.0
Vestigial wings, vg
Long wings
75.5
Curved wings, c
Straight wings
104.5
Brown eyes, bw
Red eyes
Map units
0.0
Figure 17.5
A simplified genetic linkage map. This map
shows the relative locations of a few genes along a chromosome
in Drosophila melanogaster. The name of each gene is based
on the mutant phenotype. The numbers on the left are map units
(mu). The distance between two genes, in map units, corresponds
to their recombination frequency in testcrosses.
over during egg formation in the F1 female. We can use the data
from the testcross shown in Figure 17.4 to estimate the distance
between these two genes. The map distance between two linked
genes is defined as the number of recombinant offspring divided
by the total number of offspring times 100.
Map distance Number of recombinant offspring
Total number of offspring
133 137
371 359 133 137
100
100
27.0 map units
The units of distance are called map units (mu), or sometimes centiMorgans (cM) in honor of Thomas Hunt Morgan.
One map unit is equivalent to a 1% recombination frequency.
In this example, 270 out of 1,000 offspring are recombinants, so
the recombination frequency is 27% and the two genes are 27.0
mu apart.
Genetic linkage mapping has been useful for analyzing the
genes of organisms that are easily crossed and produce many
offspring in a short time. It has been used to map the genes of
several plant species and of certain species of animals, such as
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Drosophila. However, for most organisms, including humans,
linkage mapping is impractical due to long generation times or
the inability to carry out experimental crosses. Fortunately,
many alternative methods of gene mapping have been developed in the past few decades that are faster and do not depend
on crosses. These newer cytological and molecular approaches,
which we will discuss in Chapter 20, are now used to map genes
in a wide variety of organisms.
17.3
Extranuclear Inheritance:
Organelle Genomes
In the previous section, we examined the inheritance patterns
of linked genes that violate the law of independent assortment.
In this section, we will explore inheritance patterns that violate
the law of segregation. Gene transmission may defy this law
because some genes are not found on the chromosomes in the
cell nucleus. The segregation of genes is explained by the pairing and segregation of homologous chromosomes during meiosis; genes found elsewhere in the cell do not segregate in the
same way. The transmission of genes that are located outside
the cell nucleus is called extranuclear inheritance.
Two important types of extranuclear inheritance patterns
involve genes that are found in mitochondria and chloroplasts
(Figure 17.6). Extranuclear inheritance is also called cytoplasmic inheritance because these organelles are in the cytoplasm
of the cell. As we discussed in Chapter 6, mitochondria and
chloroplasts are found in eukaryotic cells because of an ancient
endosymbiotic relationship. They contain their own genetic material, or genomes. Although these organelle genomes are much
smaller than nuclear genomes, researchers have discovered that
they are critically important in the phenotypes of organisms. In
plants, for example, the chloroplast genome carries many genes
that are vital for photosynthesis. Mitochondrial genes are critical for respiration. In humans, mutations in the mitochondrial
genome may cause inherited diseases. In this section, we will
examine the transmission patterns observed for genes found in
the chloroplast and mitochondrial genomes and consider how
mutations in these genes may affect an individual’s traits.
Chloroplast Genomes Are Often
Maternally Inherited
One of the first experiments showing an extranuclear inheritance pattern was carried out by Carl Correns in 1909. Correns
discovered that leaf pigmentation in the four-o’clock plant
(Mirabilis jalapa) follows a pattern of inheritance that does not
obey Mendel’s law of segregation. Four-o’clock leaves may be
green, white, or variegated, as shown in Figure 17.7. Correns observed that the pigmentation of the offspring depended solely on
the pigmentation of the maternal parent, a phenomenon called
maternal inheritance. If the female parent had white leaves,
357
Nuclear genome
Mitochondrial genome
(a) An animal cell
Nuclear genome
Chloroplast
genome
Mitochondrial genome
(b) A plant cell
Figure 17.6
The locations of genetic material in animal and
plant cells. The chromosomes in the cell nucleus are collectively
known as the nuclear genome. Mitochondria and chloroplasts have
small circular chromosomes, which are called the mitochondrial
and chloroplast genomes.
all of the offspring had white leaves. Similarly, if the female was
green, so were all of the offspring. The offspring of a variegated
female parent could be green, white, or variegated.
At the time, Correns did not understand that chloroplasts
contain some genes. We now know that the pigmentation of
four-o’clock leaves can be explained by the occurrence of genetically different types of chloroplasts in the leaf cells. As discussed in Chapter 8, chloroplasts are the site of photosynthesis,
and their green color is due to the presence of the pigment called
chlorophyll. Certain genes required for chlorophyll synthesis
are found within the chloroplast DNA. The green phenotype is
due to the presence of chloroplasts that have normal genes and
synthesize the usual quantity of chlorophyll. The white phenotype is caused by a mutation in a gene within the chloroplast
DNA that prevents the synthesis of most of the chlorophyll.
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UNIT III – CHAPTER 17
Correns’ crosses
Cross 1
All white
offspring
Reciprocal cross
of cross 1
All green
offspring
Cross 2
(Enough chlorophyll is made for the plant to survive.) The variegated phenotype occurs in leaves that have a mixture of the two
types of chloroplasts.
Leaf pigmentation follows a maternal inheritance pattern
because the chloroplasts in four o’clocks are inherited only
through the cytoplasm of the egg (Figure 17.8). During plant fertilization, a sperm cell from a pollen grain fertilizes an egg cell
to create a zygote, which eventually develops into a plant. In
four o’clocks, the egg cell contains several proplastids that are
inherited by the offspring, while the sperm cell does not contribute any proplastids. As discussed in Chapter 4, proplastids
develop into various types of plastids, including chloroplasts.
Thus, the phenotype of a four-o’clock plant depends on the
types of proplastids it inherits from the maternal parent. If the
maternal parent transmits only normal proplastids, all offspring
will have green leaves (Figure 17.8a). Alternatively, if the maternal parent transmits only mutant proplastids, all offspring
will have white leaves (Figure 17.8b). The genetic composition
of the paternal parent does not affect the outcome. Because an
egg cell contains several proplastids, an offspring from a variegated maternal parent may inherit only normal proplastids, only
Normal proplastid will
produce chloroplasts with a
normal amount of green
pigment.
Mutant proplastid will
produce chloroplasts
with very little pigment.
Egg
cell
Green, white,
or variegated
offspring
Reciprocal cross
of cross 2
(a) Egg cell from a maternal
parent with green leaves
(b) Egg cell from a maternal
parent with white leaves
All green
offspring
Figure 17.7
Maternal inheritance in the four-o’clock plant.
The genes for green pigment synthesis in plants are part of the
chloroplast genome. The white phenotype in four o’clocks is
due to chloroplasts with a mutant allele that greatly reduces
green pigment production. The variegated phenotype is due to
a mixture of normal and mutant chloroplasts. In four o’clocks,
the egg contains all of the plastids that are inherited by the
offspring, so the phenotype of the offspring is determined by
the female parent.
Biological inquiry: In this example, where is the gene located that
causes the green color of four-o’clock leaves? How is this gene
transmitted from parent to offspring?
(c) Possible egg cells from a maternal parent with variegated leaves
Figure 17.8
Plastid composition of egg cells from green,
white, and variegated four-o’clock plants. In this drawing
of four-o’clock egg cells, normal proplastids are represented
as green and mutant proplastids as white. Proplastids do not
differentiate into chloroplasts in egg cells, and they are not
actually green. (a) A green plant produces eggs carrying normal
proplastids. (b) A white plant produces eggs carrying mutant
proplastids. (c) A variegated plant produces eggs that may
contain either or both types of proplastids.
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mutant proplastids, or a mixture of normal and mutant proplastids. Consequently, the offspring of a variegated maternal parent
can be green, white, or variegated individuals (Figure 17.8c).
The variegated phenotype is due to segregation events that
occur after fertilization. As a zygote containing both types of
chloroplasts divides to produce a multicellular plant, some cells
may receive mostly normal chloroplasts. Further division of
these cells gives rise to a patch of green tissue. Alternatively, as
a matter of chance, other cells may receive mostly mutant chloroplasts that are defective in chlorophyll synthesis. This results in
a patch of tissue that is white.
In most species of plants, the egg cell provides most of the
zygote’s cytoplasm, while the much smaller male gamete often
provides little more than a nucleus. Therefore, chloroplasts are
most often inherited via the egg. In seed-bearing plants, maternal inheritance of chloroplasts is the most common transmission pattern. However, certain species exhibit a pattern called
biparental inheritance, in which both the pollen and the egg
contribute chloroplasts to the offspring. Others exhibit paternal
inheritance, in which only the pollen contributes these organelles. For example, most types of pine trees show paternal inheritance of chloroplasts.
Mitochondrial Genomes Are Maternally Inherited
in Humans and Most Other Species
Mitochondria are found in nearly all eukaryotic species. Similar
to the transmission of chloroplasts in plants, maternal inheritance is the most common pattern of mitochondrial transmission in eukaryotic species, although some species do exhibit
biparental or paternal inheritance. The mitochondrial genome
of many mammalian species has been analyzed and usually
contains a total of 37 genes. Twenty-four genes encode tRNAs
and rRNAs, which are needed for translation inside the mitochondrion. Thirteen genes encode proteins that are involved in
oxidative phosphorylation. As discussed in Chapter 7, the primary function of the mitochondrion is the synthesis of ATP via
oxidative phosphorylation.
In humans, as in most species, mitochondria are maternally
inherited. Researchers have discovered that mutations in human
mitochondrial genes can cause a variety of rare diseases (Table
17.2). These are usually chronic degenerative disorders that affect the brain, eyes, heart, muscle, kidney, and endocrine glands.
For example, Leber’s hereditary optic neuropathy (LHON) affects
the optic nerve. It may lead to the progressive loss of vision in
one or both eyes. LHON can be caused by a mutation in one of
several different mitochondrial genes.
17.4
X Inactivation, Genomic
Imprinting, and Maternal
Effect
We will end our discussion of complex inheritance patterns by
considering examples in which the timing and control of gene
expression create inheritance patterns that are determined by
Table 17.2
359
Examples of Human Mitochondrial
Diseases
Disease
Description
Leber’s hereditary
optic neuropathy
Caused by a mutation in one of several
mitochondrial genes that encode electrontransport proteins. The main symptom is loss
of vision.
Neurogenic muscle
weakness
Caused by a mutation in a mitochondrial gene
that encodes a subunit of mitochondrial ATP
synthase, which is required for ATP synthesis.
Symptoms involve abnormalities in the nervous
system that affect the muscles and eyes.
Mitochondrial
encephalomyopathy,
lactic acidosis, and
strokelike episodes
Mutations in mitochondrial genes that encode
tRNAs for leucine and lysine. Symptoms include
strokelike episodes, secretion of lactic acid into
the bloodstream, seizures, migraine headaches,
and lack of coordination.
Maternal
myopathy and
cardiomyopathy
A mutation in a mitochondrial gene that
encodes a tRNA for leucine. The primary
symptoms involve muscle abnormalities, most
notably in the heart.
Myoclonic epilepsy
and ragged-red
muscle fibers
A mutation in a mitochondrial gene that
encodes a tRNA for lysine. Symptoms include
epilepsy, dementia, blindness, deafness, and
heart and kidney malfunctions.
the sex of the individual or by the sex of the parents. The first
two patterns, called X inactivation and genomic imprinting, are
types of epigenetic inheritance. In epigenetic inheritance, modification of a gene or chromosome during egg formation, sperm
formation, or early stages of embryo growth alters gene expression in a way that is fixed during an individual’s lifetime. Epigenetic changes permanently affect the phenotype of the individual, but they are not permanent over the course of many
generations and they do not change the actual DNA sequence.
For example, a gene may undergo an epigenetic change that inactivates it for an individual’s entire life, so it is never expressed
in that individual. However, when the same individual makes
gametes, the gene may become activated and remain active
during the lifetime of an offspring that inherits the gene.
At the end of this section, we will also consider genes that
exhibit a bizarre inheritance pattern called the maternal effect,
in which the genotype of the mother directly determines the phenotype of her offspring. Surprisingly, for maternal effect genes,
the genotypes of the father and of the offspring themselves do
not affect the offspring’s phenotype. As you will learn, this phenomenon is explained by the accumulation of gene products that
the mother provides to her developing eggs.
In Female Mammals, One X Chromosome
Is Inactivated in Each Somatic Cell
In 1961, the British geneticist Mary Lyon proposed the phenomenon of X inactivation, in which one X chromosome in the somatic
cells of female mammals is inactivated, meaning that its genes
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UNIT III – CHAPTER 17
Orange
fur allele
Barr body
O
(a) Calico cat
1
In the early embryo,
all X chromosomes
are initially active.
Black fur
allele
O
B
B
O
O
B
O
B
O
B
O
B
O
O
B
B
B
Figure 17.9
X-chromosome inactivation in female mammals.
This light micrograph shows the nucleus of a human female cell. The
label shows the Barr body, a condensed, inactivated X chromosome
found just inside the nuclear envelope in the somatic cells of
female mammals.
are not expressed. The Lyon hypothesis, as X inactivation also
came to be known, was based on two lines of evidence. The first
evidence came from microscopic studies of mammalian cells. In
1949, Murray Barr and Ewart Bertram identified a highly condensed structure in the cells of female cats that was not found in
the cells of male cats. This structure was named a Barr body after
one of its discoverers (Figure 17.9). In 1960, Susumu Ohno correctly proposed that a Barr body is a highly condensed X chromosome. Lyon’s second line of evidence was the inheritance
pattern of variegated coat colors in certain mammals. A classic
case is the calico cat, which has randomly distributed patches
of black and orange fur (Figure 17.10a).
According to the Lyon hypothesis, the calico pattern is explained by the permanent inactivation of one X chromosome in
each cell that forms a patch of the cat’s skin, as shown in Figure 17.10b. The gene involved is an X-linked gene that occurs
as an orange allele, XO, and a black allele, XB. A female cat that
is heterozygous for this gene will be calico. (The white underside is due to a dominant allele of a different autosomal gene.)
At an early stage of embryonic development, one of the two
X chromosomes is randomly inactivated in each of the cat’s
somatic cells, including those that will give rise to the hairproducing skin cells. As the embryo grows and matures, the
pattern of X inactivation is maintained during subsequent cell
divisions. For example, skin cells derived from a single embryonic cell in which the XB-carrying chromosome has been inactivated will produce a patch of orange fur, because they express
only the XO allele that is carried on the active chromosome.
Alternatively, a group of skin cells in which the chromosome
carrying XO has been inactivated will express only the XB allele,
producing a patch of black fur. Because the primary event of
X inactivation is a random process that occurs at an early stage
of development, the result is an animal with randomly distributed patches of black and orange fur.
B
O
2
In each embryonic
cell, random
inactivation occurs
for one of the X
chromosomes, which
becomes a Barr body.
B
O
O
B
B
O
O
Barr
bodies
3
As development
proceeds, the pattern
of X inactivation is
maintained during
cell division.
(b) Process of X inactivation
Figure 17.10
Random X-chromosome inactivation in a
calico cat. (a) A calico cat. (b) X inactivation during embryonic
development. The calico pattern is due to random X-chromosome
inactivation in a female that is heterozygous for the X-linked
gene with black and orange alleles. The cells at the top of this
figure represent a small mass of cells making up the very early
embryo. In these cells, both X chromosomes are active. At an
early stage of embryonic development, one X chromosome is
randomly inactivated in each cell. The initial inactivation pattern
is maintained in the descendents of each cell as the embryo
matures into an adult. The pattern of orange and black fur in
the adult cat reflects the pattern of X inactivation in the embryo.
Biological inquiry: If a female cat is homozygous for the orange
allele, would it show a calico phenotype?
In female mammals that are heterozygous for X-linked
genes, approximately half of their somatic cells will express one
allele, while the rest of their somatic cells will express the other
allele. These heterozygotes are called mosaics because they
are composed of two types of cells, analogous to the differentcolored pieces in the pictures called mosaics. The phenomenon
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of mosaicism is readily apparent in calico cats, in which the
alleles affect fur color. Likewise, human females who are heterozygous for X-linked genes are mosaics, with one allele expressed in some cells and the alternative allele in other cells.
Women who are heterozygous for recessive X-linked alleles
usually show the dominant trait because the expression of the
dominant allele in 50% of their cells is sufficient to produce the
dominant phenotype.
On rare occasions, a female who is heterozygous for a recessive X-linked disease-causing allele may show mild or even severe disease symptoms. Because the pattern of X-chromosome
inactivation is random, there will be a small percentage of heterozygous women who happen to inactivate the X chromosome carrying the normal allele in a large percentage of their
cells, as a matter of bad luck. As an example, let’s consider the
recessive X-linked form of hemophilia that we discussed in
Chapter 16. This type of hemophilia is caused by a defect in a
gene that encodes a blood-clotting factor, called factor VIII,
that is made by cells in the liver and secreted into the bloodstream. X inactivation in humans occurs when an embryo is 10
days old. At this stage, the liver contains only about a dozen
cells. In most females who are heterozygous for the normal
and hemophilia alleles, roughly half of their liver cells will
express the normal allele. However, on rare occasions, all or
most of the dozen embryonic liver cells might happen to inactivate the X chromosome carrying the dominant normal allele.
Following growth and development, such a female will have a
very low level of factor VIII and as a result will show symptoms
of hemophilia.
At this point, you may be wondering why X inactivation
occurs. Researchers have proposed that X inactivation achieves
dosage compensation between male and female mammals. The
X chromosome carries many genes, while the Y chromosome has
only a few. The inactivation of one X chromosome in the female
reduces the number of expressed copies (doses) of X-linked genes
from two to one. As a result, the expression of X-linked genes in
females and males is roughly equal.
The X Chromosome Has an X Inactivation
Center That Controls Compaction into a
Barr Body
After the Lyon hypothesis was confirmed, researchers became
interested in the genetic control of X inactivation. The cells of
humans and other mammals have the ability to count their X
chromosomes and allow only one of them to remain active.
Additional X chromosomes are converted to Barr bodies. In normal females, two X chromosomes are counted and one is inactivated. In normal males, one X chromosome is counted and
none inactivated. On occasion, however, people are born with
abnormalities in the number of their sex chromosomes. In these
disorders, known as Turner syndrome, Triple X syndrome, and
Klinefelter syndrome, the cells inactivate the number of X chromosomes necessary to leave a single active chromosome.
Chromosome
Composition
Number of
Barr Bodies
Normal female
XX
1
Normal male
XY
0
Turner syndrome (female)
XO
0
Triple X syndrome (female)
XXX
2
Klinefelter syndrome (male)
XXY
1
Phenotype
Although the genetic control of inactivation is not entirely
understood at the molecular level, a short region on the X chromosome called the X inactivation center (Xic) is known to
play a critical role. Eeva Therman and Klaus Patau identified Xic
from its key role in X inactivation. The counting of human X
chromosomes is accomplished by counting the number of Xics.
The Xic on each X chromosome is necessary for inactivation to
occur. Therman and Patau found that in cells with two X chromosomes, if one of them is missing its Xic due to a chromosome mutation, neither X chromosome will be inactivated. This
is a lethal condition for a human female embryo.
The expression of a specific gene within the X inactivation
center is required for compaction of the X chromosome into
a Barr body. This gene, discovered in 1991, is named Xist (for
X inactive specific transcript). The Xist gene product is a long
RNA molecule that does not encode a protein. Instead, the role
of Xist RNA is to coat one of the two X chromosomes during
the process of X inactivation. The Xist gene on the inactivated
X chromosome continues to be expressed after other genes on
this chromosome have been silenced.
The process of X inactivation can be divided into three
phases: initiation, spreading, and maintenance (Figure 17.11).
During initiation, one of the X chromosomes is targeted for inactivation. This chromosome is inactivated during the spreading phase, so called because inactivation begins near the X
inactivation center and spreads in both directions along the
chromosome. Spreading requires the transcription of the Xist
gene and coating of the X chromosome with Xist RNA. After
coating, proteins associate with the Xist RNA and promote compaction of the chromosome into a Barr body. Maintenance refers
to replication of the compacted chromosome during subsequent
cell divisions. While initiation and spreading occur only during
embryonic development, maintenance occurs throughout the
individual’s life. Continued activity of the Xist gene on an inactivated X chromosome maintains this chromosome as a Barr
body during cell division. Whenever a somatic cell divides in
a female mammal, the Barr body is replicated to produce two
Barr bodies.
The Transcription of an Imprinted Gene
Depends on the Sex of the Parent
As we have seen, X inactivation is a type of epigenetic inheritance
in which a chromosome is modified in the early embryo, permanently altering gene expression in that individual. Other types
of epigenetic inheritance occur in which genes or chromosomes
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UNIT III – CHAPTER 17
Barr
body
Coating by Xist RNA
and additional proteins
To be
inactivated
Further
spreading
Xic
1
Initiation: Occurs during
embryonic development. The
X inactivation centers (Xics)
are counted and one of the X
chromosomes is targeted for
inactivation.
Figure 17.11
Xic
Xic
2
Xic
Spreading: Occurs during embryonic development.
It begins at the Xic and progresses toward both
ends until the entire chromosome is inactivated.
The Xist gene, located within the Xic, encodes an
RNA that coats the X chromosome and promotes
its compaction into a Barr body.
Igf-2m Igf-2m
(homozygous dwarf)
Offspring
genotype
Maintenance: Occurs from embryonic
development through adult life. The
inactivated X chromosome is maintained
as a Barr body during subsequent cell
divisions.
The process of X inactivation.
are modified in the gametes of a parent, permanently altering
gene expression in the offspring. Genomic imprinting refers
to a phenomenon in which a segment of DNA is imprinted, or
marked, in a way that affects gene expression throughout the
life of the individual who inherits that DNA.
Genomic imprinting occurs in numerous species, including
insects, plants, and mammals. Imprinting may involve a single
gene, a part of a chromosome, an entire chromosome, or even
all of the chromosomes inherited from one parent. It is permanent in the somatic cells of a given individual, but the marking
of the DNA is altered from generation to generation. Imprinted
genes do not follow a Mendelian pattern of inheritance because
imprinting causes the offspring to distinguish between maternally and paternally inherited alleles. Depending on how a par-
Parents
3
Igf-2 Igf-2
(homozygous normal)
Igf-2 Igf-2m
(heterozygous)
ticular gene is marked by each parent, the offspring will express
either the maternal or the paternal allele, but not both.
Let’s consider a specific example of imprinting that involves
a gene called Igf-2 that is found in mice and other mammals.
This gene encodes a growth hormone called insulin-like growth
factor 2 that is needed for proper growth. If a normal copy of
this gene is not expressed, a mouse will be dwarf. The Igf-2 gene
is known to be located on an autosome, not on a sex chromosome. Because mice are diploid, they have two copies of this
gene, one from each parent.
Researchers have discovered that mutations can occur in the
Igf-2 gene that block the function of the Igf-2 hormone. When
mice carrying normal or mutant alleles are crossed to each other,
a bizarre result is obtained (Figure 17.12). If the male parent
Igf-2 Igf-2
(homozygous normal)
Igf-2m Igf-2m
(homozygous dwarf)
Igf-2 Igf-2m
(heterozygous)
Allele that is
transcribed
in offspring
Igf-2
(normal)
Igf-2m
(nonfunctional)
Phenotype
Normal
Dwarf
Igf-2
Igf-2m
normal allele
mutant allele
silenced allele (from female parent)
expressed allele (from male parent)
Figure 17.12
An example of genomic imprinting in the mouse. In the cross on the left, a homozygous male with the normal Igf-2
allele is crossed to a homozygous female carrying a defective allele, Igf-2m. An offspring is phenotypically normal because the paternal
allele is expressed. In the cross on the right, a homozygous male carrying the defective allele is crossed to a homozygous normal female.
In this case, an offspring is dwarf because the paternal allele is defective and the maternal allele is not expressed.
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is homozygous for the normal allele and the female is homozygous for the mutant allele, all the offspring grow to a normal size.
In contrast, if the male is homozygous for the mutant allele and
the female is homozygous for the normal allele, all the offspring
are dwarf. The reason this result is so surprising is that the normal and dwarf offspring have the same genotype but different
phenotypes! These phenotypes are not the result of any external
influence on the offspring’s development. Rather, the allele that
is expressed in their somatic cells depends on which parent contributed which allele. In mice, the Igf-2 gene inherited from the
mother is imprinted in such a way that it cannot be transcribed
into mRNA. Therefore, only the paternal gene is expressed. The
mouse on the left side of Figure 17.12 is normal because it expresses a functional paternal gene. In contrast, the mouse on the
right is dwarf because the paternal gene is a mutant allele that
results in a nonfunctional hormone. In both cases, the maternal
gene is inactive due to imprinting.
Why is the maternal gene not transcribed into mRNA? To
answer this question we need to consider the molecular function of genes. As discussed in Chapter 13, the attachment of
methyl (¬ CH3) groups to the bases of DNA can alter gene transcription. For most genes, methylation silences gene expression
by causing the DNA to become more compact. For a few genes,
methylation may enhance gene expression by attracting activator proteins to the promoter. Researchers have discovered that
DNA methylation is the marking process that occurs during the
imprinting of certain genes, including the Igf-2 gene.
Figure 17.13 shows the imprinting process in which a maternal gene is methylated. The left side of the figure follows the
marking process during the life of a female individual; the right
side follows the same process in a male. Both individuals received a methylated gene from their mother and a nonmethylated
copy of the same gene from their father. Via cell division, the zygote develops into a multicellular organism. Each time a somatic
cell divides, enzymes in the cell maintain the methylation of the
maternal gene, while the paternal gene remains unmethylated.
If the methylation inhibits transcription of this gene, only the
paternal copy will be expressed in the somatic cells of both the
male and female offspring.
The methylation state of an imprinted gene may be altered
when individuals make gametes. First, as shown in Figure 17.13,
the methylation is erased. Next, the gene may be methylated
again, but that depends on whether the individual is a female or
male. In females making eggs, both copies of the gene are methylated; in males making sperm, neither copy is methylated. When
we consider the effects of methylation over the course of two
or more generations, we can see how this phenomenon creates
an epigenetic transmission pattern. The male in Figure 17.13
has inherited a methylated gene from his mother that is transcriptionally silenced in his somatic cells. Although he does not
express this gene during his lifetime, he can pass on an active,
nonmethylated copy of this exact same gene to his offspring.
Genomic imprinting is a recently discovered phenomenon
that has been shown to occur for a few genes in mammals. For
some genes, such as Igf-2, the maternal allele is silenced, while
for other genes the paternal allele is silenced. Biologists are still
trying to understand the reason for this curious marking process.
Male offspring
Female offspring
After fertilization, somatic cells
retain the methylation pattern
inherited from the parents.
1
Maternal
Paternal
chromosome
chromosome
Paternal
chromosome
All
somatic
cells
All
somatic
cells
– CH3
– CH3
– CH3
– CH3
– CH3
– CH3
Erasure
2
Male gameteproducing cell
No methylation
During egg formation, the gene
is always methylated, while
during sperm formation it is not.
– CH3
– CH3
– CH3
– CH3
– CH3
– CH3
Formation
of sperm
Formation
of eggs
Figure 17.13
– CH3
– CH3
– CH3
During gamete formation,
methylation is erased.
New methylation
– CH3
– CH3
– CH3
– CH3
– CH3
– CH3
Erasure
Female gameteproducing cell
3
Maternal
chromosome
– CH3
– CH3
– CH3
Genomic imprinting via DNA methylation.
The cells at the top of this figure have a methylated gene
inherited from the mother and a nonmethylated version of the
same gene inherited from the father. This pattern of methylation
is the same in male and female offspring and is maintained in
their somatic cells. The methylation is erased during gamete
formation, but in females the gene is methylated again at a later
stage in the formation of eggs. Therefore, females always transmit
a methylated, transcriptionally silent copy of this gene, while
males transmit a nonmethylated, active copy.
Brooker−Widmaier−Graham−Stiling:
Biology
364
III. Nucleic Acid Structure
and DNA Replication
111
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17. Complex Patterns of
Inheritance
UNIT III – CHAPTER 17
For Maternal Effect Genes, the Genotype
of the Mother Determines the Phenotype
of the Offspring
In epigenetic inheritance, genes are altered in ways that affect
their expression in an individual or the individual’s offspring.
As we have seen, some of these alterations produce strange inheritance patterns, in which organisms with the same genotype
have different phenotypes. Another strange inheritance pattern,
with a very different explanation, involves a category of genes
called maternal effect genes.
Inheritance patterns due to maternal effect genes were first
identified in the 1920s by A. E. Boycott, in his studies of the freshwater snail Lymnaea peregra. In this species, the shell and internal organs can be arranged in either a right-handed (dextral) or a
left-handed (sinistral) direction. The dextral orientation is more
common and is dominant to the sinistral orientation. Whether a
snail’s body curves in a dextral or a sinistral direction depends
on the pattern of cell division immediately following fertilization. Figure 17.14 shows the results of Boycott’s crosses of truebreeding strains of snails with either a dextral or a sinistral orientation. When a dextral female (DD) was crossed to a sinistral
male (dd), all of the offspring were dextral. However, crossing a
sinistral female (dd) to a dextral male (DD) produced the opposite result: all of the offspring were sinistral. These seemingly
contradictory outcomes could not be explained in terms of Mendelian inheritance.
Alfred Sturtevant later suggested that snail coiling is due
to a maternal effect gene that exists as a dextral (D) and a sinistral (d) allele. In the cross shown on the left, the P generation
female is dextral (DD) and the male is sinistral (dd). In the
cross on the right, the female is sinistral (dd) and the male is
dextral (DD). In either case, the F1 offspring are Dd. When the
F1 individuals from these two crosses are mated to each other, a
genotypic ratio of 1 DD : 2 Dd : 1 dd is predicted for the F2 generation. Because the D allele is dominant to the d allele, a
Mendelian inheritance pattern would produce a 3:1 phenotypic
ratio of dextral to sinistral snails. Instead, the snails of the F2
generation were all dextral. To explain this observed result, Sturtevant proposed that the phenotype of the F2 offspring depended
solely on the genotype of the F1 mother. Because the F1 mothers
were Dd, and the D allele is dominant, the F2 offspring were
dextral even if their genotype was dd!
Sturtevant’s hypothesis is supported by the ratio of phenotypes seen in the F3 generation. When members of the F2 generation were crossed, the F3 generation exhibited a 3:1 ratio of
dextral to sinistral snails. These F3 phenotypes reflect the genotypes of the F2 mothers. The ratio of genotypes for the F2 females was 1 DD : 2 Dd : 1 dd. The DD and Dd females produced
dextral offspring, while the dd females produced sinistral offspring. This is consistent with the 3:1 phenotypic ratio in the
F3 generation.
The peculiar inheritance pattern of maternal effect genes can
be explained by the process of egg maturation in female animals
(Figure 17.15). Maternal cells called nurse cells surround a de-
P
DD
dd
dd
DD
F1
Dd
All sinistral
Dd
All dextral
F2
Males and
females
1 DD : 2 Dd : 1 dd
All dextral
Cross to each other
F3
Males and
females
3 dextral : 1 sinistral
Figure 17.14
The inheritance of snail coiling direction as
an example of a maternal effect gene. In the snails shown in
this experiment, the direction of body coiling is controlled by a
single pair of genes. D (dextral, or right-handed) is dominant to d
(sinistral, or left-handed). The genotype of the mother determines
the phenotype of the offspring. A DD or Dd mother will produce
dextral offspring and a dd mother will produce sinistral offspring,
regardless of the genotypes of the father and of the offspring
themselves.
Biological inquiry: An offspring has a genotype of Dd and coils
to the left. What is the genotype of its mother?
veloping egg cell and provide it with nutrients. Within these
diploid nurse cells, both copies of a maternal effect gene are
activated to produce their gene products. The gene products are
transported into the egg, where they persist for a significant time
during embryonic development. The D and d gene products influence the pattern of cell division during the early stages of the
snail’s embryonic development. If an egg receives only the D
gene product, the snail will develop a dextral orientation, while
an egg that receives only the d gene product will produce a
112
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III. Nucleic Acid Structure
and DNA Replication
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17. Complex Patterns of
Inheritance
COMPLEX PATTERNS OF INHERITANCE
Mother is DD.
DD
Nurse
cells
DD
D gene
products
DD
DD
Mother is Dd.
365
Mother is dd.
Dd
dd
Dd
DD
Dd
DD
dd
D and d
gene
products
Dd
Dd
Dd
d gene
products
dd
dd
dd
dd
Egg
All offspring are dextral because the
egg received the gene products of
the D allele.
All offspring are dextral because the
egg received the gene products of the
D and d alleles, but the D gene
products are dominant.
All offspring are sinistral because
the egg received the gene products
of the d allele.
Figure 17.15
The mechanism of maternal effect in snail coiling. In this simplified diagram, the mother’s diploid nurse cells
transfer gene products to the egg as it matures. These gene products persist after fertilization, affecting development of the early embryo.
If the nurse cells are DD or Dd, they will transfer the dominant D gene product to the egg, causing the offspring to be dextral. If the nurse
cells are dd, only the d gene product will be transferred to the egg and the offspring will be sinistral.
snail with a sinistral orientation. If an egg receives both D and
d gene products, the snail will be dextral because the D gene
product is dominant over d. In this way, the gene products of
nurse cells, which are determined by the mother’s genotype, influence the development of the offspring.
Several dozen maternal effect genes have been identified in
experimental organisms, such as Drosophila. Recently, they have
also been found in mice and humans. As we will discuss in
Chapter 19, the products of maternal effect genes are critically
important in the early stages of animal development.
17.3
•
17.1
A variety of inheritance patterns are more complex than Mendel
had realized. Many of these do not obey one or both of his laws
of inheritance. (Table 17.1)
When the alleles of one gene mask the effects of the alleles of a
different gene, this type of gene interaction is called epistasis.
(Figure 17.1)
•
Quantitative traits such as height and weight are polygenic, which
means that several genes govern the trait. Often, the alleles of
such genes contribute in an additive way to the phenotype. This
produces continuous variation in the trait, which is graphed as
a bell curve. (Figure 17.2)
17.2
Mitochondria and chloroplasts carry a small number of genes.
The inheritance of such genes is called extranuclear inheritance.
(Figure 17.6)
•
Chloroplasts in the four-o’clock plant are transmitted via the egg,
a pattern called maternal inheritance. (Figures 17.7, 17.8)
•
Several human diseases are known to be caused by mutations in
mitochondrial genes, which follow a maternal inheritance pattern.
(Table 17.2)
Gene Interactions
•
17.4
When two different genes are on the same chromosome, they are
said to be linked. Linked genes tend to be inherited as a unit,
unless crossing over separates them. (Figures 17.3, 17.4)
•
The percentage of offspring produced in a two-factor testcross can
be used to map the relative locations of genes along a chromosome.
(Figure 17.5)
X Inactivation, Genomic Imprinting,
and Maternal Effect
•
Epigenetic inheritance refers to patterns in which a gene is
inactivated during the life of an organism, but not over the course
of many generations.
•
X inactivation in mammals occurs when one X chromosome is
randomly inactivated in females. If the female is heterozygous
for an X-linked gene, this can lead to a variegated phenotype.
(Figures 17.9, 17.10)
•
X inactivation occurs in three phases: initiation, spreading, and
maintenance. (Figure 17.11)
•
Imprinted genes are inactivated by one parent but not both. The
offspring expresses only one of the two alleles. (Figure 17.12)
•
During gamete formation, methylation of a gene from one parent
is a mechanism to achieve imprinting. (Figure 17.13)
Genes on the Same Chromosome: Linkage,
Recombination, and Mapping
•
Extranuclear Inheritance: Organelle Genomes
•
Brooker−Widmaier−Graham−Stiling:
Biology
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III. Nucleic Acid Structure
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17. Complex Patterns of
Inheritance
113
UNIT III – CHAPTER 17
•
For maternal effect genes, the genotype of the mother determines the
phenotype of the offspring. This is explained by the phenomenon that
the mother’s nurse cells contribute gene products to egg cells that
are needed for early stages of development. (Figures 17.14, 17.15)
1. Quantitative traits such as height and weight are governed by
several genes that usually contribute in an additive way to the
trait. This is called
a. independent assortment.
b. discontinuous inheritance.
c. maternal inheritance.
d. linkage.
e. polygenic inheritance.
2. When two genes are located on the same chromosome they are
said to be
a. homologous.
d. linked.
b. allelic.
e. polygenic.
c. epistatic.
8. When a gene is inactivated during gamete formation and that gene is
maintained in an inactivated state in the somatic cells of offspring,
such an inheritance pattern is called
a. linkage.
b. X inactivation.
c. maternal effect.
d. genomic imprinting.
e. polygenic inheritance.
9. Calico coat pattern in cats is the result of
a. X inactivation.
d. genomic imprinting.
b. epistasis.
e. maternal inheritance.
c. organelle heredity.
10. Maternal effect inheritance can be explained by
a. gene products that are given to an egg by the nurse cells.
b. the methylation of genes during gamete formation.
c. the spreading of X inactivation from the Xic locus.
d. the inheritance of alleles that contribute additively to a trait.
e. none of the above.
3. Based on the ideas proposed by Morgan, which of the following
statements concerning linkage is not true?
a. Traits determined by genes located on the same chromosome are
likely to be inherited together.
b. Crossing over between homologous chromosomes can create new
gene combinations.
c. Crossing over is more likely to occur between genes that are closer
together.
d. The probability of crossing over depends on the distance between
the genes.
e. All but one of the above statements are correct.
1. Define linkage and linkage group.
4. In genetic linkage mapping, 1 map unit is equivalent to
a. 100 base pairs.
b. 1 base pair.
c. 10% recombination frequency.
d. 1% recombination frequency.
e. 1% the length of the chromosome.
2. What were the expected results of Bateson and Punnett’s cross?
5. Organelle heredity is possible because
a. gene products may be stored in organelles.
b. mRNA may be stored in organelles.
c. some organelles contain genetic information.
d. conjugation of nuclei occurs before cellular division.
e. both a and c.
6. In many organisms, organelles such as the mitochondria are contributed
by only the egg. This phenomenon is known as
a. biparental inheritance.
b. paternal inheritance.
c. maternal effect.
d. maternal inheritance.
e. both c and d.
7. Modification of a gene during gamete formation or early development
that alters the way the gene is expressed during the individual’s
lifetime is called
a. maternal inheritance.
b. epigenetic inheritance.
c. epistasis.
d. multiple allelism.
e. alternative splicing.
2. Explain extranuclear inheritance and give two examples.
3. Define genomic imprinting.
1. What hypothesis were Bateson and Punnett testing when conducting
the crosses in the sweet pea?
3. How did the observed results differ from the predicted results? How
did Bateson and Punnett explain the results of this particular cross?
1. Discuss two types of gene interactions.
2. Discuss the concept of linkage.
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