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Chapter22
Population Genetics
• Individuals can carry only two different alleles
of a given gene. A group of individuals can
carry a large number of different alleles, give
rise to a reservoir of genetic diversity. Diversity
contained in the population can be measured
by the Hardy-Weinberg law. Mutation is the
ultimate source of genetic variation and other
factors such as drift, migration, and selection
can alter the amount of genetic variation in
population
22.1 Population and gene pool
22.2 Calculating allele frequency
22.3 The Hardy-Weinberg law
22.4 Extension of the Hardy-Weinberg law
22.5 Using the Hardy-Weinberg law, calculating
heterozygote frequency
22.6 Factors that later allele frequency in
population
22.7 Natural selection
22.8 Mutation
22.9 Migration
22.10 Genetic drift
22.11 Nonrandom mating
• Alfred Russell Wallace and Charles Darwin first
identified natural selection as the mechanism of
adaptive evolution in the mid-nineteenth century,
based on a series of observations of populations of
organisms:
• (1) Phenotypic variations exist among individuals
within populations;
• (2) these differences are passed from parents to
offspring;
• (3) more offspring are born than will survive and
reproduce; and
• (4) some variants are more successful at surviving
and/or reproducing than others. In populations where
all four factors operate, the relative abundance of the
population's different phenotypes changes across
generations. In other words, the population evolves.
• Although Wallace and Darwin described how organisms
evolve by natural selection, there was no accurate model of
the mechanisms responsible for variation and inheritance.
Gregor Mendel published his work on the inheritance of
traits in 1865,
• For many years, theorists focused on developing
mathematical models that would describe the genetic
structure of populations. Prominent among the theoreticians
who developed these models were Sewall Wright, Ronald
Fisher, and J. B. S. Haldane.
• Following their work, experimentalists and field workers
tested the models using biochemical and molecular
techniques that measure variation directly at the protein and
DNA levels. These experiments examined allele frequencies
and the forces that alter the frequencies, such as selection,
mutation, migration, and random genetic drift. In this
chapter we consider some general aspects of population
genetics and also discuss other areas of genetics that relate
to evolution.
22.1
Populations and Gene Pools
• Members of a species often range over a wide
geographic area.
• A population is a group of individuals from the same
species that lives in the same geographic area(孟德尔
群体 ), and that actually or potentially interbreeds.
• If we consider a single genetic locus in this population,
we may find that individuals within the population
have different genotypes. To study population genetics,
we compute frequencies at which various alleles and
genotypes occur, and how these frequencies change
from one generation to the next.
• When we consider generational changes in alleles and
genotypes, we look at gene pools.
• A gene pool consists of all gametes made by all the
breeding members of a population
in a single generation
• Gene pool基因库
将群体中所有个体共有的全部基因定义称为一个
基因库（gene pool）。
• : gametes to zygotes - next generation.
alleles
proportion of gametes in a gene pool
22.2
Calculating Allele Frequencies
•Most genetic population researchers first measure the
frequencies at which alleles occur at a particular locus. To
do this, the genotypes of a large number of individuals in
the population must be determined.
•In some cases, researchers can infer genotypes directly
from phenotypes.
•In other cases, proteins or DNA sequences are analyzed to
determine genotypes.
•To understand how allele frequencies are calculated, we
consider an example that involves HIV infection rates.
• In 1996, Rong Liu and colleagues discovered that two
exposed-but-uninfected individuals were homozygous for
a mutant allele of a gene called CC-CKR-5.
• The CC-CKR-5 gene, chromosome 3, a protein called the
C-C chemokine （ 趋 化 因 子 ） receptor-5(CCR5).
Chemokines are cell-surface signaling molecules found
on cells in the immune system. When cells with CCR5
receptor proteins bind to chemokine signals, the cells
move into inflamed tissues to fight infection.
• The CCR5 protein is a co-receptor for strains of HIV-1.
To gain entry into cells, a protein called Env (short for
envelope protein) on the surface of HIV-1 binds to the
CD4 protein on the surface of the host cell. Binding to
CD4 causes Env to change shape and form a second
binding site. This second site binds to CCR5, which in
turn initiates the fusion of the viral protein coat with the
host cell membrane. The merging of viral envelope with
cell membrane transports the HIV viral core into the host
• The mutant allele of the CCR5 gene contains a 32bp deletion in one of its coding regions. As a result,
the protein encoded by the mutant allele is
shortened and made nonfunctional. The protein
never makes it to the cell membrane, so HIV-1
cannot enter these cells. The gene's normal allele is
called CCR51 (or 1) and its allele with the 32-bp
deletion is called CCK5- 32 (or 32), The two
uninfected individuals described by Liu both had
the genotype 32/ 32.
• As a result, they had no CCR5 on the surface of
their cells, and were resistant to infection by strains
of HIV-1 that require CCR5 as a co-receptor.
• At least three 32/32 individuals who are
infected with HIV-1 have been found. Curiously,
researchers have not discovered any adverse
effects
associated
with
this
genotype.
Heterozygotes with genotype 1/32 are
susceptible to HIV-1 infection, but evidence
suggests that they progress more slowly to AIDS.
Table 22.1 summarizes the genotypes possible at
the CCRS locus, and the phenotypes associated
with each.
Table 22.1 CCRS genotype and phenotype
1/ 1
susceptible to sexually transmitted HIV-1 strain
1/ 32
susceptible, but may progress to AIDS slowly
32/ 32 resistant to most sexually transmitted HIV-1s
• The discovery of the CCR5-  32 allele, and the fact
that it provides some protection against AIDS,
generates two important questions: Which human
populations harbor the  32 allele, and how common
is it? To address these questions, several teams of
researchers surveyed a large number of people from a
variety of populations. Genotypes were determined
by direct analysis of DNA (Figure 22-1).
Figure 22-2 shows the
frequency of the
CCR5-A32 allele in the
18 European
populations surveyed.
The studies show that
populations in
Northern Europe
have the highest
frequencies of the A32
allele. The frequency
of the allele declines to
the south and to the
west.
In populations without European ancestry the A32 allele is
essentially absent. The highly patterned global distribution of the
A32 allele presents an evolutionary puzzle that we'll return to later
in the chapter
22.3
The Hardy-Weinberg Law
• The large variation in the frequency of the CCR5-A32
allele among populations raises a number of questions.
For example, can we expect the allele to increase in
populations in which it is currently rare? Population
genetics explores such questions using a mathematical
model developed independently by the British
mathematician Godfrey H. Hardy and the German
physician Wilhelm Weinberg.
• This model, called the Hardy-Weinberg law, shows
what happens to allele and genotype in an "ideal"
population (free of many of the complications that
affect real populations) using a set of simple
assumptions.
• 1. Individuals of all genotypes have equal rates of
survival and equal reproductive success; that is, there
is no selection.
• 2. No new alleles are created or converted from one
allele into another by mutation.
• 3. Individuals do not migrate into or out of the
population.
• 4. The population is infinitely large, which in practical
terms means that the population is large enough that
mate randomly sampling errors and other random
effects are negligible.
• 5.Individuals in the population mate randomly
• The Hardy-Weinberg law demonstrates that an "ideal"
population has these properties:
• 1. The frequency of alleles does not change from
generation to generation; in other words, the population
does not evolve.
• 2. After one generation of random mating, offspring
genotype frequencies can be predicted from the parent
allele frequencies.
• What makes the Hardy-Weinberg law useful, however, is
its assumptions. By specifying the assumptions under
which the population cannot evolve, the Hardy-Weinberg
law identifies the real-world forces that cause allele
frequencies to change. In other words, by holding certain
conditions constant, the Hardy-Weinberg law isolates the
forces of evolution.
• A Demonstration of the Law
• To demonstrate how the Hardy-Weinberg law works,
we begin with a specific case, and then consider the
general case. In both examples, we focus on a single
locus with two alleles, A and a.
• Imagine a population in which the frequency of allele
A, in both eggs and sperm, is 0.7,
a is 0.3, Note that 0.7 + 0.3 = 1, indicating that
all the alleles for gene A present in the gene pool are
accounted for. We assume, per Hardy-Weinberg
requirements, that individuals mate randomly, which
we visualize as follows. We place all the gametes in
the gene pool, in a barrel and stir. We then randomly
draw eggs and sperm from the barrel and pair them to
make zygotes. What genotype frequencies does this
give us?
The probability of genotype AA will occur 49%
Aa is 0.21 + 0.21 = 0.42 = 42 %
aa is 9 %
• We started with the frequency of a particular
allele in a specific gene pool and calculated
the probability that certain genotypes would
be produced from this pool. When the
zygotes develop into adults and reproduce,
what will be the frequency of distribution of
alleles in the new gene pool?
• Recall that under the Hardy-Weinberg law,
we assume that all genotypes have equal
rates of survival and reproduction. This
means that in the next generation, all
genotypes contribute equally to the new
gene pool.
• The AA individuals 49% carry allele A,
• Likewise, Aa individuals 42% Half (0.5) of
these gametes carry allele A.
• Frequency of allele A in the gene pool is 0.49 +
(0.5) 0.42 = 0.7.
• The other half carry allele a.
• The aa individuals 9 % (0.5) 0.42 + 0.09 = 0.3.
As a check on our calculation, note that 0.7 +
0.3 = 1.0, accounting for all of the gametes in
the gene pool of the new generation.
• We have arrived back where we began, with a gene pool
in which the frequency of allele A is 0.7 and the
frequency of allele a is 0.3.
• These calculations demonstrate the Hardy-Weinberg law:
Allele frequencies in our population do not change from
one generation to the next, and after just one generation
of random mating the genotype frequencies can be
predicted from the allele frequencies. In other words, this
population does not evolve.
• use variables instead of, numerical values for the allele
frequencies.
• A - p a - q, p + q = 1.
• Zygote that carry allele A is p X p. AA = p2.
Aa=2pq.
aa=q2
Figure 22-4 shows these calculations
•p2 + 2pq + q2 = 1
• For our general case we ask what the allele
frequencies in the new gene pool will be when these
zygotes develop into adults and reproduce. All
gametes from AA individuals carry allele A, as do
half of the gametes from Aa individuals. Thus we
predict that the frequency of allele A in the new
gene pool will be
• p2 + (1/2) 2pq = p2 + pq
Or P2 + p(l ~ p) = p2 + P - P2 = P
• Likewise, the frequency of allele a in the new gene
pool will be
• (1/2)2pq + q2 = pq + q2
Or (1 - q)q + q2 = q - q2 + q2 = q
• Consequences of the Law
• The Hardy-Weinberg law has several important
consequences.
• First, it shows that dominant traits do not necessarily
increase from one generation to the next.
• Second, it demonstrates that genetic variability can be
maintained in a population since, once established in an
ideal population, allele frequencies remain unchanged.
• Third, if we invoke Hardy-Weinberg assumptions, then
knowing the frequency of just one genotype enables us
to calculate the frequencies of all other genotypes. This
relationship is particularly useful in human genetics
because we can now calculate the frequency of
heterozygous carriers for recessive genetic disorders
even when all we know is the frequency of affected
individuals
• We began this discussion by asking whether we can
expect the CCR5-32 allele to increase in populations
in which it is currently rare.
• From what we now know about the Hardy-Weinberg
law, we can say for the general case that if (l)
individuals of all genotypes have equal rates of
survival and reproduction, (2) there is no mutation, (3)
no one migrates into or out of the population, (4) the
population is extremely large, (5) individuals in the
population choose their mates randomly, then the
frequency of the 32 allele will not change.
• Of course, for real populations, few if any of these
assumptions are likely to hold.
• The general case demonstrates the most
important role of the Hardy-Weinberg law: It
is the foundation upon which population
genetics is built. By showing that "ideal"
populations do not evolve, we can use the
Hardy-Weinberg law to identify forces that do
cause populations to evolve.
• when the assumptions of the Hardy-Weinberg law are
broken—• because of natural selection,
• mutation, migration, and
• random sampling errors (also known as genetic
drift)—the allele frequencies in a population may
change from one generation to the next. Nonrandom
mating does not, by itself, alter allele frequencies, but
by altering genotype frequencies it indirectly affects
the course of evolution. The Hardy-Weinberg law
tells geneticists where to look to find the causes of
evolution in real populations.
• We return to the CCR5-A32 allele later in the chapter
to see how a population genetics perspective has
generated fruitful hypotheses for further research.
• Testing for Equilibrium
• One way we establish whether one or more of the
Hardy-Weinberg assumptions do not hold in a given
population is by determining whether the population's
genotypes are in equilibrium. To do this, we first
determine the frequencies of the genotypes, either
directly from the phenotypes (if heterozygotes are
recognizable) or by analyzing proteins or DNA
sequences. We then calculate the allele frequencies from
the genotype frequencies, as demonstrated earlier.
Finally, we use the parents' allele frequencies to predict
the offspring's genotype frequencies. According to the
Hardy-Weinberg law, the genotype frequencies are
predicted to fit the p2 + 2pq + q2 = 1 relationship. If
they do not, then one or more of the assumptions are
invalid for the population in question.
• We will use the CCR5 genotypes of a population in
Britain to demonstrate the Hardy-Weinberg law. The
population includes 283 individuals, of which 223
have genotype 1/1, 57 have genotype 1/A32, and 3
have genotype A32/A32. These numbers represent
genotype frequencies of 223/283 = 0.788, 57/283 =
0.201, and 3/283 = 0.011, respectively. From the
genotype frequencies we compute the CCR5I allele
frequency as 0.89 and the frequency of the CCR5-A32
allele as 0.11. From these allele frequencies, we can
use the Hardy-Weinberg law to determine whether this
population is in equilibrium. The allele frequencies
predict the genotype frequencies as follows:
• Expected frequency of genotype 1/1 = p2 = (0.89)2 - 0.792
• Exp genotype 1/A32 - 2pq = 2(0.89)(0.11) = 0.196
• Expected genotype A32IA32 = q2 = (0.11 )2 = 0.012
• These expected frequencies are nearly identical to
the observed frequencies. Our test of this population
has failed to provide evidence that Hardy-Weinberg
assumptions are being violated. This conclusion is
confirmed by a X2 analysis (see Chapter 3).
• The X2 value in this case is tiny: 0.00023. To be
statistically significant at even the most generous,
accepted level, p = 0.05, the X2 value would have to
be 3.84. (In a test for Hardy-Weinberg equilibrium,
the degrees of freedom are given by k - 1 - m, where
k is the number of genotypes and m is the number of
independent allele frequencies estimated from the
data.
• On the other hand, if the Hardy-Weinberg test had
demonstrated that the population is not in
equilibrium, it would indicate that one or more
assumptions are not being met. To illustrate this,
imagine two hypothetical populations,
one living on East Island,all 1/1, 100 %
other living on West Island, A32/A32, 100 %
• Now imagine that 500 people from each island
move to the previously uninhabited Central Island.
• However, it would take only one generation of random
mating on Central Island to bring the offspring to the
expected allele frequencies, as shown in Figure 22-5.
Therese Markow and colleagues documented a real
human population that is not in Hardy-Weinberg
equilibrium. These researchers studied 122 Havasupai,
a population of Native Americans in Arizona. They
determined the genotype of each Havasupai individual
at two loci in the major histocompatibility complex
(MHC). These genes, HLA-A and HLA-8, encode
proteins that are involved in the immune system's
discrimination between self and nonself. The immune
systems of individuals heterozygous at MHC loci
appear to recognize a greater diversity of foreign
invaders and thus may be better able to fight disease.
• Markow and colleagues observed significantly more
individuals who are heterozygous at both loci, and
significantly fewer homozygous individuals than would
be expected under the Hardy-Weinberg law. Violation of
either or both of two Hardy-Weinberg assumptions
could explain the excess of heterozygotes among the
Havasupai.
• First, Havasupai fetuses, children, and adults who are
heterozygous for HLA-A and HLA-B may have higher
rates of survival than individuals who are homozygous.
• Second, rather than choosing their males randomly,
Havasupai people may somehow prefer mates whose
MHC genotypes differ from their own.
22.4 Extensions of the
Hardy-Weinberg Law
• We commonly find several alleles of a single locus
in a population. The ABO blood group in humans
(discussed in Chapter 4) is such an example. The
locus I (isoagglutinin) has three alleles (IA, IB, and
IO), 6 genotypic
• A and B codominant, both dominant to O.
• AA , AO phenotypic identical,
• BB and BO
”
only 4 distinguished
• Let p, q, and r represent A, B, and 0, respectively.
• p+q+r=1
• Under Hardy-Weinberg assumptions, the frequencies
of the genotypes are given by
• (P + q + r)2 =p2 + q2+r2 + 2pq + 2r + 2qr = 1
• If we know the frequencies of blood types for a
population, we can then estimate the frequencies for
the three alleles of the ABO system.
• E.g., in one population sampled,
• A = 0.53, B = 0.13,AB - 0.08, and O = 0.26. Because
the O allele is recessive, the population's frequency of
type O blood equals the proportion of the recessive
genotype r2. Thus,
• r2 = 0.26 ,r = √.26 =.51
• Using r, we can estimate the allele frequencies for the A
and B alleles. The A allele is present in two genotypes,
AA and AO. The frequency of the AA genotype is
represented by p2, and the AO genotype by Ipr,
Therefore, the combined frequency of type A blood and
type O blood is given by
• p2 + 2pr + r2 = 0.53 + 0.26
• If we factor the left side of the equation and take the
sum of the terms on the right, we get
• (p + r)2 = 0.79
• p + r = √0./79, p = 0.89 - r ,p = 0.89 - 0.51 = 0.38
• Having estimated p and r, the frequencies of allele A and
allele 0, we can now estimate the frequency for the B
allele:
• p+q+r=1 q= 1 -p-r
22.5 Using the Hardy-Weinberg law:
Calculating Heterozygote Frequency
• In one application, the Hardy-Weinberg law allows us to
estimate the frequency of heterozygotes in a population. The
frequency of a recessive trait can usually be determined by
counting such individuals in a sample of the population.
With this information and the Hardy-Weinberg law, we can
then calculate the allele and genotype frequencies. Cystic
fibrosis, an autosomal recessive trait, has an incidence of
about 1/2500 = 0.0004 in people of northern European
ancestry. Individuals with cystic fibrosis are easily
distinguished from the population at large by such
symptoms as salty sweat,excess amounts of thick mucus in
the lungs, and susceptibility to bacterial infections. Because
this is a recessive trait, individuals with cystic fibrosis must
be homozygous.
• Their frequency in a population is
represented by q2, provided that mating has
been random in the previous generation.
The frequency of the recessive allele
therefore is
• q = √q2 = √ 0.0004 = 0.02
• Since p + q = 1, then the frequency of p is
• p=1 - q=1- 0.02 = 0.98
• In the Hardy-Weinberg equation, the
frequency of heterozygotes is 2pq,
• 2pq = 2(0.98)(0.02) = 0.04, or 4%, or 1/25
• Thus, heterozygotes for cystic fibrosis are
rather common in the population (4%),
even though the incidence of homozygous
recessives is only 1/2500, or 0.04 percent.
•In general, the frequencies of all three genotypes can be
estimated once the frequency of either allele is known and
Hardy-Weinberg assumptions are invoked. The relationship
between genotype and allele frequency is shown in Figure
22-6.
•it is important to note that
heterozygotes increase rapidly in
a population as the values of p
and q move from 0 or 1. This
observation confirms our
conclusion that when a recessive
trait such as cystic fibrosis is rare,
the majority of those carrying the
allele are heterozygotes. In
populations in which the
frequencies of p and q are
between 0.33 and 0.67,
heterozygotes occur at higher
frequency than either
homozygote.
22.6 Factors That Alter Allele
Frequencies in Populations
• We have noted that the Hardy-Weinberg law establishes
an ideal population that allows us to estimate allele and
genotype frequencies in populations in which the
assumptions of random mating, absence of selection and
mutation, and equal viability and fertility hold. Obviously,
it is difficult to find natural populations in which all these
assumptions hold. In nature, populations are dynamic, and
changes in size and gene pool are common. The HardyWeinberg law allows us to investigate populations that
vary from the ideal. In this and following sections, we
discuss factors that prevent populations from reaching
Hardy-Weinberg equilibrium, or that drive populations
toward a different equilibrium, and the relative
contribution of these factors to evolutionary change.
22.7
Natural Selection
• The first assumption of the Hardy- Weinberg law is
that individuals of all genotypes have equal rates of
survival and equal reproductive success. If this
assumption does not hold, allele frequencies may
change from one generation to the next. To see why,
let's imagine a population of 100 individuals in which
the frequency of allele
• A - 0.5 , a - 0.5. Assuming the previous generation
mated randomly, the genotype frequencies
• (0.5)2 - 0.25 for AA,
25 AA individuals
• 2(0.5X0.5) = 0.5 for Aa, 50 Aa individuals
• (0.5)2 = 0.25 for aa, 25 aa individuals.
• Now suppose that individuals with different genotypes
have different rates of survival:
All 25 AA individuals survive to reproduce,
90 percent or 45 of the Aa individuals
80 percent or 20 of the aa individuals
• When the survivors reproduce, each contributes two
gametes to the new gene pool, giving us 2(25) + 2(45) +
2(20) = 180 gametes. What are the frequencies of the two
alleles in the surviving population?
• 50 A gametes from AA + 45 A gametes from Aa, so the
frequency of A is (50 + 45)/180 = 0.53.
• Frequency of allele a is (45 + 40)/180 = 0.47.
• Allele A has increased, while allele a has declined.
• A difference among individuals in survival and/or
reproduction rate is called natural selection. Natural
Fitness and Selection
Selection occurs whenever individuals type enjoy an
advantage over other genotypes. However, selection may be
weak or strong, depending on the magnitude of the
advantage. In the example above, selection was strong.
Weak selection might involve just a fraction of a percent
difference in the survival rates of different genotypes.
Advantages in survival and reproduction ultimately translate
into increased genetic contribution to future generations. An
individual's genetic contribution to future generations is
called fitness. Thus, genotypes associated with high rates of
survival and/or high reproductive success are said to have
high fitness, whereas genotypes associated with low rates of
survival and/or low reproductive success are said to have
low fitness.
wAA for genotype AA, waa = 1
wAa for genotype Aa, wAa = 0.9
waa for aa. wafl = 0.8
\Let's consider selection against deleterious
alleles. Fitness values wAA = 1, wAa = 1, and
wbb = 0 describe a situation in which allele a
is a lethal recessive.
Homozygote recessive individuals die without
leaving offspring, the frequency of allele a
will decline. The decline in the frequency of
allele a is described by the equation
Qg= qo / 1-gqo
intensity of selection
• The manner in which selection affects allele frequencies
allows us to make some inferences about the CCK5-A32
allele A32/A32, 1/1 and 1/A32
current frequency of the A32 allele is 0.10.
the genotype frequencies 0.81 for 1/1,
0.18 for 1/A32, and 0.01 for A32/A32.
• Imagine also that 1 percent of the 1/1 and 1/A32
individuals in this population will contract HIV and die
of AIDS.
• fitness levels as follows: w1/1 = 0.99; w1/432 = 0.99;
wA32/A32 = 1.0. Given the assigned fitness, we can
predict that the frequency of the CCR5-A32 allele in the
next generation will be 0.100091.
•In fact, it will take about 100 generations (about 2000 years)
for the frequency of the A32 allele to reach just 0.11 (Figure
22-9). In other words, the frequency of the A32 allele will
probably not change much over the next few generations in
most populations that currently harbor it.
• A population genetic perspective sheds light on
the CCR5-A32 story in other ways as well. Two
research groups have analyzed genetic variation
at marker loci closely linked to the CCR5 gene.
Both groups concluded that most, if not all
present-day copies of the A32 allele are
descended from a single ancestral copy that
appeared in northeastern Europe at most a few
thousand years ago. In fact, one group estimates
that the common ancestor of all A32 alleles
existed just 700 years ago. How could a new
allele rise from a frequency of virtually zero to
as high as 20 percent in roughly 30 generations?
• It seems that there must have been strong selection in
favor of the A32 allele. The agent of selection cannot
have been HIV-l. because HIV-1 moved from
chimpanzees to humans too recently. Because
selection occurred about 700 years ago, J. C. Stephens
suggests that the agent of selection was bubonic
plague. During the Black Death of 1346-1352,
between a quarter and a third of all Europeans died
from plague. Bubonic plague is caused by the
bacterium
Yersinia
pestis.
This
bacterium
manufactures a protein that kills some kinds of white
blood cells. Stephens hypothesizes that the process
through which the bacterial protein kills white cells
involves the CCR5 gene product. If true, some
mechanism makes individuals homozygous for the
A32 allele more likely to survive plague epidemics.
• If past epidemics of bubonic plague are responsible for the
high frequency of the CCR5-A32 allele in European
populations, men the virtual absence of the allele in nonEuropean populations is at first somewhat puzzling. Perhaps
plague has been more common in Europe than elsewhere.
Alternatively, perhaps other populations have different
alleles of the CCR5 gene that also confer protection against
the plague. Teams of researchers looking for other alleles of
the CCR5 gene in various populations have found a total of
20 mutant alleles, including A32. Sixteen of these alleles encode proteins different in structure from that encoded by the
CCR51 allele. Some, like A32, are loss-of-function alleles.
• Some of the alleles appear confined to Asian, others to
African. as high as 3-4 percent. Together, these discoveries
are consistent with the hypothesis that alteration or loss of
the CCR5 protein protects against an as-yet-unidentified
infectious disease or diseases.
Selection in Natural Populations
effect of natural selection,
for example, studied the effect of the insecticide
chlorpyrifos on allele frequencies in populations of
house mosquitoes (Figure 22-10). Chlorpyrifos kills
mosquitoes by interfering with the function of the
enzyme acetylcholinesterase (ACE), which under
normal
circumstances
breaks
down
the
neurotransmitter acetylcholine. An allele of the gene
encoding ACE called Ace" encodes a slightly altered
version of ACE that is immune to interference by
chlorpyrifos.
FIGURE 22-10
Pesticides used to
control insects act
as selective
agents, changing
allele frequencies
of resistance
genes in the
populations
• Chevillon measured the frequency of the AceR
allele in nine populations. In the first four
locations, chlorpyrifos had been used to
control mosquitoes for 22 years; in the last five
locations, chlorpyrifos had never been used.
Chevillon predicted that the frequency of AceR
would be higher in the exposed populations.
The researchers also predicted that the
frequencies of alleles for enzymes unrelated to
the physiological effects of chlorpyrifos would
show no such pattern. Among the control
enzymes studied was aspartate amino
transferase 1.
•The results appear in Figure
22-11. As the researchers
predicted, the frequency of the
AceR allele was significantly
higher in the exposed
populations. Also as predicted,
the frequencies of the most
common alleles of the control
enzyme genes showed no such
trends. The explanation is that
during the 22 years of
exposure to the pesticide,
mosquitoes had higher rates of
survival if they carried the
AceR allele. In other words,
the AceR allele had been
favored by natural selection
Natural Selection and Quantitative Traits Selection for such
traits can be classified as
(1) directional, (2) stabilizing, or (3) disruptive.
(2) stabilizing
In contrast, tends to favor intermediate types, with both extreme
phenotypes being selected against. One of the clearest demonstrations
of stabilizing selection is provided by the data of Mary Karn and
Sheldon Penrose on human birth weight and survival for
13,730children born over an 11-year period. Figure 22-13 shows the
distribution of birth weight and the percentage of mortality at 4 weeks
of age. Infant mortality increases on either side of the optimal birth
weight of 7.5 pounds, and quite dramatically so at the low end. At the
genetic level, stabilizing selection acts to keep a population well
adapted to its environment. In this situation, individuals closer to the
average for a given trait will have higher fitness.
(3) disruptive
Disruptive selection is selection against intermediates
and for both phenotypic extremes. It can be viewed
as the opposite of stabilizing selection because die
intermediate types are selected against. In one set of
experiments, John Thoday applied disruptive
selection to a population of Drosophila based on
bristle number. In every generation he allowed only
the flies widi high or low bristle numbers to breed.
After several generations, most of the flies could be
easily placed in a low or high bristle category (Figure
22-14). In natural populations, such a situation
might exist for a population in a heterogeneous
environment. The types and effects of selection are
summarized in Figure 22-15.
22.8
Mutation
• Reshuffled each generation to produce new
genotypes in the offspring. But do not produce
new alleles.
• Mutation alone acts to create new alleles. It is
important to keep in mind that mutational events
occur at random—that is, without regard for
any possible benefit or disadvantage to the
organism. In this section we consider whether
mutation is, by itself, a significant factor in
causing allele frequencies to change.
• To determine whether mutation is a significant force
in changing allele frequencies, we measure the rate at
which mutations are produced. As most mutations are
recessive, it is difficult to observe mutation rates
directly in diploid organisms. Indirect methods using
probability and statistics or large-scale screening
programs are employed. For certain dominant
mutations, however, a direct method of measurement
can be used. To ensure accuracy, several conditions
must be met:
• 1. The allele must produce a distinctive phenotype that can be
distinguished from similar phenotypes produced by recessive alleles.
• 2. The trait must be fully expressed or completely penetrant so that mutant
individuals can be identified.
• 3. An identical phenotype must never be produced by non genetic agents
such as drugs or chemicals.
• First.Mutation rates that must be known ,can be
stated as the number of new mutant alleles per
given number of gametes.
• 1/100,000 1 X 10-5. In humans, a dominant form
of dwarfism known as achondroplasia
• u = 1.4 X 10-5 ± 0.5 X 10-5
• Knowing the rate of mutation, we can estimate the
extent to which mutation can cause allele
frequencies to change from one generation to the
next. We represent the normal allele as d, and the
allele for achondroplasia as D.
• Imagine a population of 500,000 individuals in
which everyone has genotype dd. The initial
frequency of d 1.0, and the initial frequency of D is
0.
• If each individual contributes 2 gametes to the gene
pool, the gene pool will contain 1,000,000 gametes, all
carrying allele d.
• While the gametes are in the gene pool, 1.4 of every
100,000 d alleles mutates into a D allele.
• The frequency of allele d is now (1,000,00014)/1,000,000 = 0.999986, and the frequency of D is
14/1,000,000 = 0.000014.
• More generally, if we have two alleles, A with frequency p and a
with frequency q, and if u represents the rate of mutations
converting A into a, then the frequencies of the alleles in the next
generation are given by
• Pg+1 =pg-upg,
and
qg+l = qg + upg.
• where pg+1 and qg+l represent the allele frequencies in
the next generation, and pg and qg represent the allele
frequencies in the present generation.
• Figure 22-16 shows the replacement rate (change over
time) in allele A for a population in which the initial
frequency of A is 1.0, and the rate of mutations (/j.)
converting A into a is 1.0 X 10~5. At this mutation rate,
it will take about 70,000 generations to reduce the
frequency of A to 0.5. Even if the rate of mutation
increases through exposure to higher levels of
radioactivity or chemical mutagens, the impact of
mutation on allele frequencies will be extremely weak.
The ultimate source of the genetic variability, mutation
provides the raw material for evolution, but by itself
p\ay$ a relatively insignificant role in changing allele
frequencies. Instead, the fate of alleles created by
mutation is more likely to be determined by natural
selection (discussed previously) and genetic drift
(discussed later).
• The frequency for the mutant alleles causing cystic
fibrosis an autosomal recessive disorder, which we
discussed previously in relation to calculating
heterozygote frequencies, is about 2 percent in
European populations. Until recently, most individuals
with two mutant alleles died before reproducing,
meaning that selection against homozygous recessives
was rather strong. This creates a puzzle: In the face of
selection against them, what has maintained the mutant
alleles at an overall frequency of 2 percent? Although
several hypotheses have been put forward, many
evolutionary geneticists prefer the heterozygote
superiority hypothesis. According to the heterozygote
superiority hypothesis, selection against homozygous
mutant individuals is counter balanced by selection in
favor of heterozygotes.
• Recent work suggests that cystic fibrosis heterozygotes
may have enhanced resistance to typhoid fever.
Typhoid fever is caused by the bacterium Salmonella
typhi, which infiltrates cells of the intestinal lining. In
laboratory studies, mouse intestinal cells that were
heterozygous for CFTR-AF508, the analog of the most
common cystic fibrosis mutation in humans, acquired
86 percent fewer bacteria than did cells homozygous
for the wild-type allele. Whether humans heterozygous
for CFTR-A508 also enjoy resistance to typhoid fever
remains to be established. If they do, then cystic
fibrosis will join sickle-cell anemia as an example of
heterozygote superiority.
22.9
Migration
• Occasionally, a species divides into populations that to
some extent are separated geographically. Various
evolutionary forces, including selection can establish
different allele frequencies in such populations.
Migration occurs when individuals move between the
populations. Imagine a species in which a single locus
has two alleles, A and a. There are two populations of
this species, one on a mainland, and one on an island.
The frequency of A on the mainland is represented by
pm and the frequency of A on the island is/>j. Under the
influence of migration from the mainland to the island,
the frequency of A in the next generation on the island
(/?,.) is given by
• where m represents migrants from (he mainland to
the island. Under these conditions, the frequency
of A in the next generation on the island (/>,.) will
be affected by migration. For example, assume
that pt = 0.4 and pm = 0.6, and that 1 0 percent of
the parents of the next generation are migrants
from the mainland, so that m = 0. 1 . In the next
generation, the frequency of allele A on the island
will be
• /),• = [(1 - 0.1) X 0.4] + (0.1 X 0.6) = 0.36 +
0.06 - 0.42
• In this case, migration from the mainland has
changed the frequency of A on the island from
0.40 to 0.42 in a single generation.
• If either m is large or if pm is very different from
p{, then a rather large change in the frequency of A
can occur in a single generation. If migration is the
only force acting to change the allele frequency on
the island, then an equilibrium will be attained
only when p, = pm. These calculations reveal that
the change in allele frequency attributable to
migration is proportional to the differences in
allele frequency between the donor and recipient
populations and to the rate of migration. As m can
have a wide range of values, the effect of
• i migration can substantially alter allele
frequencies in popu-I lations, as shown for the 6
allele of the ABO blood group in Figure 22-17.
Although migration can be difficult to quan-| tify,
it can often be estimated.
• I
Migration can also be regarded as the flow of
genes be-j tween populations that were once, but
are no longer, geo-! graphically isolated. Esteban
Parra and colleagues measured j allele
frequencies for several different DNA sequence
poly-I morphisms in African-American and
European-Am eric an ] populations, and in
African and European populations rep-I
resentative of the ancestral populations from which
the two : American populations are descended.
• One locus they stud-; ied, a restriction site
polymorphism called FY-NULL, has two alleles,
FY-NULL*! and FY-NULL*2. Figure 22-18 shows
the frequency of FY-NULL*! in each population.
The frequency of this allele is 0 in the three
African populations, and 1.0 in the three European
populations, but lies between these extremes in all
African-American and European-American
populations. The simplest explanation for these
data is that genes have mixed between American
populations with predominantly African ancestry
and American populations with predominantly
European ancestry. Based on FY-NULL and
several other loci, researchers estimate that
African-American populations derive between
11.6 and 22.5 percent of their ancestry from
22.10
Genetic Drift
• In laboratory crosses, one condition essential to
realizing theoretical genetic ratios (e.g., 3:1,
1:2:1,9:3:3:1) is a fairly large sample size. A large
sample size is also important to the study of
population genetics as allele and genotype
frequencies are examined or predicted. For
example, if a population consists of 1000
randomly mating heterozygotes (Aa), the next
generation will consist of approximately 25
percent AA, 50 percent Aa, and 25 percent aa
genotypes. Provided that the initial and subsequent
populations are large, only minor deviations from
• However, if a population consists of only one set
of heterozygous parents and they produce only
two offspring, the allele frequency can change
drastically. We can also predict genotypes and
alleie frequencies in the offspring in this case. As
Table 22.5 shows, in 10 of 16 times such a cross is
made, the allele frequencies would be altered. In 2
of 16 times, either the A or a allele would be
eliminated in a single generation.
• Founding a population with only one set of
heterozygous parents that produce two offspring is
an extreme example, but it illustrates the point that
large interbreeding populations are essential to
maintain Hardy-Weinberg equilibrium. In small
populations, significant random fluctuations in allele frequencies are possible by chance deviation.
• To study genetic drift in laboratory populations of
Drosophila melanogaster, Warwick Kerr and
Sewall Wright set up over 100 lines, with four
males and four females as the parents for each line.
Within each line, the frequency of the sex-linked
bristle mutant forked (/) and its wild-type allele (/+)
was 0.5. In each generation, four males and four
females were chosen at random to parent the next
generation. After 16 generations, the complete loss
of one allele and the fixation of the other had
occurred in 70 lines—29 in which only the
forked allele was present and 41 in which the
wild-type
• allele had become fixed. The remaining lines were
still segregating the two alleles or had gone extinct.
If fixation had occurred randomly, then an equal
number of lines should have become fixed for
• How are small populations created in nature? In
one scenario, a large population may be split by
some event (like war), creating a small isolated
subpopulation. A disaster such as an epidemic
might occur, leaving a small number of survivors
to breed. Or, a small group might emigrate from
the larger population and become founders in a
new environment, such as a volcanically created
island.
• Allele frequencies in certain isolated human
populations demonstrate the role of drift as an
evolutionary force in natural populations. The
Pingelap atoll in the western Pacific Ocean (lat.
6° N, long. 160° E) has in the past been
devastated by typhoons and famine, and
around 1780 there were only about nine
• Today there are fewer than 2000 inhabitants,
all of whose ancestry can be traced to the
typhoon survivors. About 4-10 percent of the
current population is blind from infancy.
These people are affected by an autosomal
recessive disorder, achromatopsia, which
causes ocular disturbances, a form of color
blindness, and cataract formation. The
disorder is extremely rare in the human
population as a whole. However, the mutant
allele is present at a relatively high frequency
in the Pingelap population. Genealogical
• 22.11 Nonrandom Mating
• We have explored how violations of the first four assumptions of the Hardy-Weinberg law, in the form of
selection, mutation, migration, and genetic drift, can
cause allele frequencies to change. The fifth
assumption is that the members of a population mate
at random. Nonrandom mating itself does not directly
alter the frequencies of alleles. It can, however, alter
the frequencies of genotypes in a population and
thereby indirectly affect the course of
• The most important form of nonrandom mating, and
the form we focus on here, is inbreeding, mating
between relatives. For a given allele, inbreeding
increases the proportion of homozygotes in the
population. Over time, with complete inbreeding,
only homozygotes will remain in the population. To
• Inbreeding
• Figure 22-19 shows the results of four generations of
self-fertilization starting with a single individual
heterozygous for one pair of alleles. By the fourth
generation, only about 6 percent of the individuals are
still heterozygous, and 94 percent of the population is
homozygous. Note, however, that alleles A and a still
remain at 50 percent.
• In humans, inbreeding (called consanguineous
marriage) is related to population size, mobility, and
social customs governing marriages among relatives.
To describe the amount of inbreeding in a population,
Sewall Wright devised the coefficient of inbreeding.
Expressed as F, the coefficient of inbreeding is
defined as the probability that the two alleles of a
• Figure 22-20 shows a pedigree of a first-cousin
marriage. The fourth-generation female (shaded
pink) is the daughter of first cousins (purple).
Suppose her great-grandmother (green) was a
carrier of a recessive lethal allele, a. What is the
probability that the fourth-generation female will
inherit two copies of her great-grandmother's
lethal allele? For this to happen, (1) the greatgrandmother had to pass a copy of the allele to her
son, (2) her son had to pass it to his daughter, and
(3) his daughter has to pass it to her daughter (the
pink female). Also, (4) the great-gran dm other
had to pass a copy of the allele to her daughter, (5)
her daughter had io pass it to her son, and (6) her
son has to pass it to his daughter (the pink female).
• Each of the six necessary events has an individual
probability of 1/2, and they all have to happen, so
the overall probability that the pink female will
inherit two copies of her great-grandmother's
lethal allele is (1/2)6 = 1/64. This takes us most of
the way toward calculating F for a child of a firstcousin marriage. We need only note that the
fourth-generation female could also inherit two
copies of any
of the other three alleles present in her greatgrandparents. Because any of four possibilities
would give the pink female two alleles identical
• Genetic Effects of Inbreeding
• Inbreeding results in the production of individuals
homozy-gous for recessive alleles that were
previously concealed in heterozygotes. Because
many recessive alleles are deleterious when
homozygous, one consequence of inbreeding is an
increased chance that an individual will be
homozygous for a recessive deleterious allele.
Inbred populations often have a lowered mean
fitness. Inbreeding depression is a measure of the
loss of fitness caused by inbreeding. In domesticated plants and animals, inbreeding and selection
have been used for thousands of years, and these
organisms already have a high degree of
homozygosity at many loci. Further inbreeding
will usually produce only a small loss of fitness.
• However, inbreeding among individuals from
large, randomly maiing populations can produce
high levels of inbreeding depression. This effect
can be seen by examining the mortality rates in
offspring of inbred animals in zoo pop• many zoos use DNA fingerprinting to estimate the
related-ness of animals used in breeding programs
and choose the least related animals as parents.
• As natural populations of endangered species
decrease, the concern about inbreeding is a factor
in designing programs to restore these species.
One example is a project in Scandanavian zoos to
preserve the Fennoscandic wolf. Conservationists
established a captive-bred wolf population wilh
four founding individuals.
• Later, two Russian wolves were added to the
population to reduce the level of inbreeding, a
strategy some conservationists later came to regret
because it introduced foreign alleles into the
Fennoscandic gene pool. Because the captive wolf
line was founded by such a small number of
individuals, it is severely inbred, and individuais
show inbreeding depression in the form of smaller
body weight, reduced reproductive success, and
reduced longevity. Furthermore, a number of
wolves in the line are blind.
• Researchers concluded that blindness in the
captive wolf
• locus.
• The bad news is that all the remaining pure-bred
Fennoscandic wolves (i.e., individuals with no
genes from the two Russian wolves) have at least
a 6 percent chance of being
• carriers for blindness. Some pure-bred individuals
have a 67
• dividuals with a greater than 30 percent chance of
being carriers can be removed from the breeding
population without reducing the remaining genetic
variation in the population by more than 10
percent. Removing the likely carriers would
reduce the frequency of the blindness allele from
14 percent to 7 percent, and would improve the
long-term prospects of maintaining a viable
Fennoscandic wolf population.
• abortions, neonatal deaths, congenital deformities
• No matter what the baseline mortality rate for
children of unrelated parents, however, children of
first cousins virtually always have a higher death
rate—typically by about 4.5 percentage points.
Over many generations, inbreeding should
eventually reduce the frequency of deleterious
recessive alleles (if homozygotes die before
reproducing). However, some studies indicate that
parents who are first cousins tend to have more
children to compensate for those lost to genetic
disorders. On average, two-thirds of the surviving
offspring are heterozygous carriers of the
deleterious allele.
• It is important to note that inbreeding is not
always harmful. Indeed, inbreeding has long been
recognized as a useful tool for breeders of
domesticated plants and animals. When an
• If members of two favorable inbred lines are
mated, hybrid
•
ther of the parental lines. This phenol
• grams established for maize, crop yields increased
tremendously. Unfortunately, the hybrid vigor
extends only through the first generation. Many
hybrid lines are sterile, and those that are fertile
show subsequent declines in yield.
• crossing the original inbred parental tines.
• Hybrid vigor has been explained in two ways. The
first theory, the dominance hypothesis,
incorporates the obvious reversal of inbreeding
depression, which inevitably must occur
• ailed hybrid
• The F, hybrids are heterozygotes at all loci shown.
The deleterious recessive alleles present in the
homozygous form in the parents is masked by the
more favorable dominant alleles in the hybrids.
Such masking is thought to cause hybrid vigor.
The second theory, overdominance. holds that in
many cases the heterozygote is superior to either
homozygote. This may relate to the fact that in the
heterozygote two forms of a gene product may be
present, providing a form of biochemical diversity.
Thus, the cumulative effect of heterozy-gosity at
many loci accounts for the hybrid vigor. Most
• plained by both hypotheses.
• We have seen that nonrandom mating can drive
the genotype frequencies in a population away
from their expected values under the Hardy-We in
berg law. This can indirectly affect the course of
evolution. As in stocks purposely inbred by animal
and plant breeders, inbreeding in a natural population may increase the frequency of homozygotes
for a deleterious recessive allele. As in domestic
stocks, this increases the efficiency with which
selection removes the deleterious allele from the
population.
That’ s all for
this chapter !