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Genetic Variation in
Individuals and Populations:
Mutation and Polymorphism
FACTORS THAT DISTURB HARDYWEINBERG EQUILIBRIUM

A number of assumptions underlie the HardyWeinberg law. First is that the population is large and
mating is random. A very small population in which
random events can radically alter an allele frequency
may not meet this first assumption.
 This first assumption is also breached when the
population contains subgroups whose members choose
to marry within their own subgroup rather than the
population at large.
 Second is that allele frequencies are not changing over
time. This means that there is no migration in or out of
the population by groups whose allele frequencies at a
locus of interest are radically different from the allele
frequencies in the population as a whole.

Similarly, selection for or against particular alleles
and new mutations adding alleles to the gene pool
break the assumptions of the Hardy-Weinberg
law.
 In practice, some of these violations are more
damaging than others to the application of the law
to human populations. Violating the assumption of
random mating can cause large deviations from
the frequency of individuals homozygous for an
autosomal recessive condition that we might
expect from population allele frequencies.

On the other hand, changes in allele frequency due
to mutation, selection, or migration usually cause
more minor and subtle deviations from HardyWeinberg equilibrium.
 Finally, when Hardy-Weinberg equilibrium does
not hold for a particular disease allele at a
particular locus, it may be instructive to
investigate why the allele and its associated
genotypes are not in equilibrium.
Exception to Large Population with
Random Mating

The principle of random mating is that for any
locus, an individual of a given genotype has a
purely random probability of mating with an
individual of any other genotype, the proportions
being determined only by the relative frequencies
of the different genotypes in the population.
 One's choice of mate, however, may not be at
random. In human populations, nonrandom mating
may occur because of three distinct but related
phenomena: stratification, assortative mating,
and consanguinity.
Stratification

Stratification describes a population in
which there are a number of subgroups that
have remained relatively genetically
separate during modern times.
 Worldwide, there are numerous stratified
populations; for example, the U.S.
population is stratified into many subgroups
including whites, African Americans, and
numerous Native American, Asian, and
Hispanic groups.

Similarly stratified populations exist in other parts
of the world as well. When mate selection in a
population is restricted to members of one
particular subgroup within that population, the
result for any locus with more than one allele is an
excess of homozygotes in the population as a
whole and a corresponding deficiency of
heterozygotes compared with what one would
predict under random mating from allele
frequencies in the population as a whole.

Suppose a population contains a minority group
constituting 10% of the population in which a
mutant allele for an autosomal recessive disease
has a frequency qmin = 0.05.
 In the remaining majority 90% of the population,
qmaj is 0. An example of just such a situation is
the African American population of the US and
the mutant allele at the β-globin locus responsible
for sickle cell disease.
 The overall frequency of the disease allele in the
total population, qpop, is therefore equal to
0.05/10 = 0.005, and, simply applying the HardyWeinberg law, the frequency of the disease in the
population as a whole would be q2pop = 0.000025
if mating were perfectly random throughout the
entire population.

If, however, a minority group mates nearly exclusively
with other members of the minority group, then the
frequency of affected individuals in the minority group
would be (q2min) = 0.0025.
 Because the minority group is one tenth of the entire
population, the true frequency of disease in the total
population is 0.0025/10 = 0.00025, 10-fold higher than
one would expect from applying the Hardy-Weinberg
law to the population as a whole without consideration
of stratification.
 By way of comparison, stratification has no effect on
the frequency of autosomal dominant disease and
would have only a minor effect on the frequency of Xlinked disease by increasing the small number of
females homozygous for the mutant allele.
Assortative Mating

Assortative mating is the choice of a mate because
the mate possesses some particular trait.
 Assortative mating is usually positive; that is,
people tend to choose mates who resemble
themselves (e.g., in native language, intelligence,
stature, skin color, etc.)
 To the extent that the characteristic shared by the
partners is genetically determined, the overall
genetic effect of positive assortative mating is an
increase in the proportion of the homozygous
genotypes at the expense of the heterozygous
genotype.

A clinically important aspect of assortative mating
is the tendency to choose partners with similar
medical problems, such as congenital deafness or
blindness or exceptionally short stature (dwarfism).
 In such a case, the expectations of Hardy-Weinberg
equilibrium do not apply because the genotype of
the mate at the disease locus is not determined by
the allele frequencies found in the general
population.
 For example, in the case of two parents with
achondroplasia, offspring homozygous for the
achondroplasia gene have a severe, lethal form of
dwarfism that is almost never seen unless both
parents are achondroplasia heterozygotes.

When mates have autosomal recessive
disorders caused by the same mutation or by
allelic mutations in the same gene, all of
their offspring will also have the disease.
 Of course, not all blindness, deafness, or
short stature has the same genetic basis;
many families have been described, for
example, in which two parents with albinism
have had children with normal pigmentation
or two deaf parents have had hearing
children because of locus heterogeneity.

Even if there is genetic heterogeneity with
assortative mating, however, the chance that two
individuals are carrying mutations in the same
disease locus is increased over what it would be
under true random mating, and therefore the risk
of the disorder in their offspring is also increased.
 Although the long-term population effect of this
kind of positive assortative mating on disease gene
frequencies is insignificant, a specific family may
find itself at very high genetic risk.
Consanguinity and Inbreeding

Consanguinity, like stratification and positive
assortative mating, brings about an increase in the
frequency of autosomal recessive disease by
increasing the frequency with which carriers of an
autosomal recessive disorder mate.
 Unlike the disorders in stratified populations, in
which each subgroup is likely to have a high
frequency of a few alleles, the kinds of recessive
disorders seen in the offspring of related parents
may be very rare and unusual because
consanguineous mating allows uncommon alleles
to become homozygous.

Similarly, in genetic isolates, the chance of mating
with another carrier of a particular recessive
condition may be as high as that observed in
cousin marriages, a phenomenon known as
inbreeding.
 For example, among Ashkenazi Jews in North
America, mutant alleles for Tay-Sachs disease
(GM2 gangliosidosis) are relatively more common
than in other ethnic groups.
 The frequency of Tay-Sachs disease is 100 times
higher in Ashkenazi Jews (1 in 3600) than in most
other populations (1 in 360,000). Thus, the TaySachs carrier frequency among Ashkenazi Jews is
approximately one in 30 (q2 = 1/3600, q = 1/60,
2pq = ~1/30) as compared to a carrier frequency
of about one in 300 in non-Ashkenazis.
Exceptions to Constant Allele
Frequencies
Genetic Drift in Small Populations

Chance events can have a much greater effect on
allele frequencies in a small population than in a
large one. If the population is small, random effects,
such as increased fertility or survival of the carriers
of a mutation, occurring for reasons unrelated to
carrying the mutant allele (which would be
selection, not a random event), may cause the allele
frequency to change from one generation to the next.

In a large population, such random effects would
average out, but in a small population, allele
frequencies can fluctuate from generation to
generation by chance.
 This phenomenon, known as genetic drift, can
explain how allele frequencies can change as a
result of chance operating on the small gene pool
contained within a small population.
Mutation and Selection

In contrast to nonrandom mating, which can
substantially upset the relative frequency of
various genotypes predicted by Hardy-Weinberg
equilibrium, changes in allele frequency due to
selection or mutation usually occur slowly, in
small increments, and cause much less deviation
from Hardy-Weinberg equilibrium, at least for
recessive diseases.
 Mutation rates are generally well below the
frequency of heterozygotes for autosomal
recessive diseases, and so new mutation would
have little effect in the short term on allele
frequencies for such diseases.

In addition, most deleterious recessive alleles are
hidden in heterozygotes and not subject to
selection. As a consequence, selection is not likely
to have major short-term effects on the allele
frequency of these recessive alleles.
 Therefore, to a first approximation, HardyWeinberg equilibrium may apply even for alleles
that cause severe autosomal recessive disease.
 For dominant or X-linked disease, however,
mutation and selection do perturb allele
frequencies from what would be expected under
Hardy-Weinberg equilibrium by substantially
reducing or increasing certain genotypes.

Fitness is the chief factor that determines
whether a mutation is lost immediately,
becomes stable in the population, or even
becomes, over time, the predominant allele
at the locus concerned.
 The frequency of an allele in a population
represents a balance between the rate at
which mutant alleles appear through
mutation and the effects of selection.
 If either the mutation rate or the
effectiveness of selection is altered, the
allele frequency is expected to change.

Whether an allele is transmitted to the succeeding
generation depends on its fitness (f), which is a
measure of the number of offspring of affected
persons who survive to reproductive age,
compared with an appropriate control group.
 If a mutant allele is just as likely as the normal
allele to be represented in the next generation, f
equals 1. If an allele causes death or sterility,
selection acts against it completely, and f equals 0.
 A related parameter is the coefficient of selection,
s, which is a measure of the loss of fitness and is
defined as 1 - f, that is, the proportion of mutant
alleles that are not passed on and are therefore lost
as a result of selection.

In the genetic sense, a mutation that prevents
reproduction by an adult is just as lethal as one
that causes a very early miscarriage of an embryo,
because in neither case is the mutation transmitted
to the next generation.
 Fitness is thus the outcome of the joint effects of
survival and fertility. In the biological sense,
fitness has no connotation of superior endowment
except in a single respect: comparative ability to
contribute to the gene pool of the next generation.
Selection in Recessive Disease

Selection against harmful recessive mutations has
far less effect on the population frequency of the
mutant allele than does selection against dominant
mutations because only a small proportion of the
genes are present in homozygotes and are
therefore exposed to selective forces.
 Even if there were complete selection against
homozygotes (f = 0), as in many lethal autosomal
recessive conditions, it would take many
generations to reduce the gene frequency
appreciably because most of the mutant alleles are
carried by heterozygotes with normal fitness.

For example, the frequency of mutant alleles
causing phenylketonuria q, is approximately 1%
in many white populations. Two percent of the
population (2 × p × q) is heterozygous, with one
mutant allele, whereas only 1 individual in 10,000
(q2) is a homozygote with two mutant alleles. The
proportion of mutant alleles in homozygotes is
given by:

Thus, only approximately 1% of all the mutant alleles
in the population are in affected homozygotes and
therefore are exposed to selection if dietary treatment
were not available.
 Removal of selection against an autosomal recessive
disorder such as PKU by successful medical
treatment would have just as slow an effect on
increasing the gene frequency over many generations.
 Thus, as long as mating is random, genotypes in
autosomal recessive diseases can be considered to be
in Hardy-Weinberg equilibrium, despite selection
against homozygotes for the recessive allele.
 The mathematical relationship between genotype and
allele frequencies described in the Hardy-Weinberg
law holds for most practical purposes in recessive
disease.
Selection in Dominant Disorders

Dominant mutant alleles are directly exposed to
selection, in contrast to recessive mutant alleles,
most of which are "hidden" in heterozygotes.
 Consequently, the effects of selection and mutation
are more obvious and can be more readily measured
for dominant traits.
 A genetic lethal dominant allele, if fully penetrant, is
exposed to selection in heterozygotes, removing all
alleles responsible for the disorder in a single
generation.
 Several human diseases are thought or known to be
autosomal dominant traits with zero or near-zero
fitness and thus always result from new rather than
inherited autosomal dominant mutations (Table 9-9).
Table 9-9. Examples of Disorders Occurring as Sporadic Conditions due to New Mutations with Zero Fitness
Acrodysostosis
Multiple congenital abnormalities, especially short hands with
peripheral dysostosis, small nose, and mental deficiency
Apert syndrome
Craniosynostosis, broad thumb and great toe, shallow orbits,
hypertelorism, frequent but variable mental deficiency; mutation in
fibroblast growth factor receptor 2 gene. Very rarely, a person with
this dysmorphic syndrome has offspring; if so, 50% of the offspring
are affected.
Atelosteogenesis
Early lethal form of short-limbed dwarfism
Cornelia de Lange
syndrome
Mental retardation, micromelia, synophrys, and other abnormalities;
can be caused by mutation in the NIPBL gene
Lenz-Majewski
hyperostosis syndrome
Dense, thick bone; symphalangism; cutis laxa
Osteogenesis
imperfecta, type 2
Perinatal lethal type, with a defect in type 1 collagen
Thanatophoric
dysplasia
Early lethal form of short-limbed dwarfism due to mutations in
fibroblast growth factor receptor 3 gene

In some, the genes and specific mutant alleles are
known, and family studies show new mutations in
the affected individuals that were not inherited
from the parents.
 In other conditions, the genes are not known, but a
paternal age effect has been seen, suggesting (but
not proving) a new mutation in the paternal
germline as a possible cause of the disorder.
 The implication for genetic counseling is that the
parents of a child with an autosomal dominant,
genetic lethal condition have a low risk of
recurrence because the condition would generally
require another independent mutation to recur
(except that the possibility of germline mosaicism
must be kept in mind).
Mutation and Selection Balance
in Dominant Disease

If a dominant disease is deleterious but not lethal,
affected persons may reproduce but will
nevertheless contribute fewer than the average
number of offspring to the next generation; that is,
their fitness, f, may be reduced.
 Such a mutation is lost through selection at a rate
proportional to the loss of fitness of heterozygotes.
 The frequency of the mutant alleles responsible
for the disease in the population therefore
represents a balance between loss of mutant alleles
through the effects of selection and gain of mutant
alleles through recurrent mutation.

A stable allele frequency is reached at whatever
level balances the two opposing forces: one
(selection) that removes mutant alleles from the
gene pool and one (new mutation) that adds new
ones back. The mutation rate per generation, μ, at
a disease locus must be sufficient to account for
that fraction of all the mutant alleles (allele
frequency q) that are lost by selection from each
generation. Thus,
μ = sq

When a genetic disorder limits reproduction so severely
that the fitness is zero (s = 1), it is referred to as a genetic
lethal.
 For a dominant genetic lethal disorder, every allele in the
population must be a new mutation since none can be
inherited (in the absence of gonadal mosaicism).
 In achondroplasia, the fitness of affected patients is not
zero, but they have only about one fifth as many children
as people of normal stature in the population. Thus, their
average fitness, f, is 0.20, and the coefficient of selection,
s, is 0.80.
 In the subsequent generation, only 20% of current
achondroplasia alleles are passed on from the current
generation to the next. Because the frequency of
achondroplasia is not decreasing, new mutations must be
responsible for replacing the 80% of mutant genes in the
population lost through selection.

If the fitness of affected persons suddenly
improved (because of medical advances, for
example), the observed incidence of the disease in
the population would increase and reach a new
equilibrium.
 Retinoblastoma and certain other dominant
embryonic tumors with childhood onset are
examples of conditions that now have a greatly
improved prognosis, with a predicted consequence
of increased disease frequency in the population.
 Allele frequency, mutation rate, and fitness are
related; thus, if any two of these three
characteristics are known, the third can be
estimated.
Mutation and Selection Balance
in X-Linked Recessive Mutations

For those X-linked phenotypes of medical interest
that are recessive, or nearly so, selection occurs in
hemizygous males and not in heterozygous
females, except for the small proportion of
females who are manifesting heterozygotes with
low fitness.
 Because males have one X chromosome and
females two, the pool of X-linked alleles in the
entire population's gene pool will be partitioned,
with one third of mutant alleles present in males
and two thirds in females.

As we saw in the case of autosomal dominant
mutations, mutant alleles lost through selection
must be replaced by recurrent new mutations to
maintain the observed disease incidence.
 If the incidence of a serious X-linked disease is
not changing and selection is operating against,
and only against, hemizygous males, the mutation
rate, μ, must equal the coefficient of selection, s
(the proportion of mutant alleles that are not
passed on), times q, the allele frequency, times 1/3
since selection is operating on only one third of
the mutant alleles in the population, that is, those
present in males. Thus,
μ = sq / 3

For an X-linked genetic lethal disease, s = 1 and
one third of all copies of the mutant gene
responsible is lost from each generation.
 Therefore, one third of all persons who have such
X-linked lethal disorders are predicted to carry a
new mutation, and their genetically normal
mothers have a low risk of having subsequent
children with the same disorder (assuming no
mosaicism).
 In less severe disorders such as hemophilia A, the
proportion of affected individuals representing
new mutations is less than one third (currently
about 15%).

Because the treatment of hemophilia is improving
rapidly, the total frequency of mutant alleles can
be expected to rise relatively rapidly and to reach a
new equilibrium, as we saw in the case of
autosomal dominant conditions.
 Assuming that the mutation rate at this locus stays
the same, the proportion of hemophiliacs who
result from a new mutation will decrease, even
though the incidence of the disease increases.
Such a change would have significant implications
for genetic counseling for this disorder.
Migration and Gene Flow

Migration can change allele frequency by the
process of gene flow, defined as the slow
diffusion of genes across a barrier.
 Gene flow usually involves a large population and
a gradual change in gene frequencies.
 The genes of migrant populations with their own
characteristic allele frequencies are gradually
merged into the gene pool of the population into
which they have migrated. (The term migrant is
used here in the broad sense of crossing a
reproductive barrier, which may be racial, ethnic,
or cultural and not necessarily geographical and
requiring physical movement from one region to
another.)

The frequencies of the 32-base pair deletion allele
of the CCR5 cytokine receptor gene, ΔCCR5, have
been studied in many populations all over the
world.
 The frequency of the ΔCCR5 allele is highest,
approximately 10%, in western Europe and Russia
and declines to a few percent in the Middle East
and the Indian subcontinent.
 The ΔCCR5 allele is virtually absent from Africa
and the Far East, suggesting that the mutation
originated in whites and diffused into the more
easterly populations.

Figure 9-10 Frequency of ΔCCR5 alleles in
populations from Europe, the Middle East, and the
Indian subcontinent.





Another example of gene flow between population
groups is reflected in the frequency of specific mutant
alleles causing PKU.
There is strong evidence that the most common
mutations were of Celtic origin. These same
mutations have now turned up in many populations
around the world.
The presence of the same PKU alleles in different
populations reflects the geographical migration of the
Celts.
Thus, the frequency of PKU is approximately 1/4500
in Ireland, but the disorder is progressively less
prevalent across northern and southern Europe.
There has been considerably less gene flow to East
Asia; the incidence of PKU in Japan is only about
1/109,000.
ETHNIC DIFFERENCES IN THE FREQUENCY OF
VARIOUS GENETIC DISEASES

The previous discussion of the Hardy-Weinberg
law explained how, at equilibrium, genotype
frequencies are determined by allele frequencies
and remain stable from generation to generation,
assuming the allele frequencies in a large, isolated,
randomly mating population remain constant.
 However, there is a problem of interest to human
geneticists that the Hardy-Weinberg law does not
address: Why are allele frequencies different in
different populations in the first place? In
particular, why are some mutant alleles that are
clearly deleterious when present in homozygotes
relatively common in certain population groups
and not in others?

The human species of more than 6 billion members
is separated into many subpopulations, or ethnic
groups, distinguishable by appearance, geographical
origin, and history.
 Although the 25,000 genes and their location and
order on the chromosomes are nearly identical in all
humans, we saw earlier that extensive polymorphism
exists between individuals in a population.
 Most variation is found in all human populations, at
similar frequencies. Other alleles, however, although
present in all groups, may demonstrate dramatic
differences in frequency among population groups;
and finally, some allelic variants are restricted to
certain populations, although they are not
necessarily present in all members of that group.

It is likely that because modern humans lived in
small isolated settlements until quite recently, as
mutations occurred in the various groups, the
differences in the frequency of certain alleles
persisted and could even become magnified.
 A number of factors are thought to allow
differences in alleles and allele frequencies among
ethnic groups to develop.
 Two such factors are genetic drift, including
nonrandom distribution of alleles among the
individuals who founded particular subpopulations
(founder effect), and heterozygote advantage
under environmental conditions that favor the
reproductive fitness of carriers of deleterious
mutations.

For the population geneticist and anthropologist,
selectively neutral genetic markers provide a
means of tracing human history by tracking gene
flows.
 For example, some polymorphisms exist only in
populations in sub-Saharan Africa, resulting in
more polymorphic diversity among sub-Saharan
Africans themselves than there is between subSaharan Africans and any other ethnic groups.
 These data support the notion that modern humans
in Africa developed substantial genetic diversity
over a million years or more, well before the rest
of the world's populations were derived 40,000 to
100,000 years ago from smaller subgroups that
migrated out of Africa, carrying a more limited
genetic diversity.

Differences in frequencies of alleles that cause genetic
disease are significant for the medical geneticist and
genetic counselor because they cause different disease
risks in specific population groups.
 Well-known examples include Tay-Sachs disease in
people of Ashkenazi Jewish ancestry, sickle cell
disease in African Americans, and cystic fibrosis and
PKU in white populations.
 The inherited disease of hemoglobin, β-thalassemia, is
a clear example of ethnic differences both in disease
frequency and in which alleles are responsible in
populations with a high incidence of disease.

The disease is common in people of
Mediterranean or East Asian descent and very
rare in other ethnic groups. Even though dozens
of different alleles can cause β-thalassemia,
certain alleles tend to be far more common in
some populations than in others, so that each
population has only a few common alleles.
 For example, the most common β-thalassemia
alleles responsible for more than 90% of the
disease in Mediterranean people are very rare in
people from Southeast Asia or the Asian
subcontinent; similarly, the most common alleles
in Southeast Asians and Asian Indians are quite
rare in the other two unrelated ethnic groups.

This information is of value in genetic
counseling and prenatal diagnosis. For
example, in North America, when persons
of Mediterranean descent are at risk of
having a child with β-thalassemia, testing of
parental DNA for just seven mutant alleles
has a more than 90% probability of
providing the information needed for
prenatal diagnosis
Table 9-10. Incidence, Gene Frequency, and Heterozygote Frequency for Selected
Autosomal Disorders in Different Populations
Disorder
Population
Incidence
Allele
Frequency
Heterozygote
Frequency
q2
q
2pq
U.S. African American
1 in 400
0.05
1 in 11
Hispanic American
1 in 40,000
0.005
1 in 101
1 in 2000
0.022
1 in 22
U.S. African American
1 in 100,000
0.04
1 in 125
U.S. white
1 in 2000
0.022
1 in 22
Finland
1 in 25,000
0.0063
1 in 80
Mexico
1 in 8500
0.011
1 in 47
Scotland
1 in 5300
0.014
1 in 37
Finland
1 in 200,000
0.002
1 in 250
Japan
1 in 109,000
0.003
1 in 166
Recessive
Sickle cell anemia (S/S
genotype)*
α1-Antitrypsin deficiency (Z/Z Denmark
genotype)†
Cystic fibrosis (all mutant
alleles)†
Phenylketonuria (all mutant
alleles)†
Table 9-10. Incidence, Gene Frequency, and Heterozygote Frequency for Selected
Autosomal Disorders in Different Populations
Disorder
Population
Incidence
Allele
Frequency
Heterozygote
Frequency
q2
q
2pq
U.S. Ashkenazi Jewish 1 in 3900
0.016
1 in 32
U.S. non-Ashkenazi
Jewish
1 in 112,000
0.003
1 in 170
2pq + q2
q
Regions of Quebec,
Canada
1 in 122
0.004
-
Afrikaner, South Afr.
1 in 70
0.007
-
Europe
1 in 25,000
0.00002
-
Regions of Quebec,
Canada
1 in 475
0.0011
-
Recessive
Tay-Sachs disease†
Dominant
Familial
hypercholesterolemia†
Myotonic dystrophy†
Genetic Drift




Genetic drift can explain a high frequency of a deleterious
disease allele in a population. For example, when a new
mutation occurs in a small population, its frequency is
represented by only one copy among all the copies of that gene
in the population.
Random effects of environment or other chance occurrences
that are independent of the genotype and operating in a small
population can produce significant changes in the frequency of
the disease allele.
During the next few generations, although the population size of
the new group remains small, there may be considerable
fluctuation in gene frequency. These changes are likely to
smooth out as the population increases in size.
In contrast to gene flow, in which allele frequencies change
because of admixture, the mechanism of genetic drift is chance.
Founder Effect



When a small subpopulation breaks off from a larger
population, the gene frequencies in the small population
may be different from those of the population from which
it originated because the new group contains a small,
random sample of the parent group and, by chance, may
not have the same gene frequencies as the parent group.
This form of genetic drift is known as the founder effect. If
one of the original founders of a new group just happens to
carry a relatively rare allele, that allele will have a far
higher frequency than it had in the larger group from
which the new group was derived.
One example is the high incidence of Huntington disease
in the region of Lake Maracaibo, Venezuela, but there are
numerous other examples of founder effect involving other
disease alleles in genetic isolates throughout the world.

The founder effect is well illustrated by the Old
Order Amish, a religious isolate of European
descent that settled in Pennsylvania and gave rise to
a number of small, genetically isolated
subpopulations throughout the United States and
Canada.
 The Old Order Amish tend to have large families
and a high frequency of consanguineous marriage.
 The incidence of specific rare autosomal recessive
syndromes such as the Ellis-van Creveld
syndrome of short-limbed dwarfism, polydactyly,
abnormal nails and teeth, and high incidence of
congenital heart defects in some Amish
communities, but not in others, is an illustration of
the founder effect.

Figure 9-11 The hands of a patient with Ellis-van
Creveld syndrome, a very rare disorder seen with
increased frequency in some Amish groups.

The French-Canadian population of Canada also has
high frequencies of certain disorders that are rare
elsewhere. One disease characteristic of the
relatively isolated Lac Saint Jean region of Quebec
is hereditary type I tyrosinemia; this autosomal
recessive condition causes hepatic failure and renal
tubular dysfunction due to deficiency of
fumarylacetoacetase, an enzyme in the degradative
pathway of tyrosine.
 The disease has an overall frequency of about
1/100,000 in other parts of Quebec and in Norway
and Sweden, but its frequency is 1/685 in the
Saguenay-Lac Saint Jean region.
 As expected with a founder effect, 100% of the
mutant alleles in the Saguenay-Lac Saint Jean
patients are due to the same mutation, a splice donor
site mutation in intron 12.

The population of Finland, long isolated
genetically by geography, language, and culture,
has expanded in the past 300 years from 400,000
to about 5 million.
 The isolation and population expansion have
allowed the Finnish population to develop a
distinctive pattern of single-gene disorders.
 There is a high frequency of at least 20 diseases
that are rare elsewhere. For example,
choroideremia, an X-linked degenerative eye
disease, is very rare worldwide; only about 400
cases have been described.
 Fully one third of the total number of patients,
however, are from a small region in Finland,
populated by a large extended family descended
from a founding couple born in the 1640s.

Another Finnish genetic disease is hyperornithinemia
with gyrate atrophy of the choroid and retina, an
autosomal recessive condition caused by deficiency of
ornithine aminotransferase and leading to loss of
vision in young adulthood.
 As one might expect with a founder effect, one
mutation was found in homozygous form in the
majority of apparently unrelated cases of gyrate
atrophy in Finland, but it was not observed at all in
non-Finnish cases.
 Conversely, disorders that are common in other
European populations, such as PKU, are quite rare in
Finland.
Figure 9-12 The geographical origin of cases of two genetic
disorders prevalent in Finland: X-linked choroideremia
(left) and hyperornithinemia with gyrate atrophy of the
choroid and retina (right). Most cases of each disease
originate from particular communities in Finland, but the
distributions of the diseases differ.

Thus, one of the outcomes of the founder effect
and genetic drift is that each population may be
characterized by its own particular mutant alleles
as well as by an increase or decrease in specific
diseases.
 As these examples show, genetic drift and founder
effect can favor the establishment at high
incidence of alleles that are not favorable or even
neutral but are actually harmful.
 The relative mobility of most present-day
populations, in comparison with their ancestors of
only a few generations ago, may reduce the effect
of genetic drift in the future while increasing the
effect of gene flow.
Positive Selection for Heterozygotes
(Heterozygote Advantage)

Although certain mutant alleles may be deleterious in
homozygotes, there may be environmental conditions
in which heterozygotes for some diseases have
increased fitness not only over homozygotes for the
mutant allele but also over homozygotes for the
normal allele, a situation termed heterozygote
advantage.
 Even a slight heterozygote advantage can lead to an
increase in frequency of an allele that is severely
detrimental in homozygotes, because heterozygotes
greatly outnumber homozygotes in the population. A
situation in which selective forces operate both to
maintain a deleterious allele and to remove it from the
gene pool is described as a balanced polymorphism.
Malaria and Hemoglobinopathies

A well-known example of heterozygote advantage
is resistance to malaria in heterozygotes for the
sickle cell disease mutation.
 The sickle cell allele has reached its highest
frequency in certain regions of West Africa, where
heterozygotes are more fit than either type of
homozygote because heterozygotes are relatively
more resistant to the malarial organism.
 In regions where malaria is endemic, normal
homozygotes are susceptible to malaria; many
become infected and are severely, even fatally,
affected, leading to reduced fitness.

Sickle cell homozygotes are even more seriously
disadvantaged, with a fitness approaching zero,
because of their severe hematological disease.
 Heterozygotes for sickle cell disease have red cells
that are inhospitable to the malaria organism but
do not undergo sickling under normal
environmental conditions; the heterozygotes are
relatively more fit than either homozygote and
reproduce at a higher rate.
 Thus, over time, the sickle cell mutant allele has
reached a frequency as high as 0.15 in some areas
of West Africa that are endemic for malaria, far
higher than could be accounted for by recurrent
mutation.

The heterozygote advantage in sickle cell disease
demonstrates how violating one of the fundamental
assumptions of Hardy-Weinberg equilibrium-that
allele frequencies are not significantly altered by
selection-causes the mathematical relationship
between allele and genotype frequencies to diverge
from what is expected under the Hardy-Weinberg
law.
 Consider two alleles, the normal A allele and the
mutant S allele, which give rise to three genotypes:
A/A (normal), A/S (heterozygous carriers), and S/S
(sickle cell disease).
 In a sample of 12,387 individuals from an adult
West African population, the three genotypes were
detected in the following proportions: 9365 A/A :
2993 A/S : 29 S/S.

By counting the A and S alleles in these three
genotypes, one can determine the allele
frequencies to be p = 0.877 for the A allele and q =
0.123 for the S allele.
 Under Hardy-Weinberg equilibrium, the ratio of
genotypes should be A/A : A/S : S/S = p2 : 2pq :
q2 = 9527 : 2672 : 188. The observed ratios,
however, A/A : A/S : S/S = 9365 : 2993 : 29, differ
significantly from expectations.
 The example of the sickle cell allele illustrates
how the forces of selection, operating not only on
the relatively rare S/S genotype but also on the
other two, much more frequent A/A and A/S
genotypes, distort the transmission of the A and S
alleles and cause a deviation from HardyWeinberg equilibrium in a population.

Change in the selective pressures would be
expected to lead to a rapid change in the relative
frequency of the sickle cell allele. Today, many
sickle cell heterozygotes live in non-malarial
regions, and even in malarial areas, major efforts
are being made to eradicate the mosquito
responsible for transmitting the disease.
 There is evidence that in the African American
population in the United States, the frequency of
the sickle cell gene may already be falling from its
high level in the original African population of
several generations ago, although other factors,
such as the introduction of alleles from nonAfrican populations into the African American
gene pool, may also be playing a role.

Some other deleterious alleles, including genes for
hemoglobin C, the thalassemias, and glucose-6phosphate dehydrogenase deficiency, as well as
the benign FY allele of the Duffy blood group
system, are also thought to be maintained at their
present high frequencies in certain populations
because of the protection that they provide against
malaria.
 Heterozygote advantage has also been proposed to
explain the high frequencies of cystic fibrosis in
white populations and of Tay-Sachs disease and
other disorders affecting sphingolipid metabolism
in the Ashkenazi Jewish population.
Drift Versus Heterozygote Advantage
 Determining whether drift or heterozygote
advantage is responsible for the increased
frequency of some deleterious alleles in certain
populations is not simple to do.
 The environmental selective pressure responsible
for heterozygote advantage may have been
operating in the past and not be identifiable in
modern times. The northwest to southeast gradient
in the frequency of the ΔCCR5 allele, for example,
reflects major differences in the frequency of this
allele in different ethnic groups.
For example, the highest frequency of the ΔCCR5
allele is 21%, seen among Ashkenazi Jews, and it is
nearly that high in Iceland and the British Isles. The
current AIDS pandemic is too recent to have affected
gene frequencies through selection; the variation in
allele frequencies in Europe itself is most consistent
with genetic drift acting on a neutral polymorphism.
 It is, however, possible that another selective factor
(perhaps another infectious disease such as bubonic
plague) may have elevated the frequency of the
ΔCCR5 allele in northern European populations
during a period of intense selection. Thus, geneticists
continue to debate whether genetic drift or
heterozygote advantage (or both) adequately
accounts for the unusually high frequencies that
some deleterious alleles achieve in some populations.


Population genetics uses quantitative methods to
explain why and how differences in the frequency of
genetic disease and the alleles responsible for them
arose among different individuals and ethnic groups.
 Population genetics is also important to our attempts to
identify susceptibility alleles for common, complex
disorders by use of population-based association
methods.
 Not only can the fascinating history of our species be
read in the patterns of genetic variation we now see,
but genetic heterogeneity also has important practical
implications for professionals seeking to deliver
appropriate, personalized health care to the world's
populations in ways that are both efficient and
sensitive.
CNV and SNP variation



Identical Twins are not Identical
Bruce Buehler, MD, Pediatrics, General, 11:19PM May 6, 2010
Over the past few years it has become clearer that sequencing genes is a first step, but to
understand complex diseases the next step is to look at factors that affect gene expression. Copy
number variations (CNVs) and single nucleotide polymorphisms (SNPs) interact with known
syndrome or disease causing genes. CNVs and SNPs appear to influence single genes and multiple
sites to produce complex diseases like Diabetes. Mapping all these SNPs or CNVs and assigning
causative effects is in progress. Every clinician has experienced patients with a known disease
living far longer than expected or showing much milder effects than even a sibling. Split Hand
syndrome with clefting of all four extremities in an infant can be passed by a parent who only has
one shortened metacarpal, but has the same gene. Lack of penetrance or full penetrance of a gene at
this time cannot be predicted, but it is assumed that CNVs, SNPs, and methylation may partially
control penetrance. In identical twins microarray studies of gene sequence demonstrates homology,
but SNPs and CNVs can be different between the twins. So identical twins may express similar genes
differently in regards to timing or severity of a genetic condition. It is extremely critical for
clinicians when offering a prognosis, to note the potential for variation of severity or duration of a
known genetic condition. The "mean" is helpful, but it should not be a self-fulfilling prophecy which
takes away all hope. Each individual can be unique in the course of their disease because of gene
modification, as well as external influences such as hope and attitude. The clinician has the difficult
task of balancing pessimism and optimism while presenting the "truth". Absolutes about expression
of a genetic disease are becoming harder to understand since individuality occurs at the molecular
level even in identical twins. Understanding the role of CNVs and SNPs will be another important
breakthrough for prognosis and treatment of genetic disorders.