Transcript Medical Genetics

Genetic Variation in individuals:
Mutation & Polymorphism
INHERITED VARIATION AND
POLYMORPHISM IN PROTEINS

All polymorphism is the result of differences in
DNA sequence.
 Some polymorphic loci can studied by
examining the variation in the proteins encoded
by the alleles.
 Any one individual is likely to be heterozygous
for alleles determining structurally different
polypeptides at approximately 20% of all loci
 Individuals from different ethnic groups have
even greater fraction of proteins that exhibit
detectable polymorphism.
Biochemical individuality
 Each
individual has a unique, genetically
determined chemical makeup and thus
responds in a unique manner to
environmental, dietary, and
pharmacological influences.
 Examples
of polymorphisms of medical
significance:


ABO and Rh blood groups,
Major histocompatibility complex (MHC).
ABO and Rh Blood Groups and Their
Polymorphisms

ABO and Rh systems are important in blood
transfusion, tissue and organ transplantation,
and hemolytic disease of the newborn.
The ABO System
 Human
blood can be assigned to one of
four types according to the presence on
the surface of red blood cells of two
antigens, A and B, and the presence in
the plasma of the two corresponding
antibodies, anti-A and anti-B.
ABO Genotypes and Serum Reactivity
RBC Phenotype Reaction with
Anti-A
Reaction with
Anti-B
Antibodies In
Serum
O
-
-
Anti-A, anti-B
A
+
-
Anti-B
B
-
+
Anti-A
AB
+
+
Neither
 The
reason for reciprocal relationship b/w
RBC surface antigens and serum
antibodies is uncertain, but formation of
anti-A and anti-B is believed to be a
response to the natural occurrence of Alike and B-like antigens in the environment
(e.g., in bacteria).
 The
ABO blood groups determined by a
locus on chromosome 9.
 The A, B, and O alleles at this locus are
a classic example of multiallelism

(A and B) are inherited as a codominant
trait and the third of which (O) is inherited
as a recessive trait, determine four
phenotypes.
 The
A and B antigens are made by the
action of the A and B alleles on a RBC
surface glycoprotein called H antigen.
 The
antigenic specificity is conferred by
the specific terminal sugars, added to the
H substance.



The B allele codes for a glycosyltransferase
adds d-galactose to the end H antigen  B
antigen.
The A allele codes for an enzyme that adds
N-acetylgalactosamine to the precursor H 
A antigen.
The O allele codes for a mutant version of the
transferase that lacks transferase activity,
does not detectably affect H substance at all.
 The
molecular differences in the
glycosyltransferase gene


Four nucleotide differences between the A and
B alleles result in amino acid changes that alter
specificity of the glycosyltransferase.
The O allele has a single-base pair deletion in
the coding region, a frameshift mutation that
eliminates the transferase activity in type O
individuals.
 Now
ABO blood group typing can be
performed genotype level, especially when
there are technical difficulties in serological
analysis, as is often the case in forensic
investigations or paternity testing.
 ABO
blood group is medically important
in blood transfusion and tissue/organ
transplantation.
 A compatible combination is one in
which the RBCs of a donor do not carry
an antigen that corresponds to the
antibodies in the recipient's serum.
 Although theoretically there are
universal donors (group O) and
universal recipients (group AB), a
patient is given blood of his or her own
ABO group, except in emergencies.
 In
case of incompatibility antibodies can
cause immediate destruction of ABOincompatible cells.
 In tissue and organ transplantation,
ABO compatibility of donor and
recipient, human leukocyte antigen
(HLA) compatibility, is essential to graft
survival.
The Rh System
 The
Rh system is clinically important
because of its role in hemolytic disease
of the newborn and in transfusion
incompatibilities.
 In simplest terms, the population is
separated into Rh-positive who express
on their RBCs the antigen Rh D, a
polypeptide encoded by a gene (RHD)
on chromosome 1, and Rh-negative
individuals, who do not express this
antigen.
 The
Rh-negative phenotype usually
originates from homozygosity for a
nonfunctional allele of the RHD gene.
 The frequency of Rh-negative
individuals varies in different ethnic
groups. For example, 17% of whites
and 7% of African Americans are Rhnegative, whereas the frequency among
Japanese is 0.5%.
Hemolytic Disease of the Newborn (HDN)

Rh- persons can readily form anti-Rh antibodies
after exposure to Rh+ RBCs.
 A problem when an Rh- pregnant woman is
carrying an Rh+ fetus.
 Normally during pregnancy, small amounts of
fetal blood cross the placental barrier and reach
the maternal blood stream.
 If the mother is Rh- and the fetus Rh+, the mother
will form antibodies that return to the fetal
circulation and damage the fetal RBCs, causing
HDN with consequences that can be severe if not
treated.

The risk of immunization by Rh+ fetal RBCs
can be minimized with an injection of Rh
immune globulin at 28 to 32 weeks of
gestation and again after pregnancy.
 Rh immune globulin serves to clear any Rh+
fetal cells from the mother's circulation before
she is sensitized.
 Rh immune globulin is also given after
miscarriage, termination of pregnancy, or
invasive procedures such as chorionic villus
sampling or amniocentesis, in case any Rh+
cells gained access to the mother's
circulation.

The discovery of the Rh system and its role in
hemolytic disease of the newborn has been a
major contribution of genetics to medicine.
 At one time ranking as the most common
human genetic disease, hemolytic disease of
the newborn is now relatively rare because of
preventive measures that have become
routine practice in obstetrical medicine.
The Major Histocompatibility Complex
 The
MHC is composed of a large cluster
of genes located on the short arm of
chromosome 6.
 These genes are categorized into three
classes, two of which, the class I and
class II genes, correspond to the human
leukocyte antigen (HLA) genes

The HLA class I and class II genes encode
cell surface proteins that play a critical role in
the initiation of an immune response and
specifically in the "presentation" of antigen to
lymphocytes, which cannot recognize and
respond to an antigen unless it is complexed
with an HLA molecule on the surface of an
antigen-presenting cell.
 Many hundreds of different alleles of the HLA
class I and class II genes are known and
more are being discovered, making them by
far the most highly polymorphic loci in the
human genome.
A schematic of the MHC complex on chromosome 6p
 The
class I genes (HLA-A, HLA-B, and
HLA-C) encode proteins that are an
integral part of the plasma membrane of
all nucleated cells.
 A class I protein consists of two
polypeptide subunits, a variable heavy
chain encoded within the MHC and a
nonpolymorphic polypeptide, β2microglobulin, that is encoded by a
gene outside the MHC, mapping to
chromosome 15.
 Peptides
derived from intracellular proteins
are generated by proteolytic degradation
by a large multifunctional protease (LMP);
 the peptides are then transported to the
cell surface and held in a cleft formed in
the class I molecule to display the peptide
antigen to cytotoxic T cells.
The Major Histocompatibility Complex
The interaction between MHC class I and class II molecules, foreign
proteins, and T-cell receptors. LMP, large multifunctional protease;
TAP, transporter associated with antigen processing; Ii, invariant chain;
DM, heterodimer encoded by the DMA and DMB genes; CD8+,
cytotoxic T cells; CD4+, helper T cells.
 The
class II region is composed of
several loci, such as HLA-DP, HLA-DQ,
and HLA-DR, that encode integral
membrane cell surface proteins.
 Each class II molecule is a heterodimer,
composed of α and β subunits, both of
which are encoded by the MHC.
 Class II molecules present peptides
derived from extracellular proteins that
had been taken up into lysosomes and
processed into peptides for presentation
to T cells.
 Other
gene loci are present within the
MHC but are functionally unrelated to the
HLA class I and class II genes and do not
function to determine histocompatibility or
immune responsiveness.
 Some of these genes are, however,
associated with diseases, such as
congenital adrenal hyperplasia,
caused by deficiency of 21-hydroxylase,
and hemochromatosis, a liver disease
caused by iron overload.
HLA Alleles and Haplotypes

Old, traditional system of HLA nomenclature:
the different alleles were distinguished
serologically. An individual's HLA type was
determined by seeing how a panel of different
antisera or reactive lymphocytes reacted to
his or her cells.
 These antisera and cells were obtained from
hundreds of multiparous women who
developed immune reactivity against the
paternal type I and type II antigens expressed
by their fetuses during the course of their
pregnancies.

If cells from two unrelated individuals evoked
the same pattern of reaction in a typing panel
of antibodies and cells, they would be
considered to have the same HLA types and
the allele they represented would be given a
number, such as B27 in the class I HLA-B
locus or DR3 in the class II DR locus.
 As the genes responsible for encoding the
class I and class II MHC chains were
identified and sequenced, single HLA alleles
initially defined serologically were shown to
consist of multiple alleles defined by different
DNA sequence variants even within the same
serological allele.

The 100 serological specificities at HLA-A, B, C,
DR, DQ, and DP now comprise more than 1300
alleles defined at the DNA sequence level.
 For example, more than 24 different nucleic acid
sequence variants of the HLA-B gene exist in
what was previously defined as "the" B27 allele
by serological testing.
 Most but not all of the DNA variants change a
triplet codon and therefore an amino acid in the
peptide encoded by that allele.
 Each allele that changes an amino acid in the
HLA-B peptide is given its own number, so
allele number 1, number 2, and so on in the
group of alleles corresponding to what used to
be a single B27 allele defined serologically, is
now referred to as HLA-B*2701, HLA-B*2702,
and so on.

The set of HLA alleles at the different class I and
class II loci on a given chromosome together form
a haplotype.
 The alleles are codominant; each parent has two
haplotypes and expresses both. These loci are
located close enough to each other that, in an
individual family, the entire haplotype can be
transmitted as a single block to a child.

As a result, parent and child share only one
haplotype, and there is a 25% chance that two
sibs inherit matching HLA haplotypes.
 Because acceptance of transplanted tissues
largely correlates with the degree of similarity
between donor and recipient HLA haplotypes
(and ABO/Rh blood groups), the favored donor
for bone marrow or organ transplantation is an
ABO/Rh compatible and HLA-identical sibling of
the recipient.

The inheritance of HLA haplotypes. A haplotype is usually transmitted,
as a unit. In extremely rare instances, a parent will transmit a
recombinant haplotype to the child, as seen in individual II-5, who
received a haplotype that is recombinant between the class I and class
II loci.
MHC expression

Within any one ethnic group, some HLA alleles
are found commonly; others are rare or never
seen. Similarly, some haplotypes are much more
frequent than expected, whereas others are
exceptionally rare or nonexistent.
 E.g., most of the 3 × 107 allelic combinations that
could theoretically occur to make a haplotype
among white individuals have never been
observed.
 This restriction in the diversity of haplotypes
possible in a population results from a situation
referred to as linkage disequilibrium and may
be explained by a complex interaction between a
number of factors:
 These



factors include:
low rates of meiotic recombination in the
small physical distance between HLA loci;
environmental influences that provide
positive selection for particular
combinations of HLA alleles forming a
haplotype; and
historical factors, such as how long ago the
population was founded, how many
founders there were, and how much
immigration has occurred.
 Major
differences in allele and
haplotype frequencies exist between
populations as well. What may be a
common allele or haplotype in one
population may be very rare in another.
 Once again, the differences in the
distribution and frequency of the alleles
and haplotypes within the MHC are the
result of complex genetic,
environmental, and historical factors.
HLA and Disease Association

There is association between certain
diseases and specific HLA alleles and
haplotypes.
 The etiological basis for most of the HLAdisease associations remains obscure.
 Most but not all of these disorders are
autoimmune, thought to be related to
variation in the immune response resulting
from polymorphism in immune response
genes.
Ankylosing Spondylitis

Ankylosing spondylitis, a chronic
inflammatory disease of the spine and
sacroiliac joints, is one example.
 In older studies that relied on serologically
defined B27 alleles, only 9% of Norwegians, for
example, are B27-positive, whereas more than
95% of those with ankylosing spondylitis are
B27-positive.
 Although less than 5% of B27-positive
individuals develop the disease, as many as
20% of B27-positive individuals may have
subtle, subclinical manifestations of the disease
without any symptoms or disability.

One explanation for why some B27-positive
individuals do not develop disease rests in
part on that fact that DNA sequencing has
revealed more than two dozen different
alleles within "the" HLA-B27 allele originally
defined serologically.
 The frequency of each of these different
alleles varies within a given ethnic group and
between ethnic groups.
 *If only certain of these B27 alleles
predispose to disease, while others may
actually be protective, studies in different
ethnic groups that lump all the B27 alleles
into a single allele will find quite different
rates of disease in B27-positive individuals.
Table 9-5. HLA Alleles with Strong Disease Association
Frequency
(%)*
Disease
HLA Allele
(Serological)
Patients
Controls
Odds Ratio†
Ankylosing spondylitis
B27
>95
9
>150
Reiter syndrome
B27
>80
9
>40
Acute anterior uveitis
B27
68
9
>20
Subacute thyroiditis
B35
70
14
14
Psoriasis vulgaris
Cw6
87
33
7
Narcolepsy
DQ6
>95
33
>38
Graves disease
DR3
65
27
4
Rheumatoid arthritis
DR4
81
33
9
Frequency
(%)*
Patients
Controls
Odds Ratio†
Juvenile rheumatoid DR8
arthritis
38
7
8
Celiac disease
DQ2
99
28
>250
Multiple sclerosis
DR2, DQ6
86
33
12
Type I diabetes
DQ8
81
23
14
Type I diabetes
DQ6
<1
33
0.02
Hemochromatosis
A3
75
13
20
CAH (21hydroxylase
deficiency)
B47
25
0.2
80-150
Disease
HLA Allele
(Serological)

In other cases, the association between a
particular HLA allele or haplotype and a disease
is not due to functional differences in immune
response genes encoded by the HLA alleles.
 Instead, the association is due to a particular
MHC allele being present at a very high
frequency on chromosomes that also happen to
contain disease-causing mutations in another
gene within the MHC, because of linkage
disequilibrium.
 As mentioned earlier, the autosomal recessive
disorders congenital adrenal hyperplasia due
to 21-hydroxylase deficiency and primary
hemochromatosis result from mutations in
genes that lie within the MHC.

Analysis of 21-hydroxylase mutations
responsible for adrenal hyperplasia has
revealed that certain of the mutations at this
locus originally occurred on chromosomes
with particular haplotypes and were
subsequently inherited through multiple
generations along with these specific
haplotype markers as a block.

Another example is hemochromatosis, a
common autosomal recessive disorder of iron
overload. More than 80% of patients with
hemochromatosis are homozygous for a
common mutation, Cys282Tyr, in the
hemochromatosis gene (HFE) and have
HLA-A*0301 alleles at their HLA-A locus. The
association is not the result of HLA-A*0301
somehow causing hemochromatosis.

HFE is involved with iron transport or
metabolism in the intestine; HLA-A, as a class
I immune response gene, has no effect on
iron transport. The association is due to
proximity of the two loci and the linkage
disequilibrium between the Cys282Tyr
mutation in HFE and the A*0301 allele at
HLA-A.

The functional basis of most HLA-disease
associations is unknown. HLA molecules are
integral to T-cell recognition of antigens.
 Perhaps different polymorphic alleles result in
structural variation in these cell surface
molecules, leading to differences in the
capacity of the proteins to interact with
antigen and the T-cell receptor in the initiation
of an immune response, thereby affecting
such critical processes as immunity against
infections and self-tolerance to prevent
autoimmunity.
HLA and Tissue Transplantation

HLA loci are the primary determinants of
transplant tolerance and graft rejection and
therefore play an important role in
transplantation medicine.
 Despite the impressive progress in the design
of powerful immunosuppressive drugs to
suppress rejection of organ transplants, only
an absolutely perfect match for all HLA and
blood group alleles, such as occurs between
monozygotic twins, can provide a 100%
transplantation success rate without
immunosuppressive therapy.

For the transplantation of solid organs, such as
kidneys, the percentage of grafts surviving after
10 years when the recipient and the donor are
HLA-identical siblings is 72% but falls to 56%
when the donor is a sibling who has only one
HLA haplotype in common with the recipient.
 Bone marrow transplantation is a greater
challenge than solid organ transplantation; not
only can the host reject the graft, but also the
graft, which contains immunocompetent
lymphocytes, can attack the host in what is
known as graft-versus-host disease (GVHD).
GENOTYPES AND PHENOTYPES IN POPULATIONS
Genetic Variation in Populations

Population genetics is the quantitative study of
the distribution of genetic variation in
populations and of how the frequencies of genes
and genotypes are maintained or change.
 Population genetics is concerned both with
genetic factors, such as mutation and
reproduction, and with environmental and
societal factors, such as selection and migration,
which together determine the frequency and
distribution of alleles and genotypes in families
and communities.
 Population
genetics addresses the history
and genetic structure of human populations,
the flow of genes between populations and
between generations, and, very importantly,
the optimal methods for identifying genetic
susceptibilities to common disease.
 Population genetics provides the knowledge
about different disease genes that are
common in different populations,
information that is needed for clinical
diagnosis and genetic counseling, including
determining the allele frequencies required
for risk calculations.
Genetic Factors in Human
Immunodeficiency Virus Resistance
Determine allele and genotype frequencies in
populations.
 Consider the gene CCR5, which encodes a cell
surface cytokine receptor that serves as an
entry point for certain strains of the HIV that
causes AIDS.
 A 32-base pair deletion in this gene results in
an allele (ΔCCR5) that encodes a nonfunctional
protein due to a frameshift and premature
termination.
 Individuals
homozygous for the ΔCCR5
allele are resistant to HIV infection.
 The normal allele and the 32-base pair
deletion allele, ΔCCR5, are easily
distinguished by PCR analysis of the gene.
 A sampling of 788 individuals from Europe
provides absolute numbers of individuals
who were homozygous for either allele or
heterozygous.
Role of CCR5 in HIV infection
Table 9-6. Genotype Frequencies for Normal CCR5 Allele and the
Deletion ΔCCR5 Allele
Genotype
Number of
People
Observed
Relative
Genotype
Frequency
Allele
Derived Allele
Frequencies
CCR5/CCR5
647
0.821
CCR5/ΔCCR5
134
0.168
CCR 5
0.906
ΔCCR5/ΔCCR5
7
0.011
ΔCCR 5
0.094
Total
788
1.000

On the basis of the observed genotype
frequencies, we can directly determine the
allele frequencies by simply counting the
alleles.
 When we refer to the population frequency of
an allele, we are considering a hypothetical
gene pool as a collection of all the alleles at
a particular locus for the entire population.
 For autosomal loci, the size of the gene pool
at one locus is twice the number of
individuals in the population because each
autosomal genotype consists of two alleles,
that is, a ΔCCR5/ΔCCR5 individual has two
ΔCCR5 alleles, and a CCR5/ΔCCR5
individual has one of each. In this example,
then, the observed frequency of the CCR5
allele is:
 Similarly,
one can calculate the frequency
of the ΔCCR5 allele as 0.094, either by
adding up the number of ΔCCR5 alleles
directly [(2 × 7) + (1 × 134) = 148 of a total
of 1576 alleles] or simply by subtracting
the frequency of the normal CCR5 allele,
0.906, from 1, because the frequencies of
the two alleles must add up to 1.
The Hardy-Weinberg Law

As we have shown with the CCR5 cytokine
receptor gene example, we can use a sample
of individuals with known genotypes in a
population to derive estimates of the allele
frequencies by simply counting the alleles in
individuals with each genotype.
 How about the converse? Can we calculate
the proportion of the population with various
genotypes once we know the allele
frequencies?
 Deriving genotype frequencies from allele
frequencies is not as straightforward as
counting because we actually do not know in
advance how the alleles are distributed
among homozygotes and heterozygotes.
 If
a population meets certain
assumptions, however, there is a simple
mathematical relationship known as the
Hardy-Weinberg law for calculating
genotype frequencies from allele
frequencies.
The Hardy-Weinberg Law
The Hardy-Weinberg law rests on these
assumptions:
 The population is large and matings are
random with respect to the locus in question.
 Allele frequencies remain constant over time
because:



There is no appreciable rate of mutation
Individuals with all genotypes are equally capable of
mating and passing on their genes, that is, there is
no selection against any particular genotype.
There has been no significant immigration of
individuals from a population with allele frequencies
very different from the endogenous population.
The Hardy-Weinberg law has two critical
components.
(1) The first is that under certain ideal
conditions, a simple relationship exists between
allele frequencies and genotype frequencies in
a population.
 Suppose p is the frequency of allele A and q is
the frequency of allele a in the gene pool and
alleles combine into genotypes randomly; that
is, mating in the population is completely at
random with respect to the genotypes at this
locus.

The chance that two A alleles will pair up to give
the AA genotype is p2; the chance that two a
alleles will come together to give the aa
genotype is q2; and the chance of having one A
and one a pair, resulting in the Aa genotype, is
2pq.

The Hardy-Weinberg law states that the
frequency of the three genotypes AA, Aa, and aa
is given by the terms of the binomial expansion
of (p + q)2 = p2 + 2pq + q2.
(2) A second component of the HardyWeinberg law is that if allele frequencies do not
change from generation to generation, the
relative proportion of the genotypes will not
change either; that is, the population genotype
frequencies from generation to generation will
remain constant, at equilibrium, if the allele
frequencies p and q remain constant.
 More specifically, when there is random mating
in a population that is at equilibrium and
genotypes AA, Aa, and aa are present in the
proportions p2 : 2pq : q2, then genotype
frequencies in the next generation will remain
in the same relative proportions, p2 : 2pq : q2.

Proof of this equilibrium is shown in following
table. It is important to note that HardyWeinberg equilibrium does not specify any
particular values for p and q; whatever allele
frequencies happen to be present in the
population will result in genotype frequencies
of p2 : 2pq : q2, and these relative genotype
frequencies will remain constant from
generation to generation as long as the allele
frequencies remain constant and other
conditions are met.
Frequencies of Mating Types and Offspring for a Population in HardyWeinberg Equilibrium with Parental Genotypes in the Proportion p2 : 2pq : q2
Types of
Mating
Offspring
Mother
Father
Frequency
AA
AA
AA
p2 × p2 = p4
(p4)
AA
Aa
p2 × 2pq =
2p3 q
1/2(2p3 q)
1/2(2p3 q)
Aa
AA
2pqxp2=2p3
q
1/2(2p3 q)
1/2(2p3 q)
AA
aa
p2xq2=p2q2
p2q2
aa
AA
q2xp2=p2q2
p2q2
Aa
Aa
2pqx2pq=4p
2q2
Aa
aa
aa
Aa
¼(4p2q2)
Aa
aa
½(4p2q2)
1/4(4p2q2)
2pqxq2=2pq
3
1/2(2pq3)
1/2(2pq3)
q2x2pq=2pq
3
1/2(2pq3)
1/2(2pq3)

Applying the Hardy-Weinberg formula to the
CCR5 example given earlier, with relative
frequencies of the two alleles in the gene pool of
0.906 (for the normal allele CCR5) and 0.094 (for
ΔCCR5), then p2 = 0.906 × 0.906 = 0.821, q2 =
0.094 × 0.094 = 0.009, and 2pq = (0.906 × 0.094)
+ (0.094 × 0.906) = 0.170.
 When these genotype frequencies are applied to
a population of 788 individuals, the derived
numbers of people with the three different
genotypes (647 : 134 : 7) are, in fact, identical to
the actual observed numbers.
 As long as the assumptions of the HardyWeinberg law are met in a population, we would
expect these genotype frequencies (0.821 : 0.170
: 0.009) to remain constant generation after
generation in that population.

As we have seen, Hardy-Weinberg
distributions of genotypes in populations are
simply a binomial distribution (p + q)n, where
symbols p and q represent the frequencies of
two alternative alleles at a locus (where p + q
= 1), and n = 2, representing the pair of
alleles at any autosomal locus or any X-linked
locus in females.
 If a locus has three alleles, with frequencies
p, q, and r, the genotypic distribution can be
determined from (p + q + r)2.
 In general terms, the genotypic frequencies
for any known number of alleles and with
allele frequencies p1, p2, … pn can be
derived from the terms of the expansion of
(p1 + p2 + … pn)2.
The Hardy-Weinberg Law in Autosomal
Recessive Disease



The major practical application of the HardyWeinberg law in medical genetics is in genetic
counseling for autosomal recessive disorders.
For a disease such as phenylketonuria, the
frequency of affected homozygotes in the
population can be determined accurately
because the disease is identified through
newborn screening programs.
Heterozygotes, however, are asymptomatic silent
carriers, and their population incidence is
impossible to measure directly from phenotype.
The Hardy-Weinberg law allows an estimate of
heterozygote frequency to be made and used
subsequently for counseling.
 E.g,,
the frequency of PKU is approximately
1/4500 in Ireland. Affected individuals are
usually compound heterozygotes for
different mutant alleles rather than
homozygotes for the same mutant allele. In
practice, however, we usually lump all
disease-causing alleles together and treat
them as a single allele, with frequency q,
even when there is significant allelic
heterogeneity in disease-causing alleles.

Then the frequency of affected individuals =
1/4500 = q2, q = 0.015, and 2pq = 0.029 or
approximately 3%. The carrier frequency in
the Irish population is therefore 3%, and there
would be an approximately 3% chance that a
parent known to be a carrier of PKU through
the birth of an affected child would find that a
new mate of Irish ethnicity would also be a
carrier.
 If the new mate were from Finland, however,
where the frequency of PKU is much lower
(~1/200,000), his or her chance of being a
carrier would be only 0.6%.

Recall that for X-linked genes, there are only
two possible male genotypes but three
female genotypes. To illustrate gene
frequencies and genotype frequencies when
the gene of interest is X-linked, we use the
trait known as red-green color blindness,
which is caused by mutations in the series of
red and green visual pigment genes on the X
chromosome.
 Color blindness is a good example because it
is not a deleterious trait (except for possible
difficulties with traffic lights), and color-blind
persons are not subject to selection. As
discussed later, allowing for the effect of
selection complicates estimates of gene
frequencies.

cb for all the mutant color-blindness alleles and +
for the normal allele, with frequencies q and p,
respectively.
 The frequencies of the normal and mutant alleles
can be determined directly from the incidence of
the corresponding phenotypes in males by simply
counting the alleles.
 Because females have two X chromosomes, their
genotypes are distributed like autosomal
genotypes, but because color-blindness alleles
are recessive, the normal homozygotes and
heterozygotes are not distinguishable.
 The frequency of color blindness in females is
much lower than that in males, even though the
allele frequencies are, of course, the same in
both sexes. Less than 1% of females are colorblind, but nearly 15% are carriers of a mutant
color-blindness allele.
The Hardy-Weinberg Law in X-Linked
Disease
Table 9-8. X-Linked Genes and Genotype Frequencies (Color Blindness)
Sex
Genotype Phenotype
Incidence (Approximate)
Male
X+
Normal color vision
p = 0.92
Xcb
Color blind
q = 0.08
X+/X+
Normal
(homozygote)
p2 = (0.92)2 = 0.8464
X+/Xcb
Normal
(heterozygote)
2pq = 2(0.92)(0.08) =
0.1472
Normal (total)
p2 + 2pq = 0.9936
Color blind
q2 = (0.08)2 = 0.0064
Female
Xcb/Xcb