Population genetics

Types of polymorphism

Just to remind

Restriction fragment length polymorphism (RFLP)

Single nucleotide polymorphism (SNP) 10 millions

Minisatellites/variable number tandem repeats (VNTR)

Microsatellites or short tandem repeats (STR)
Frequencies of polymorphic alleles may vary
significantly in different populations
Currently a new type of the genomic variation named CNV
(copy number variation) is extensively studied.
CNV range from Kb to Mb
Most CNV are rare variants
Some CNV can be associated with the diseases.

Allele frequency ?
Your class of 100 people has been typed for a twoallele polymorphism (alleles labeled A and a), and the
following 3 genotype counts were obtained:
Genotype
Number of individuals
A,A
30
A,a
50
a,a
20
Total number of allele = 100 x 2 = 200
Number of allele A = (30 x 2)+ 50 = 110
Number of allele a= 50 + (20 x 2) = 90
Frequency of allele A = 110/200 = 0.55

Frequency of allele a = 90/200 = 0.45

Frequencies of polymorphic alleles may

vary significantly in different populations
Neutral polymorphism : SNP rs213934 A/G
(HapMap project)
Japanese
Caucasians
African ancestry in SW USA
Nigerian

0.434
0.292
0.035
0

Polymorphism associated with disease:

sickle cell mutation
African Americans
Caucasians

0.05
0

Hardy-Weinberg equilibrium/law:
I. Genotypes distribution
Frequency of allele A = p
Frequency of allele a = q
p+q = 1

1= p2 + 2pq + q2
p2 = frequency of homozygote AA
2pq = frequency of heterozygote Aa
q2 = frequency of homozygote aa

Hardy-Weinberg Equilibrium:
Single Nucleotide Polymorphism
SNP A/C
p = 0.7 (frequency of allele A)
q = 0.3 (frequency of allele C)

1 = p2 + 2pq + q2

p2 = frequency of homozygote AA= 0.72 = 0.49

2pq = frequency of heterozygote AC = 2x0.7x0.3= 0.42
q2 = frequency of homozygote CC = 0.32 = 0.09

Expected distribution of genotypes in 100 individuals

AA= 0.49 x 100 = 49 individuals
AC = 0.42 x 100 = 42 individuals
CC = 0.09 x 100 = 9 individuals

Q
Single nucleotide polymorphism SNP17361 G/T:

the frequency of a minor allele T is 0.4. What is

the frequency of heterozygotes G/T?
A. 18%
B. 28%
C. 38%

D. 48%
E. 58%

Single nucleotide polymorphism SNP17361 G/T:

the frequency of a minor allele T is 0.4. What is

the frequency of heterozygotes G/T?
A. 18%

B. 28%
C. 38%
D. 48%
E. 58%
q = 0.4
p=1 - 0.4 = 0.6
2pq = 2 x 0.6 x 0.4 = 0.48 (48%)

Hardy-Weinberg equilibrium in
Mendelian diseases
Frequency of normal allele N = p
Frequency of mutant allele M = q
1 = p2 + 2pq + q2

p2 = frequency of normal homozygote NN

2pq = frequency of heterozygote NM
q2 = frequency of mutant homozygote MM

Hardy-Weinberg equilibrium
Autosomal dominant disease
Frequency of normal allele N = p
Frequency of mutant allele M = q

1 = p2 + 2pq + q2
p2 = frequency of healthy (normal homozygote NN)
2pq = frequency of affected (heterozygote NM)
q2 = frequency of affected (mutant homozygote MM)

Hardy-Weinberg equilibrium
Autosomal recessive disease
Frequency of normal allele N = p
Frequency of mutant allele M = q

1 = p2 + 2pq + q2
p2 = frequency of healthy (normal homozygote NN)
2pq = frequency of healthy (heterozygote NM)
q2 = frequency of affected (mutant homozygote MM)

Hardy-Weinberg equilibrium
X-linked recessive disease
Frequency of normal allele N = p
Frequency of mutant allele M = q

Females: 1 = p2 + 2pq + q2
p2 = frequency of healthy (normal homozygote NN)
2pq = frequency of healthy (heterozygote NM)
q2 = frequency of affected (mutant homozygote MM)

Males:

p = frequency of healthy (normal hemizygote N)

q = frequency of affected (mutant hemizygote M)

Most typical exam questions

Disease frequency (incidence) is given

Find disease allele frequency

Find carrier frequency
Carrier frequency is given
Find disease allele frequency
Find disease frequency
q is given

Find carrier frequency

Find disease frequency

Estimation of carrier frequency for

autosomal recessive disease
It is difficult and often impossible to identify
carrier frequency directly
Hardy-Weinberg equilibrium allows for estimation
of carrier frequency from disease incidence
Incidence of phenylketonuria (PKU) in Caucasians :
1 in 10,000
Mutant allele frequency?
Carrier frequency ?

Incidence of phenylketonuria (PKU) in Caucasians :

1 in 10,000
Mutant allele frequency
Carrier frequency ?
p= frequency of normal allele
q = frequency of mutant allele
p2 + 2pq + q2
p2 = frequency of homozygote NN
2pq = frequency of heterozygote NM
q2 = frequency of homozygote MM
Frequency of MM = q2 = 1/10,000
q= square root of 1/10000= 1/10000 = 1/100
p= 1 1/100 = 0. 99 1 (approximation can be
used because the disease/mutation is rare)
Carrier frequency = 2pq = 2 x1 x 1/100 = 1/50

optional

PKU incidence

in China : 1 in 100,000

Carrier frequency ?

PKU incidence

optional

in China : 1 in 100,000

Mutant allele frequency?

Carrier frequency ?
p= frequency of normal allele
q = frequency of mutant allele
p2 + 2pq + q2
p2 = frequency of homozygote NN
2pq = frequency of heterozygote NM
q2 = frequency of homozygote MM

Frequency of MM = q2 = 1/100,000
q=1/100000 = 1/316
p= 1 1/316 = 0. 999 1
Carrier frequency = 2pq = 2 x1 x 1/316 = 1/158

Frequencies of mutant PKU allele and

PKU carriers are different in Caucasians
and Chinese
PKU incidence in Caucasians : 1 in 10,000
q= 1/100
Carrier frequency = 1/50
PKU incidence in China : 1 in 100,000
q= 1/316
Carrier frequency = 1/158

From carrier frequency to

disease and allele
frequency
A biochemical or enzymatic carrier
testing is available just for a limited
number of genetic disorders, particularly
for Tay-Sachs disease

Tay-Sachs disease is an autosomal recessive

disorder for which the carrier frequency in

individuals of Ashkenazi Jewish descent is
about 1 in 30.
How frequent is Tay-Sachs disease in this
population?
1 = p2 + 2pq + q2
p2 = frequency of healthy (normal homozygote NN)
2pq = frequency of healthy (heterozygote NM)
q2 = frequency of affected (mutant homozygote MM)

Tay-Sachs disease is an autosomal recessive

disorder for which the carrier frequency in
individuals of Ashkenazi Jewish descent is about
1 in 30.
How frequent is Tay-Sachs disease in this
population?
2pq = 1/30
In case of rare genetic disease the frequency of
mutant allele (q) is small, thus p 1
2pq 2q = 1/30
q = 1/60
The frequency of disease = q2 = ( 1/60)2 = 1/3600
Answer: 1 in 3600

Hardy-Weinberg equilibrium
X-linked diseases

X-linked diseases
Because males have only a single X chromosome, each
affected male has one copy of the disease-causing

recessive mutation. Thus, the incidence of an X-linked

disease in males is a direct estimate of the gene
frequency in the population.

Disease frequency in males = q

X-linked recessive:
Males:
q affected
p - unaffected

Females:
q2 affected
2pq - carrier
p2 - unaffected

X-linked dominant:
Males:
q affected
p - unaffected

Females:
q2 affected
2pq - affected
p2 - unaffected

X-linked recessive
Color blindness
8% Caucasian males have color blindness
q= ?
p=?
Females
Normal non-carrier = ?
Normal carrier = ?
Color-blindness = ?

X-linked recessive

Color blindness
8% Caucasian males have color blindness

Males
q= 0.08
p = 0.92
Females
Normal non-carrier = p2 = 0.922 =0.846
Normal carrier = 2pq = 2 x 0.92 x 0.08 = 0.1472

Color-blindness = q2 = 0.082 =0.0064

optional

Blood Cells Mol Dis, 2003, 31 (2) , 201-205

G6PD deficiency in 70 of 1080 males (70/1080= 0.065)

q=
p=
Females
Normal non-carrier =
Carrier =
G6PD deficiency

optional

Blood Cells Mol Dis, 2003, 31 (2) , 201-205

G6PD deficiency in 70 of 1080 males (70/1080= 0.065)

q = 0.065
p= 1- 0.065= 0.935
Females
Normal non-carrier = p2 =0.9352 =0.874 (87.4%)
Carrier = 2pq = 2 x 0.935 x 0.065 = 0.121 (12,1%)
G6PD deficiency = q2 = 0.0652 = 0.0042 (0.4%)

Hardy-Weinberg equilibrium
Autosomal dominant disease
1 = p2 + 2pq + q2
p2 = frequency of healthy (normal homozygote NN)
2pq = frequency of affected (heterozygote NM)
q2 = frequency of affected (mutant homozygote MM)

Autosomal dominant diseases

1= p2 + 2pq + q2
Most dominant diseases are rare, it means q is small
and an approximation p 1 can be used
Most patients with AD disease are heterozygotes
Disease frequency = 2pq + q2 2pq 2q
q= disease frequency/2
Familial hypercholesterolemia in USA : 1/500 or 0.002
Therefore q= 0.001
Frequency of homozygotes = q2= (0.001)2= 0.000 001
1 in a million

optional

Hardy-Weinberg Law:
II. The population genotype frequencies from
generation to generation will remain constant, if
allele frequency remain constant
If you want to know why it is true see the
following table

Assumptions underlying the

Hardy-Weinberg law
Large population

Random mating
No migration

Factors that disturb HardyWeinberg equilibrium

Non-random mating
Stratification
Assortative mating
Consanguinity/inbreeding
Genetic drift in small population
Founder effect
Mutation selection
Migration and gene flow

Non-random mating
Assortative mating
Consanguinity/inbreeding

Stratification

Non-random mating: Assortative marriage

The choice of the mate who possesses
some particular trait

Congenital deafness
Congenital blindness
Achondroplasia

Non-random mating: Consanguinity

Marriage between relatives

Non-random mating: Inbreeding

Geographically isolated populations
Religious groups (Old Order Amish, Mennonites etc)
In genetic isolates the chance of mating with
another carrier may be as high as in consanguineous
marriages

Non-random mating: Stratification

Slide 1
(optional)

Sickle cell (SC) mutation in the USA

US population: many groups
(strata)
Whites
African Americans
Native Americans
Asian Americans
Hispanics
African Americas 10% of US population
Frequency of SC mutation in African Americans qAA=0.05
Frequency of SC mutation in other group is practically 0
Frequency of SC mutation in US population qtotal= 0.05/10 =
0.005

Stratification
African Americas(AA) 10% of US population
Frequency of sickle cell (SC) mutation in AA = qAA=0.05
Frequency of SC mutation in US population qtotal= 0.05/10 = 0.005

Slide 2
(optional)

Frequency of the SC disease expected from HardyWeinberg equilibrium in US population:

qtotal2 = 0.0052= 0.000025
However the mating is not random - most marriages are
inside the group (stratum) and the real estimate of SC
disease in African Americans is
qAA2= 0.052 = 0.0025
Because African Americans are 10% of the US population,
then the real frequency of the disease in the US
population is
0.0025/10= 0.00025

This is 10 times more than expected from HardyWeinberg equilibrium

Factors that disturb Hardy-Weinberg equilibrium

Non-random mating
Stratification
Assortative mating
Consanguinity/inbreeding
Genetic drift in small population
Founder effect
Mutation selection
Migration and gene flow

Just to remind
you where we
are

Genetic drift in small populations chance event

Increased fertility or survival of mutation
carriers for reason
unrelated to carrying the mutation
leads to a
change in allele frequency
In small populations allele frequencies can
fluctuate form generation to generation by
chance (genetic drift)

Founder effect
The founder effect is the loss of genetic
variation that occurs when a new population is
established by a very small number of individuals
from a larger population

Mutation selection
Positive selection ( increased fertility
or survival because of mutation)
Negative selection ( decreased fertility
or survival because of mutation)

Effect of mutation selection is different in

dominant and recessive diseases
Dominant disease:
all mutant alleles are under negative selective
pressure
Autosomal recessive diseases:
selection has less effect
because most mutant alleles are in heterozygotes
and therefore escape negative selection
PKU incidence in Caucasians : q2= 1/10,000
Carrier frequency = 2pq = 2 x1 x 1/100 = 1/50

Number of mutant PKU alleles in carriers

1/50
----------------------------= ---------- = 100
Number of mutant PKU alleles in affected
2/10,000

Positive selection for heterozygotes

(Heterozygote advantage)
Resistance to malaria
Sickle cell anemia/Thalassemia/G6PD deficiency
Resistance to effect of chloride-secreting diarrhea
Cystic fibrosis

Resistance to some infections

Tay-Sachs disease

Migration and gene flow

Migration can change allele frequency by gene flow
slow diffusion of genes across a barriers

Map of Ancient human migration

Ethnic differences in the frequency of genetic

diseases may be due to

Genetic drift
Founder effect
Positive selection for heterozygotes
(Heterozygote advantage)

Ashkenazi Jews (those originating from the

Western and Eastern Europe diaspora), who make up
more than 80 percent of world Jews and are
believed to be descended from about 1,500 Jewish
families dating back to the 14th century

Tay-Sachs disease is common in

Ashkenazi Jews because of:
Founder effect
Inbreeding
Heterozygote advantage

The end