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GENES and MEDICINE:

POPULATION GENETICS

POPULATION GENETICS
- the study of genetic variation in populations
- the genetic constitution of a population depends on many factors
A. Genotype Frequency
- proportion of each genotype in a population
B. Gene (Allele) Frequency
- proportion of chromosomes that contain a specific allele in a population

Example
- allele N (normal)
- allele M (mutated)
- allele NM (heterozygote)

Genotype Count (Population) Genotype Frequency

NN (homozygous normal) 49 49/100 0.49
NM (heterozygous carrier) 42 42/100 0.42
MM (homozygous mutant) 9 9/100 0.09
Total 100

Genotype Count (Population) How Many Copies? Allele Frequency

(2 Copies of Genes in Allele N or M
Pairs of Chromosome)
NN (homozygous normal) 49 2 of N (2 x 49) + 42 = 0.7
NM (heterozygous carrier) 42 N of each, M of each 200
MM (homozygous mutant) 9 2 of M
Total 100 200 42 + (2 x 9) = 0.3
200

C. Hardy-Weinberg Equilibrium
- concept based on mathematical equation (probability and statistics)
- describes the outcome of random mating within populations
- states that “in the absence of mutation, non-random mating, selection and genetic drift, the genetic
constitution of the population remains the same from one generation to the next”
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1. Equation

p2 + 2pq + q2 = 1

p = probability of having the normal allele (allele N)

q = probability of having the mutated allele (allele M)
p2 = probability of genotype NN (normal homozygote)
2pq = probability of being a carrier for the disease in the population
(allele NM)
q2 = probability of having the disease (allele M)
p+q =1

 If p = 0.7 and q = 0.3

Then (0.7)2 + 2[(0.7)(0.3)] + (0.3)2 = 1
0.49 + 0.42 + 0.09 = 1

2. Example
a. Frequency of Heterozygous Carriers in Cystic Fibrosis
- incidence of cystic fibrosis = 1 in 2000 live births

q2 = 1/2000
q = 1/44
p =1-q
p = 43/44
2pq = 1/22

 1 in 22 individuals in the whole population is a heterozygous carrier for cystic fibrosis

b. Carrier Frequency of Phenylketonuria

- prevalence of PKU is 1 in 10,000 live births

q2 = 1/10,000
calculate 2pq
q = 1/100 = 0.01
p is approximately 1

 carrier frequency = 2q = 2(1/100) = 1/50

c. Prevalence of Tay-Sachs Disease in the Ashkenazi Jewish Population

- 1 in every 30 Ashkenazi Jews is a carrier for Tay-Sachs Disease

2pq = 1/30
calculate q2
p is approximately 1
 carrier frequency = 2q = 1/30
q = 1/60
q2 = 1/3600

3. Lessons from Hardy-Weinberg

- if the prevalence of a recessive disease is known  can calculate the frequency of
heterozygous carriers (and vice versa)
- for autosomal recessive diseases
- the number of heterozygous carriers is much higher than the number of affected
homozygotes
- the vast majority of recessive genes are “hidden” in the heterozygotes
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4. Allele Frequencies in X-Linked Disorders
- the allele frequency for X-linked diseases is obtained by counting the number of affected
males in the population
- 1/10,000 males has Hemophilia A  q = 1/10,000
- the number of affected females will be q2 = 1/108
- the female carrier frequency is 2pq = 2/104 or 1/5,000
D. Factors Causing Genetic Variation in Populations
1. New mutation
- ultimate source of new genetic variation

2. Natural Selection
- disease-producing mutations  less fit, less able to survive, less able to reproduce  natural
selection tends remove mutations from the population  relatively rare genetic
diseases
- sickle cell trait and falciparum malaria (Africa and the Mediterranean)
- sickle cell trait protects against falciparum malaria  survive against malaria (natural
selection favors sickle cell trait increased the number of copies of the
mutation)
3. Genetic Drift
- gene frequency change caused by small population size
- 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
- in a small population, allele frequencies can fluctuate from
generation to generation by chance
 small population  genetic drift  predictions based on statistics can be incorrect
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a. Founder Effect

b. New Mutation

4. Gene Flow
- exchange of genes among previously separated populations
- sickle cell mutation common in American black population
- sickle cell mutation uncommon in American white population
 intermarriage (gene flow)  frequency of sickle cell mutation (down in black
population, up in white population)
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5. Effects of Consanguinity
- not a random mating (Hardy-Weinberg equation is based on random mating in a large
population)
- share a fraction of their genes (both have the genes from their ancestors)  the closer the
relationship the greater the likelihood of production of a child with the genetic disease
a. Coefficient of Relationship (Fraction of Shared Genes)
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