Population Genetics

Chanin Limwongse, MD

Chintana Sirinavin, MRCP

Population Genetics

The study of gene distribution in population How gene frequencies or genotypes are

maintained or changed Concerns both genetic factors (mutation

and mating) and environmental factor (selection and migration)

What happens with a mutant gene ?

Existing in decreased number until disappearance

Existing in increased number Existing in stable number

Gene frequency

Balance between new mutation rate, fitness, selection and other factors

New mutation rate = rate of allele loss

Gene frequencies vary among different ethnic groups

Europian / US Caucasian: cystic fibrosis, hemochromatosis

French Canadian: PKU, OPMD, familial hypercholesterolemia

Ashkenazi Jews: Tay-Sachs, dysautonomia African: sickle cell anemia Asian: and β thalassemia

Hardy-Weinberg Law

Use in calculating genotype frequency from phenotype data

p = frequency of allele A q = frequency of allele a p+q = 1

Hardy-Weinberg Law

Frequency of genotype AA = p2

Frequency of genotype aa = q2

Frequency of genotype Aa = 2pq

Sum of all genotype = p2 + 2pq + q2

= (p+q)2

= 1

Proportion of each genotype (AA:Aa:aa) will remain constant at equilibrium if allele frequencies remain constant

Hardy-Weinberg Law

For an autosomal recessive disease, disease phenotype is found in population at a frequency of 1/3600

Then carrier frequency = 2x 1/√3600

= 1/30o Gene frequency = q = 1/60

Hardy-Weinberg Law

For an autosomal dominant disease, allele frequency = ½ x population frequency of disease

For X-linked recessive disease, allele frequency = disease frequency in male

Hardy-Weinberg Law

Factors that disturb Hardy-Weinberg equilibrium (1)

Non-random matingstratification (ethnic subgroup)

assortive matingconsanguinity

All of the above will tend to increase homozygote frequency and decrease heterozygote frequency for AR disorder

Non-constant allele frequencyreduced fitness (<1) or no

fitness (= 0) selection against disease allele esp. for AD disorder

genetic driftgene flow

Factors that disturb Hardy-Weinberg equilibrium (2)

Selection against dominant allele

Lethal dominant disease or disease with near zero fitness

Results in no transmission of disease through parents

Most cases are from new mutation Disease frequency remain constant if new

mutation rate is high enough Population frequency will not comply with

Hardy-Weinberg equilibrium

Example of disease with zero fitness

Apert syndrome Thanatophoric dysplasia Cornelia de Lange syndrome Atelosteogenesis Acrodysostosis Osteogenesis imperfecta type 2

Selection and mode of inheritance

AD – significant due to expose of phenotype in heterozygote

AR – negative selection has minimal effect due to most are carrier without phenotype

thus no selection against- positive selection in carrier may maintain

high gene frequency in population XR – selection operates in hemizygous male only

therefore about 1/3 of alleles are lost in a generation if fitness = 0

Genetic drift vs, Gene flow

Drift: Fluctuation in gene frequency due to chance

Flow: Slow diffusion of genes due to population admixture

Example : drift: breaking off of a subpopulation from a larger population

flow: migration of population and merge with larger one