Lecture 2 Population Genetics

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

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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: α 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 

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Sum of all genotype = p2 + 2pq + q2 = (p+q)2 =1

Hardy-Weinberg Law 

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

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Then carrier frequency = 2x 1/√3600 = 1/30 Gene frequency = q = 1/60

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Hardy-Weinberg Law 

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

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

Factors that disturb HardyWeinberg equilibrium (1) Non-random mating stratification (ethnic subgroup) assortive mating consanguinity  All of the above will tend to increase homozygote frequency and decrease heterozygote frequency for AR disorder 

Factors that disturb HardyWeinberg equilibrium (2) 

Non-constant allele frequency reduced fitness (<1) or no fitness (= 0) selection against disease allele esp. for AD disorder genetic drift gene flow

Selection against dominant allele 

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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  

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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 