Population Genetics and Multifactorial Inheritance 2002

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1 Population Genetics and Multifactorial Inheritance 2002 Consanguinity Genetic drift Founder effect Selection Mutation rate Polymorphism Balanced polymorphism Hardy-Weinberg Equilibrium Hardy-Weinberg Equilibrium Explains why, In a large population with random mating: 1. Allele frequencies do not change from generation to generation 2. Genotype frequencies are determined by allele frequencies at that locus 1

2 2

3 Note error in AA offspring footer! 3

4 Allele frequencies in X-linked disorders Males are hemizygous for the X-chromosome: therefore frequency of affected males = frequency of the mutant allele, q For rare XLR disorders, frequency of heterozygous carrier females is twice the frequency of affected males, or 2q Frequency of homozygous females is very low, q_ Applications of HWE Determination of allele frequency and heterozygote carrier frequency in a population for which the frequency of the trait is known 4

5 Hemophilia A and Parahemophilia Hemophilia A: XLR Frequency 1/5000 Female carriers 1/2500 Parahemophilia Rare AR Frequency 1/1,000,000 Heterozygote carrier frequency 1/500 Factors that alter gene frequency Small populations/ Non-random mating Selection Mutation Migration and gene flow 5

6 Coefficient of relationship Parent-child First _ Siblings First _ Uncle-niece Second _ First cousins Third 1/8 Selected Michigan Marriage Laws (Amended 1956) SEC 3. No man shall marry his mother, grandmother, daughter, granddaughter, stepmother, grandfather s wife, son s wife, grandson s wife..or cousin of the first degree. 6

7 Genetic Drift/ Founder Effect Single (few) founder mutations Finns ( located on the edge of the populated world ) Indo-European immigration 2000 years ago Population of 50,000 in 12 th century, 5 million today Ashkenazim Migration to Rhineland in 9 th century, to Eastern Europe in 14 th century Population 10-20,000 in Poland in 16 th century, 11M worldwide today Repeated bottlenecks (pogroms) Amish 7

8 Factors that alter gene frequency Small populations/ Non-random mating Selection Mutation Migration and gene flow Selection Biological fitness (f) Positive and negative selection Selection on AD, AR, XLR 8

9 Factors that alter gene frequency Small populations/ Non-random mating Selection Mutation Migration and gene flow Effect of gene size Mutation Effect of paternal age Balance between introduction of new mutant alleles by mutation and removal by negative selection 9

10 Factors that alter gene frequency Small populations/ Non-random mating Selection Mutation Migration and gene flow Migration and gene flow Tracking human migrations Cohanim Lemba 10

11 Polymorphism The occurrence of two or more genetically determined alternative phenotypes in a population at such a frequency that the rarest could not be maintained by recurrent mutation alone Practically---a genetic locus is considered polymorphic if one or more of the rare alleles has(have) a frequency of at least Examples: MHC, SNPs, SSRs Balanced polymorphism Balance of positive and negative selection Malaria and genetic disorders of red blood cells 11

12 Multifactorial Inheritance Complex Common Diseases 12

13 Evidence for Genetic Factors in Common Complex Diseases Familial aggregation Twin studies Mendelian forms of disease Familial Aggregation 13

14 _ S IDDM _ 1 Schizophrenia 10 Increased risk to relatives: _ R NIDDM 4 Autism ~100 MD (and MD2B): A chronic condition with significant physical, mental, emotional, and financial consequences A a first degree relative (sib,parent) B a second degree relative (aunt,uncle, grandparent C More than one 1 st and/or 2 nd degree relative D No affected 1 st or 2 nd degree relatives 14

15 Evidence for Genetic Factors in Common Complex Diseases Familial aggregation Twin studies Mendelian forms of disease Twin Studies 15

16 Twin studies in infectious disease Tuberculosis (USA) Leprosy (India) Poliomyelitis (USA) Hepatitis B (Taiwan) MZ DZ 62% 18% 52% 22% 36% 6% 35% 4% Evidence for Genetic Factors in Common Complex Diseases Familial aggregation Twin studies Mendelian forms of disease 16

17 Diabetes Mellitus Maturity onset diabetes of the young (MODY) Association and Linkage ASSOCIATION of a specific allele at a genetic locus with disease in a population Candidate gene LINKAGE. Co-segregation in families of a marker locus, regardless of specific allele, with disease. 17

18 Implications Identification of genetic markers of liability to common complex disease. Environmental triggers have greatest impact on genetically predisposed. Identification of susceptible individuals aids identification of environmental triggers. Medical intervention can be focused on those at greatest risk. Threshold Model 18

19 Predictions from Threshold Model Recurrence risks are average Risk increases with # of affected relatives Risk increases with severity of malformation Differential risk increases as frequency decreases Sex differences 19

20 20

21 Affected Sib Pair 21

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