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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 Note error in “AA offspring” footer ! 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, q² Applications of HWE • Determination of allele frequency and heterozygote carrier frequency in a population for which the frequency of the trait is known 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 Coefficient of relationship • • • • Parent-child Siblings Uncle-niece First cousins First First Second Third ½ ½ ¼ 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. 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 12th century, 5 million today • Ashkenazim – Migration to Rhineland in 9th century, to Eastern Europe in 14th century – Population 10-20,000 in Poland in 16th century, 11M worldwide today – Repeated “bottlenecks” (pogroms) • Amish 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 Factors that alter gene frequency • • • • Small populations/ Non-random mating Selection Mutation Migration and gene flow Mutation • Effect of gene size • Effect of paternal age • Balance between introduction of new mutant alleles by mutation and removal by negative selection 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 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 0.01. • Examples: MHC, SNPs, SSRs Balanced polymorphism • Balance of positive and negative selection Malaria and genetic disorders of red blood cells Multifactorial Inheritance Complex Common Diseases Evidence for Genetic Factors in Common Complex Diseases • Familial aggregation • Twin studies • Mendelian forms of disease Familial Aggregation Increased risk to relatives: λR • λS – IDDM – NIDDM 10-15 4 • λ1 – Schizophrenia – Autism 10 ~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 1st and/or 2nd degree relative • D No affected 1st or 2nd degree relatives Evidence for Genetic Factors in Common Complex Diseases • Familial aggregation • Twin studies • Mendelian forms of disease Twin Studies Twin studies in infectious disease • • • • Tuberculosis (USA) Leprosy (India) Poliomyelitis (USA) Hepatitis B (Taiwan) • • • • MZ DZ 62% 52% 36% 35% 18% 22% 6% 4% Evidence for Genetic Factors in Common Complex Diseases • Familial aggregation • Twin studies • Mendelian forms of disease 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. 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 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 Affected Sib Pair