1. Population Genetics and Multifactorial Inheritance 2002 Consanguinity Genetic drift Founder effect Selection Mutation rate Polymorphism Balanced polymorphism Hardy-Weinberg Equilibrium

2. 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

5. Note error in “AA offspring” footer !

7. 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 ²

8. Applications of HWE Determination of allele frequency and heterozygote carrier frequency in a population for which the frequency of the trait is known

9. Hemophilia A and Para- hemophilia Hemophilia A: –XLR –Frequency 1/5000 –Female carriers 1/2500 Parahemophilia –Rare AR –Frequency 1/1,000,000 –Heterozygote carrier frequency 1/500

10. Factors that alter gene frequency Small populations/ Non-random mating Selection Mutation Migration and gene flow

11. Coefficient of relationship Parent-childFirst½ SiblingsFirst½ Uncle-nieceSecond¼ First cousinsThird 1/8

12. 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.

13. 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

15. Factors that alter gene frequency Small populations/ Non-random mating Selection Mutation Migration and gene flow

16. Selection Biological fitness (f) Positive and negative selection Selection on AD, AR, XLR

17. Factors that alter gene frequency Small populations/ Non-random mating Selection Mutation Migration and gene flow

18. Mutation Effect of gene size Effect of paternal age Balance between introduction of new mutant alleles by mutation and removal by negative selection

19. Factors that alter gene frequency Small populations/ Non-random mating Selection Mutation Migration and gene flow

20. Tracking human migrations Cohanim Lemba

21. 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

22. Balanced polymorphism Balance of positive and negative selection Malaria and genetic disorders of red blood cells

23. Multifactorial Inheritance Complex Common Diseases

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

26. Familial Aggregation

27. Increased risk to relatives: λ R λ S –IDDM10-15 –NIDDM 4 λ 1 –Schizophrenia 10 –Autism~100

28. 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

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

30. Twin Studies

31. Twin studies in infectious disease Tuberculosis (USA) Leprosy (India) Poliomyelitis (USA) Hepatitis B (Taiwan) 62% 18% 52% 22% 36% 6% 35% 4% MZ DZ

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

33. Diabetes Mellitus Maturity onset diabetes of the young (MODY)

34. 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.

35. 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.

36. Threshold Model

38. 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

41. Affected Sib Pair