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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
  • 2. 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
  • 3.  
  • 4.  
  • 5. Note error in “AA offspring” footer !
  • 6.  
  • 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-child First ½
    • Siblings First ½
    • Uncle-niece Second ¼
    • First cousins Third 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
  • 14.  
  • 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. Migration and gene flow
    • 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
  • 24.  
  • 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
      • IDDM 10-15
      • 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
  • 37.  
  • 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
  • 39.  
  • 40.  
  • 41. Affected Sib Pair

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