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Population substructure

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  • Common for Asian patients to be rapid acetylators. isoniazid (anti-TB) sulfonamides (antibacterial) procainamide (antiarrhythmic) hydralzaine (antihypertensive)
  • Transcript

    • 1. Population substructure
      • Most organisms do not occupy a continuous range in time and space
    • 2. Toads and roads
      • Panmictic
      • A=a=p=q=0.5 initially
      • What will happen to the frequency of A and a, assuming that both alleles are neutral and the toad population is finite?
    • 3. Toads and roads
      • Panmixia within each subpopulation
      • A=a=p=q=0.5 initially in all subpopulations
      • What will happen to the frequency of A and a, assuming that both alleles are neutral and each toad subpopulation is finite?
    • 4. Toads and roads Subpopulations can diverge in allele frequencies even if there is random mating within each subpopulation . This population differentiation is due to random genetic drift. The result of population subdivision is reduced heterozygosity and deviation from HWE among subpopulations .
    • 5. Wright’s Fixation Index ( F ST ) Sewall Wright 1889-1988
    • 6. Hierarchical F statistics
      • I = individual
      • S = subpopulation
      • T = total population (assumed panmictic)
      • F IS can be thought of as:
      • F
      • Proportional loss of heterozygosity due to recent common ancestry
      • F ST can be thought of as:
      • Proportional loss of heterozygosity due to population subdivision and subsequent random genetic drift
      • Proportion of total genetic variance found among populations rather than within them
      • F IT can be thought of as:
      • Proportional loss of heterozygosity due to recent common ancestry and population substructure
    • 7. Hierarchical F statistics
      • H I = observed heterozygosity (usually with molecular markers) averaged among individuals within a subpopulation
      • H S = expected (HWE) heterozygosity for each subpopulation, averaged across all subpopulations (2pq)
      • H T = expected (HWE) total heterozygosity based on allele frequency and without reference to any population substructure (2pq)
      • F IS = (H S -H I )/H S
      • F ST = (H T -H S )/H T
      • F IT = (H T -H I )/H T
      • AA: p 2 + pq F ST
      • Aa: 2pq – 2pq F ST
      • aa: q 2 + pq F ST
    • 8. Hierarchical F statistics
      • According to Sewall Wright:
      • F ST ranges from 0-1
      • 0 = no genetic differentiation; panmixia
      • 0.00–0.05 = little genetic diff
      • 0.05-0.15 = moderate genetic diff
      • 0.15-0.25 = great genetic diff
      • 0.25-1.00 = very great genetic diff
      • 1 = complete genetic differentiation
      From Hamrick and Godt (1989) 134 124 11 60 78 N 0.099 Outcrossing (wind) 0.197 Outcrossing (animal) 0.100 Mixed (wind) 0.216 Mixed (animal) 0.510 Selfing F ST Plant mating system
    • 9. Hierarchical F statistics
      • According to Sewall Wright:
      • F ST ranges from 0-1
      • 0 = no genetic differentiation; panmixia
      • 0.00–0.05 = little genetic diff
      • 0.05-0.15 = moderate genetic diff
      • 0.15-0.25 = great genetic diff
      • 0.25-1.00 = very great genetic diff
      • 1 = complete genetic differentiation
      From Hartl & Clark, Principles of Population Genetics 0.076 Horseshoe crab 0.109 Drosophila equinoxialis 0.676 Jumping rodent 0.113 House mouse 0.077 Yanomamo villages 0.069 Human ‘races’ F ST Organism
    • 10.
      • Drugs metabolized by N-acetyltransferase
        • Nydrazid (anti-TB)
        • Sulfonamides (antibiotic)
        • Procanbid (antiarrhythmic)
        • Hydralzaine (antihypertensive)
        • Caffeine
      Price Evans DA. N-acetyltransferase in pharmacogenetics of drug metabolism. In Kalow W, ed. Pharmacogenetics of drug metabolism. International encyclopedia of pharmacology and therapeutics. New York: Pergamon Press, 1992: 43:95-178. From Anne Chung www.apamsa.org/files/APAMSA%20presentation-general.ppt
    • 11. Racial differences in human populations
      • Why is this observation interesting to evolutionary biologists?
      • Why is this observation interesting to physicians and drug companies?
      • Why is this observation interesting (and contentious) to society?
      • What evolutionary and non-evolutionary mechanisms could explain this observation?
    • 12. American Anthropological Association (Am Anthropol 1998; 100: 712-713)
      • It has become clear that human populations are not unambiguous, clearly demarcated, biologically distinct groups. . . . Throughout history whenever different groups have come into contact, they have interbred. The continued sharing of genetic materials has maintained humankind as a single species. . . . Any attempt to establish lines of division among biological populations is both arbitrary and subjective.
    • 13. Does “race” have biological meaning?
      • Is shared skin color a good surrogate for shared ancestry?
      • How could shared ancestry in human populations be determined?
    • 14. How could shared ancestry in human populations be determined?
      • Is shared skin color a good surrogate for shared ancestry?
      • Can the genetic distance tree above be reconciled with the statement from the AAA?
      • Should human population structure be considered during drug development/testing?
      • What evolutionary and non-evolutionary mechanisms could explain variation in drug response among human populations?
    • 15. Migration and F ST
      • At equilibrium, F ST = 1/(4 N m + 1)
      • What is N m, in biological terms?
      • What effect does migration have on population differentiation due to genetic drift?

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