1 / 26

Population Genetics: Chapter 3

Population Genetics: Chapter 3. Epidemiology 217 January 16, 2011. Outline. Allele Frequency Estimation Hardy-Weinberg equilibrium (HWE) HWE Game Population Substructure. Allele Frequency. Diploid, autosomal locus with 2 alleles: A and a Allele frequency is the fraction:.

Download Presentation

Population Genetics: Chapter 3

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Population Genetics: Chapter 3 Epidemiology 217January 16, 2011

  2. Outline • Allele Frequency Estimation • Hardy-Weinberg equilibrium (HWE) • HWE Game • Population Substructure

  3. Allele Frequency • Diploid, autosomal locus with 2 alleles: A and a • Allele frequency is the fraction: No. of particular allele No. of all alleles in population

  4. Allele (Gamete) Frequency • Let p = Freq(A) frequency of the dominant allele • Let q = Freq(a) frequency of the recessive allele Then, p + q =1

  5. Genotype Frequency • p2 = frequency of homozygous dominant genotype • q2 = frequency of homozygous recessive genotype • 2pq = frequency of heterozygous genotype Then, p2 +2pq + q2 =1

  6. Estimating Allele Frequencies from Genotype Frequencies Genotypes: AA Aa aa Frequency: p2 2pq q2 • Frequency of A allele = p2 + ½ (2pq) • Frequency of a allele = q2 + ½ (2pq)

  7. Ex. Calculation: Allele Frequencies Assume N=200 in each of two populations • Pop 1: 90 AA 40 Aa 70 aa (N=200) • Pop 2: 45 AA 130Aa 25 aa (N=200) In Pop 1: • p = 90/200 + ½ (40/200) = 0.45 + 0.10 = 0.55 • q = 70/200 + ½ (40/200) = 0.35 + 0.10 = 0.45 In Pop 2: • p = 45/200 + ½ (130/200) = 0.225 + 0.325 = 0.55 • q = 25/200 + ½ (130/200) = 0.125 + 0.325 = 0.45

  8. Take home points • p + q =1 (sum of the allele frequencies = 1) • p2 + 2pq + q2 =1 (sum of the genotype frequencies = 1) • Two populations with markedly different genotype frequencies can have the same allele frequencies

  9. Hardy-Weinberg The Hardy–Weinberg principle states that both allele and genotype frequencies in a population remain constant—that is, they are in equilibrium—from generation to generation unless specific disturbing influences are introduced p2 + 2pq + q2 = 1

  10. Hardy-Weinberg Assumptions • Allele frequencies do not vary IF: • Large population • Random mating • No in or out migration • No isolated groups within the population • No mutation • No selection (no allele is advantageous)

  11. Test of Hardy-Weinberg Equilibrium 1. Calculate observed allele & genotype frequencies 100 GG 30 AG 20 AA Genotype frequencies GG = 100/150 = 0.67 AG =30/150 = 0.20 AA = 20/150 = 0.13 Allele frequencies G alleles = 100*2 + 30 = 230 A alleles =20*2 + 30 = 70 Total alleles = 300 G afq (p) = 230/300 = 0.71 A afq (q) = 1-p = 0.23

  12. Test of Hardy-Weinberg Equilibrium 2. Calculate expected genotype frequencies based on HW: p2 + 2pq + q2 = 1 p2 (GG) = 0.77 * 0.77 = 0.59 2pq (AG) = 2 * 0.77 * 0.23 = 0.35 q2 (AA) = 0.23 * 0.23 = 0.05

  13. Test of Hardy-Weinberg Equilibrium 3. Compare expected genotype frequencies to observed frequencies Chi-square test = Σ(observed – expected)2/expected = 29.17 with 1 degree of freedom p = 6.6 x 10-8 > Out of H-W

  14. HWE can be easily expanded to account for any number of alleles at a locus • 3 allele case (p1, p2, p3) Allele frequencies: p1 + p2 + p3 = 1 Genotype frequencies: p12 + p22 + p32 + 2p1p2 + 2p1p3 + 2p2p3= 1 • 4 allele case (p1, p2, p3, p4) Allele frequencies: p1 + p2 + p3 + p4= 1 Genotype frequencies: p12 + p22 + p32 + p42 + 2p1p2 + 2p1p3 + 2p2p3 + 2p3p4= 1

  15. Application of Hardy-Weinberg Equilibrium • For genetic association studies: • Used as QC measure to assess the accuracy of the genotyping method • Expect SNPs to be in HWE among control populations (ethnic-specific) • Violations of HWE could indicate genotyping errors or bias in data

  16. HWE Game • Everyone receives ~5 pairs of cards • Two allele model: Red (R allele) & Black (B allele) • Random Mating: Exchange one card from each pair with another person (keep cards face down) • Determine genotype frequency: RR, RB, BB • Determine allele frequency: R, B

  17. Population Stratification Population stratification is a form of confounding in genetic studies where a gene under study shows marked variation in allele frequency across subgroups of a population and these subgroups differ in their baseline risk of disease

  18. Population Stratification: Confounding Exposure of Interest True Risk Factor Disease Genotype of Interest Ethnicity True Risk Factor Disease Wacholder, JNCI, 2000

  19. Population Stratification: Gm3;5,13,14 in admixed sample of Native Americans of the Pima and Papago tribes Study Population: 4,290 Pima and Papago Indians Genetic Variant: Gm 3;5,13, 15 haplotype (Gm system of human immunoglobulin G) Outcome: Type 2 diabetes Question: Is the Gm 3; 5,13, 15 haplotype associated with Type 2 diabetes? Knowler, AJHG, 1998

  20. Population Stratification: Gm3;5,13,14 in admixed sample of Native Americans of the Pima and Papago tribes Unadjusted for ethnic background OR = 0.27 (95% 0.18-0.40)

  21. Population Stratification: Gm3;5,13,14 in admixed sample of Native Americans of the Pima and Papago tribes Adjusted for ethnic background OR = 0.83 (95% 0.58-1.18)

  22. Ancestry Informative Markers • Polymorphisms with known allele frequency differences across ancestral groups • Useful in estimating ancestry in admixed individuals • Example: Duffy locus (codes for blood group) • 100% sub-Saharan Africans vs. other groups • protects P. vivax (malaria)

  23. Example AIM: Duffy locus http://www.ncbi.nlm.nih.gov/projects/SNP

  24. Population Inbreeding Population inbreeding occurs when there is a preference of mating between close relatives or because of geographic isolation in a population. This will cause deviations in HWE by causing a deficit of heterozygotes.

  25. How to quantify the amount of inbreeding in a population? • Inbreeding coefficient, F • The probability that a random individual in the population inherits two copies of the same allele from a common ancestor • F ranges 0 to 1: F is low in random mating populations F close to 1 in self-breeding population (plants)

  26. Kinship & Reproduction: Icelandic couples # of children # of children that reproduce # of grandchildren mean lifespan of children Helgason, Science, 2008

More Related