Lecture 19: Causes and Consequences of Linkage Disequilibrium

1. Lecture 19: Causes and Consequences of Linkage Disequilibrium March 21, 2014

2. Exam 2 • Wednesday, March 26 at 6:30 in lab • Genetic Drift, Population Structure, Population Assignment, Individual Identity, Paternity Analysis, and Linkage Disequilibrium • Sample exam posted on website • Review on Monday, March 24

3. Last Time • Multiple loci and independent segregation • Estimating linkage disequilibrium • Effects of drift on LD

4. Today • Effects of inbreeding, population structure, mutation, and selection on LD • LD calculation: effects of admixture • Selective sweeps and LD

5. How should inbreeding affect linkage disequilibrium?

7. For c=0.5: Joint effects of selfing and recombination on LD • High levels of inbreeding cause associations even between unlinked loci (c=0.5) • LD can be predicted as a function of selfing rate and recombination rate Where S is selfing rate andλ = 1-2c (scales recombination effect from 0 to 1, just like selfing)

8. Population admixture and LD • If differentiated populations mix, nonrandom allelic associations result • Hybridization of different species fixed for different alleles at two loci: A1 A2 B2 B1 What is D’ in this case? If D is positive, Dmax is lesser of p1q2 or p2q1 If D is negative, Dmax is lesser of p1q1 or p2q2

9. A2 A1 A1 A2 A1 A1 A2 A2 A2 A1 B1 B1 B2 B2 B2 B1 B2 B1 B1 B2 C2 C2 C1 C2 C1 C1 C1 C1 C2 C1 D1 D1 D2 D1 D2 D1 D1 D2 D1 D2 E1 E2 E2 E2 E1 E2 E1 E1 E2 E1 Historical population admixture and LD Two populations with fixed allelic differences (e.g., different species) Recombinant gametes are undetectable: LD is low Hybrids between these will be completely heterozygous with strong allelic associations Recombinant gametes will have high LD between adjacent markers: few recombinations to break up allelic associations

10. Gamete Pool with Low Mutation Gamete Pool with High Mutation Mutation and LD: High mutation rates • Allelic associations are masked by high mutation rates, so LD is decreased

11. LD and neutral markers • Low LD is the EXPECTED condition unless other factors are acting • If LD is low, neutral markers represent very small segment of the genome in most cases • In most parts of the genome, LD declines to background levels within 1 kb in most cases (though this varies by organism and population) • Care must be taken in drawing conclusions about selection based on population structure derived from neutral markers

12. Selection and Linkage Disequilibrium (LD) • Selection can create LD between unlinked loci • Epistasis: two or more loci interact with each other nonadditively • Phenotype depends on alleles at multiple loci Change in D over time due to epistatic interactions between loci with directional selection Why does D decline after generation 15 in this scenario? D for D > 0

13. Epistasis and LD • Begin with highly diverse haplotype pool • Directional selection leads to increase of certain haplotype combinations • Generates nonrandom association between alleles at different loci (LD)

14. Recombination vs Polymorphism in Poplar Nucleotide diversity (π) is positively correlated with population recombination rate (4Nec) (R2=0.38)

15. Recombination vs Polymorphism Recombination rate varies substantially across Drosophila genome Nucleotide diversity is positively correlated with recombination rate Hartl and Clark 2007

16. Why is polymorphism reduced in areas of low recombination?(or why is polymorphism enhanced in areas of high recombination)

17. Selection and LD • Selection affects target loci as well as loci in LD • Hitchhiking: neutral alleles increase in frequency because of selective advantage of allele at another locus in LD • Selective Sweep: selectively advantageous allele increases in frequency and changes frequency of variants in LD • Background Selection: selection against detrimental mutants also removes alleles at neutral loci in LD • Hill-Robertson Effect: directional selection at one locus affects outcome of selection at another locus in LD

18. Selective Sweep in Plasmodium Pyrimethamine used to treat malaria parasite (Plasmodium falciparum) Parasite developed resistance at locus dhfr, which rapidly became fixed in population (6 years on Thai border) Microsatellite variation wiped out in vicinity of dhfr http://medinfo.ufl.edu/

19. Selective Sweep • Positive selection leads to increase of a particular allele, and all linked loci • Results in enhanced LD in region of selected polymorphism • Accentuated in rapidly expanding population

20. Derived Alleles and Selective Sweeps • Recent, incomplete selective sweeps are expected to leave a molecular signature of • High frequency of derived alleles • Strong geographic differentiation • Elevated LD A C AA AA AC chimp Africans Europeans

21. Voight et al. 2006 Plos Biology 4: 446-458 LD Provides evidence of recent selection • Regions under recent selection experience selective sweep, show high LD locally • Patterns of LD in human genome provide signature of selection • A statistic based on length of haplotypes and frequency of “derived alleles” reveals regions under selection (“iHS” statistic) • Selective sweep for lactase enzyme in Europeans after domestication of dairy cows

22. Some factors that affect LD Factor Effect Recombination rate Higher recombination lowers LD Genetic Drift Increases LD Inbreeding Increases LD Population Structure Increases LD Mutation rate High mutation rate decreases overall LD Epistasis Increases LD Selection Locally increased LD