1. Lecture 23: Causes and Consequences of Linkage Disequilibrium November 16, 2012

2. Last Time uSignatures of selection based on synonymous and nonsynonymous substitutions uMultiple loci and independent segregation uEstimating linkage disequilibrium

3. Today uRecombination and LD uDrift and LD uMutation and LD uSelection and LD  Hitchhiking and selective sweeps

4. Effects of recombination rate on LD uDecline in LD over time with different theoretical recombination rates (c) uEven with independent segregation (c=0.5), multiple generations required to break up allelic associations Where t is time (in generations) and e is base of natural log ( 2.718)

5. LD varies substantially across human genome NATURE|Vol 437|27 October 2005 Average r 2 for pairs of SNP separated by 30 kb in 1 Mb windows uLD affected by location relative to telomeres and centromeres, chromosome length, GC content, sequence polymorphism, and repeat composition uHighest and lowest levels of LD found in gene-rich regions

6. Human HapMap Project and Whole Genome Scans uLD structure of human Chromosome 19 (www.hapmap.org)www.hapmap.org  1 common SNP genotyped every 700 bp for 270 individuals (3.4 million SNP)  9.2 million SNP in total NATURE|Vol 437|27 October 2005

7. LD in the Poplar Genome 5 3 1 1 3 2 2 4 1 2 uLD declines rapidly with distance uLD higher in genes than in genome as a whole uLoci separated by kilobases still in LD!

8. Recombination Across Poplar Chromosomes uSubstantial variation in recombination rate uRelated to repeat composition, methylation, and distance from centromere

9. Recombination rate varies among individuals uRate is often higher in females than males uRate varies among individuals within males and females Variation in recombination rate in the MHC region (3.3 Mb in human sperm donors

10. Genetic Drift and LD uBegin with highly diverse haplotype pool uDrift leads to chance increase of certain haplotypes uGenerates nonrandom association between alleles at different loci (LD)

11. Genetic Drift and LD Why doesn’t recombination reduce LD in this situation?

12. Expected Gamete Frequencies: Double Homozygote A1A1 B1B1 A1A1 B1B1 NonRecombinant Recombinant NonRecombinant A1A1 B1B1 A1A1 B1B1 A1A1 B1B1 Meiosis A1A1 B1B1

13. Expected Gamete Frequencies: Double Heterozygote A2A2 A1A1 B1B1 B2B2 A1A1 B1B1 Meiosis A2A2 B2B2 A1A1 B2B2 A2A2 B1B1 NonRecombinant Recombinant NonRecombinant

14. LD is partially a function of recombination rate uExpected proportions of gametes produced by various genotypes over two generations Where c is the recombination rate and D 0 is the initial amount of LD Double heterozygote is only case where recombination matters

15. Effect of Drift on LD uDrift and recombination will have opposing effects on LD Where r 2 is the squared correlation coefficient for alleles at two loci, N e is effective population size, and c is recombination rate u4Nec is “population recombination rate”, uExpression approaches 0 for large populations or high recombination rates

16. Combined effects of Drift and Recombination uLD declines as a function of population recombination rate (N e r in this figure, same as N e c) uEffects of chance fluctuation of gamete frequencies

17. How should inbreeding affect linkage disequilibrium?

19. Mutation and LD: High mutation rates uAllelic associations are masked by high mutation rates, so LD is decreased Gamete Pool with Low MutationGamete Pool with High Mutation

20. LD and neutral markers uLow LD is the EXPECTED condition unless other factors are acting uIf 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) uCare must be taken in drawing conclusions about selection based on population structure derived from neutral markers

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

22. Epistasis and LD uBegin with highly diverse haplotype pool uDirectional selection leads to increase of certain haplotype combinations uGenerates nonrandom association between alleles at different loci (LD)

23. Recombination vs Polymorphism in Poplar Nucleotide diversity (π) is positively correlated with population recombination rate (4N e c) (R 2 =0.38)

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

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

26. Selection and LD uSelection affects target loci as well as loci in LD uHitchhiking: neutral alleles increase in frequency because of selective advantage of allele at another locus in LD uSelective Sweep: selectively advantageous allele increases in frequency and changes frequency of variants in LD uBackground Selection: selection against detrimental mutants also removes alleles at neutral loci in LD uHill-Robertson Effect: directional selection at one locus affects outcome of selection at another locus in LD

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

28. Selective Sweep uPositive selection leads to increase of a particular allele, and all linked loci uResults in enhanced LD in region of selected polymorphism uAccentuated in rapidly expanding population

29. 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 ACACAA A C chimpAfricansEuropeans

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

31. Some factors that affect LD FactorEffect Recombination rateHigher recombination lowers LD Genetic DriftIncreases LD InbreedingIncreases LD Mutation rateHigh mutation rate decreases overall LD EpistasisIncreases LD SelectionLocally increased LD