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

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

Last Time uMultiple loci and independent segregation uEstimating linkage disequilibrium uEffects of drift on LD

Today uEffects of inbreeding, population structure, mutation, and selection on LD uLD calculation: effects of admixture uSelective sweeps and LD

How should inbreeding affect linkage disequilibrium?

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

Population admixture and LD uIf differentiated populations mix, nonrandom allelic associations result uHybridization of different species fixed for different alleles at two loci: What is D’ in this case? A1A1 B1B1 A2A2 B2B2 If D is positive, D max is lesser of p 1 q 2 or p 2 q 1 If D is negative, D max is lesser of p 1 q 1 or p 2 q 2

Historical population admixture and LD Two populations with fixed allelic differences (e.g., different species) 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 Recombinant gametes are undetectable: LD is low A1 B1 C1 D1 E1 A1 B1 C1 D1 E1 A2 B2 C2 D2 E2 A2 B2 C2 D2 E2 A1 B1 C1 D1 E1 A2 B2 C2 D2 E2 A2 B2 C1 D1 E1 A2 B2 C2 D1 E1 A1 B1 C1 D1 E2 A1 B1 C1 D2 E2

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

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

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

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)

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

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

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

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

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

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

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 ACAA A C chimpAfricansEuropeans

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 Plos Biology 4:

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