Lecture 19: Causes and Consequences of Linkage Disequilibrium

March 21, 2014

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

Last Time

Multiple loci and independent segregation

Estimating linkage disequilibrium

Effects of drift on LD

Today

Effects of inbreeding, population structure, mutation, and selection on LD

LD calculation: effects of admixture

Selective sweeps and LD

How should inbreeding affect linkage disequilibrium?

Joint effects of selfing and recombination on LD

tt DSSS

D

2

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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

For c=0.5:Where S is selfing rate andλ = 1-2c (scales recombination effect from 0 to 1, just like selfing)

Population admixture and LD If differentiated populations mix, nonrandom allelic associations

result

Hybridization of different species fixed for different alleles at two loci:

What is D’ in this case?

A1 B1A2 B2

If D is positive, Dmax is lesser of p1q2 or p2q1

If D is negative, Dmax is lesser of p1q1 or p2q2

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

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E1

A2

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A1

B1

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A2

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E1

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Mutation and LD: High mutation ratesAllelic associations are masked by high mutation rates, so LD is decreased

Gamete Pool with Low Mutation Gamete Pool with High Mutation

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

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

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?

),min( 1221max qpqpD for D > 0

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)

Recombination vs Polymorphism in Poplar

Nucleotide diversity (π) is positively correlated with population recombination rate (4Nec)

(R2=0.38)

LG VII

Position (Mb)

0 2 4 6 8 10 12 14

Rat

e

0.000

0.001

0.002

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4Nec

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 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

http://medinfo.ufl.edu/

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

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

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 AA

A C

chimp Africans Europeans

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

Voight et al. 2006 Plos Biology 4: 446-458

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