Linkage Disequilibrium (Gametic Disequilibrium)

Linkage - physical proximity of 2 genes in an individual

Linkage disequilibrium - non-random association of alleles at different loci in a population

Synteny - two loci that are on the same chromosome

Haplotype - the specific combination of alleles at different loci

Need to consider 2 or more loci simultaneously

  • the effective number of loci being examined will be the same as the actual number only if they are in linkage equilibrium i.e. they segregate independently of each other during meiosis

  • with data from multiple loci, we must test for linkage disequilibrium to make sure our loci are truly independent

  • consideration of multilocus genotypes especially important with genomic data (markers may not be independent)

  • In large randomly breeding pops at equilibrium, alleles at diff loci are expected to be randomly associated: this is linkage equilibrium

  • ex. 2 autosomal loci simultaneously under HWE assumptions

    • if the loci are on different chromosomes, they’re unlinked

    • heterozygotes at both loci will produce all four types of gametes in equal frequencies

    • if the loci are on the same chromosome but distant enough for recombination to occur, there will be equal frequencies of all 4 types of gametes, and they will be unlinked

    • if two loci are close together on the same chromosome, they are usually linked, so that the frequency of the parental gamete types, AB and ab, will be greater than the non-parently gametes: r < 0.5

  • We use gametic frequencies to describe non-random associations among alleles at different loci

  • D is used to estimate deviation from random association of alleles at 2 loci

  • D’ is a standardized value (0-1): otherwise, the range of values is dependent on the allele frequencies

  • D or D’ are coefficients of gametic disequilibrium

  • if D’ is 0 then the pop is in linkage equilibrium

  • if D’ > 0 the you have linkage disequilibrium

  • D = (G1G4) - (G2G3) where G1 is AB; G2 is Ab; G3 is aB; G4 is ab

    • if a pop is a 50:50 mix of Ab and ab gametes

    • G1 = 0.5

    • G2 - 0

    • G3=0

    • G4=0.5

    • then D = (0.5)(0.5)-(0)(0)=0.25 = linkage disequilibrium

  • The amount of linkage disequilibrium (value of D) will decay from gen to gen as a function of the recombination rate, r

Causes of non-random associations among loci

  • Physical proximity

  • Genetic drift

  • Natural selection

  • Population subdivision

  • Recent mixing of different pops (admixture/hybridization)

can be leverages to estimate Ne, the extent of natural selection, pop subdivision, and admixture

can be used to map genes on chromosomes: linkage mapping

Genetic drift and Ne

  • as Ne decreases within a pop, there will be relatively few parents contributing genes to the next gen

  • genetic drift will act on this small gene pool to increase the likelihood of non-random associations of alleles among different loci (increase the likelihood of linkage disequilibrium)

  • LD will be common in threatened species bc they have small pop sizes and/or have experienced bottlenecks

  • use the magnitude of LD to estimate Ne with a single sample

    • assumes mating is random and LD has arisen from drift, not immigration, overlapping gens, or admixture

Natural Selectrion

  • genetic hitchhiking: increase in freq of a neutral or weakly selected mutation due to linkage with a positively selected mutation

  • Directional selection

    • if b is a new favored mutation, its selected advantage may carry either the A or a allele at a linked locus, depending on which allele is initially linked

    • Selective sweep: rapid increase in freq by natural selection of an initially rare allele that also fixes (or nearly fixes) alleles at closely linked loci and thus reduces genetic variation in a region of a chromosome

    • neutral alleles that are linked to alleles under selection will appear non-neutral

Pop Subdivision

  • will generate non-random associations of alleles among multiple loci (LD) if the allele freqs differ among subpops at these loci

  • this is an extension, from 1 to 2 loci, of the Wahlund Principle: the excess of homozygotes caused by pop subdivision

    • loci that are not in LD within each pop appear linked when considered jointly across pop

    • can detect genetic subpops by looking at LD among many pairs of loci

Recent Mixing of Different Pops (Admixture/Hybridization)

  • admixture between pops, subspecies, or species will result in LD

  • the F1 hybrid will be heterozygoes for all loci at which the two parental groups are fixed for different alleles. the gametes produced by the F1 hybrids will depend on how tightly linked the 2 loci are:

    • if unlinked, then all 4 gametes will be produced and D will decrease by half with each gen

    • if loci are linked, D will decay at a rate slower than ½ per gen

Linkage mapping

  • prereq to QTL analysis bc it provides info about the number, location, and interaction btwn diff QTL

  • Uses the recombination rate: when loci are on diff chromosomes or are far apart on the same chromosome they will assort independently

  • if two loci are close together on the same chromosome, crossing over is less likely and they will have a low recombination rate

  • we can estimate r by crossing parents with two differently allele combinations and quantifying the number of recombinants in their offspring

  • 1% recombinant offspring = one map unit or 1 centimorgan (cM)

  • fewer the number of recombinants, the closer together the loci