Lecture 12

• Physical linkage


  Colocation of two loci on the same chromosome

  
• Linkage


  Physical linkage
• Unlinked loci


  • Recombination rate r = 0.5
  • Alleles at each locus are inherited independently due to independent assortment

  
• Linked loci


  • Alleles at tightly linked loci are likely to be inherited together because crossover is unlikely to happen between them (r ≪ 0.5)
  • Alleles at distantly linked loci are more likely to have crossovers between them and may be inherited more independently (r ≤ 0.5)

  
• Linkage equilibrium


  Genotypes at one locus are independent of genotypes at another locus

  
• Linkage disequilibrium (LD)


  Genotypes at the two loci are not independent

  
• If, and only if, two loci are in linkage equilibrium, then the frequency of B on A-bearing chromosomes equals the frequency of B on a-bearing chromosomes, and the AB haplotype frequency equals the allele frequency of A times the allele frequency of B (and for Ab, aB, and ab), and the coefficient of linkage disequilibrium (D) equals zero

  
• Coefficient of linkage disequilibrium (D)

  • D = gABgab - gAbgaB, where g are the relevant haplotype frequencies
  • D can take on values between -0.25 and +0.25
  • If D = -0.25, only Ab and aB haplotypes are present
  • If D = 0, the loci are in linkage equilibrium
  • If D = +0.25, only AB and ab haplotypes are present

  
• Calculating the coefficient of linkage disequilibrium

  • Population 1: D = 0.48*0.08 - 0.12*0.32 = 0 (loci in linkage equilibrium)
  • Population 2: D = 0.44*0.04 - 0.16*0.36 = -0.04 (loci in linkage disequilibrium)

  
• Evolution at one locus can affect another locus

  If the loci are in linkage disequilibrium
• Causes of linkage disequilibrium

  • Linkage (most important)
  • Selection on multi-locus genotypes
  • Population admixture
  • Non-random mating

  
• New mutations start in complete linkage disequilibrium with all loci on the same chromosome
• Recombination is the only mechanism that reduces linkage disequilibrium between linked loci

  
• Linkage disequilibrium blocks


  The size of LD blocks varies across the genome due to population history, recombination rate, mutation rate, and natural selection

  
• Selection on multi-locus genotypes causing linkage disequilibrium

  • Individuals with certain multi-locus genotypes have higher fitness, leading to LD in the survivors

  
• Population admixture causing linkage disequilibrium


  • Mixing of two previously isolated gene pools that were in linkage equilibrium produces a new gene pool in LD

  
• Recombination reduces linkage disequilibrium, with the rate of LD decay depending on the recombination rate (r) between loci

  
• Importance of linkage disequilibrium

  • Theoretical importance: single-locus models may make inaccurate predictions for loci in LD
  • Practical applications: genome-wide association studies, detecting selection, determining population history

  
• Genome-wide association studies (GWAS)


  Exploit LD to help locate genes associated with disease or other traits

  
• Detecting selection


  Selective sweeps and genetic hitchhiking can be identified by looking for valleys of reduced genetic diversity around a positively selected locus

  
• Estimating the age of an allele


  Genotype the gene of interest and nearby neutral loci, estimate recombination rate in the region, and use LD to infer the age of the allele