balancing selection

Andrés AM, Hubisz MJ, Indap A, Torgerson DG, Degenhardt JD, Boyko AR, Gutenkunst RN, White TJ, Green ED, Bustamante CD, Clark AG, Nielsen R 2009 Targets of balancing selection in the human genome. Mol Biol Evol 26:2755-2764.

  • current biological understanding of balancing selection is mostly limited to a few loci localized by candidate gene approaches
  • this is mainly due to the difficulties associated with the detection of this type of selection at a whole-genome level
  • the genomic signal of recent balancing selection (extended linkage disequilibrium [LD]) is detectable by LD-based methods
  • it is indistinguishable from incomplete sweeps of positive selection
  • the signal of long-term balancing selection is specific (excess of polymorphism) but narrow due to the long-term effects of recombination
  • previous efforts have failed to detect convincing targets in the human genome (Asthana et al. 2005; Bubb et al. 2006)
  • we find a small but strongly supported set of genes with signatures of selection
  • providing an unbiased catalog of candidate targets of balancing selection in the human genome
  • the choice of an adequate null model is crucial for detection of selection because some demographic scenarios can mimic the effects of selection on diversity
  • we applied a method designed to minimize the effects of demography in neutrality tests (Nielsen et al. 2009)
  • the method uses the complete data set to estimate parameters of the past demographic history that best fit the data and considers such estimates as the null (neutral) demographic model against which neutrality is tested
  • because linkage phase of haplotypes in this data is unknown, LD was measured by the composite LD (Weir 1996), which does not require phase information and avoids introducing uncertainty during haplotype inference
  • we detect 60 genes with significant signatures of long-term balancing selection (table 1) as shown by their excess of polymorphism (significant HKAlow test) and excess of intermediate-frequency alleles (significant MWUhigh test)
  • the average ratio of counts of polymorphic to divergent sites in nonextreme genes is 0.6, whereas the ratio is 1.9 for extreme genes in both populations
  • historically proposed targets of balancing selection are either cases of recent selection (β-globin, CFTR, G6PD) − not targeted or detected by our method − or genes (like ABO) that show incomplete signatures of selection according to our strict criterion
  • an excess of heterozygotes (one of the signatures of present-day overdominance) has been reported for olfactory receptors (Alonso et al. 2008)
  • we find no evidence of increased selection in this functional category
  • Asthana et al. (2005) reported that transspecific polymorphism between humans and chimpanzees is rare
  • suggesting a limited role of long-term balancing selection in the two species
  • the power to detect events of transspecific polymorphism is small (Clark 1997; Wiuf et al. 2004) and still limited by the data
  • focusing on variants recovered from genomic sequence reads, Bubb et al. (2006) also failed to detect convincing targets of long-term balancing selection in humans
  • they focused on large genomic regions with high SNP density and high LD