Biased gene conversion skews allele frequencies in human populations, increasing the disease burden of recessive alleles

Am J Hum Genet. 2014 Oct 2;95(4):408-20. doi: 10.1016/j.ajhg.2014.09.008.


Gene conversion results in the nonreciprocal transfer of genetic information between two recombining sequences, and there is evidence that this process is biased toward G and C alleles. However, the strength of GC-biased gene conversion (gBGC) in human populations and its effects on hereditary disease have yet to be assessed on a genomic scale. Using high-coverage whole-genome sequences of African hunter-gatherers, agricultural populations, and primate outgroups, we quantified the effects of GC-biased gene conversion on population genomic data sets. We find that genetic distances (FST and population branch statistics) are modified by gBGC. In addition, the site frequency spectrum is left-shifted when ancestral alleles are favored by gBGC and right-shifted when derived alleles are favored by gBGC. Allele frequency shifts due to gBGC mimic the effects of natural selection. As expected, these effects are strongest in high-recombination regions of the human genome. By comparing the relative rates of fixation of unbiased and biased sites, the strength of gene conversion was estimated to be on the order of Nb ≈ 0.05 to 0.09. We also find that derived alleles favored by gBGC are much more likely to be homozygous than derived alleles at unbiased SNPs (+42.2% to 62.8%). This results in a curse of the converted, whereby gBGC causes substantial increases in hereditary disease risks. Taken together, our findings reveal that GC-biased gene conversion has important population genetic and public health implications.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Bias*
  • Evolution, Molecular
  • Gene Conversion*
  • Gene Frequency
  • Genes, Recessive / genetics*
  • Genetic Diseases, Inborn / genetics*
  • Genetics, Population*
  • Genome, Human / genetics*
  • Humans
  • Models, Genetic
  • Models, Theoretical
  • Polymorphism, Single Nucleotide / genetics
  • Recombination, Genetic
  • Selection, Genetic / genetics*