Lachance Joseph, Tishkoff Sarah A
Departments of Biology and Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA.
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.
基因转换导致遗传信息在两个重组序列之间进行非相互转移，并且有证据表明这一过程偏向于G和C等位基因。然而，人类群体中GC偏向性基因转换（gBGC）的强度及其对遗传病的影响尚未在基因组规模上进行评估。利用非洲狩猎采集者、农业人群和灵长类外群的高覆盖全基因组序列，我们量化了GC偏向性基因转换对群体基因组数据集的影响。我们发现遗传距离（FST和群体分支统计量）会受到gBGC的影响。此外，当祖先等位基因受gBGC青睐时，位点频率谱向左偏移；当衍生等位基因受gBGC青睐时，位点频率谱向右偏移。由gBGC导致的等位基因频率变化模拟了自然选择的作用。正如预期的那样，这些影响在人类基因组的高重组区域最为强烈。通过比较无偏位点和有偏位点的相对固定率，估计基因转换强度约为Nb ≈ 0.05至0.09。我们还发现，受gBGC青睐的衍生等位基因比无偏单核苷酸多态性位点处的衍生等位基因更有可能是纯合的（增加42.2%至62.8%）。这导致了“转换之咒”，即gBGC会大幅增加遗传病风险。综上所述，我们的研究结果表明，GC偏向性基因转换具有重要的群体遗传学和公共卫生意义。
