Department of Biology, Stanford University, Stanford, CA 94305, USA.
Proc Natl Acad Sci U S A. 2013 May 21;110(21):8615-20. doi: 10.1073/pnas.1220835110. Epub 2013 May 6.
Population genomic studies have shown that genetic draft and background selection can profoundly affect the genome-wide patterns of molecular variation. We performed forward simulations under realistic gene-structure and selection scenarios to investigate whether such linkage effects impinge on the ability of the McDonald-Kreitman (MK) test to infer the rate of positive selection (α) from polymorphism and divergence data. We find that in the presence of slightly deleterious mutations, MK estimates of α severely underestimate the true rate of adaptation even if all polymorphisms with population frequencies under 50% are excluded. Furthermore, already under intermediate rates of adaptation, genetic draft substantially distorts the site frequency spectra at neutral and functional sites from the expectations under mutation-selection-drift balance. MK-type approaches that first infer demography from synonymous sites and then use the inferred demography to correct the estimation of α obtain almost the correct α in our simulations. However, these approaches typically infer a severe past population expansion although there was no such expansion in the simulations, casting doubt on the accuracy of methods that infer demography from synonymous polymorphism data. We propose a simple asymptotic extension of the MK test that yields accurate estimates of α in our simulations and should provide a fruitful direction for future studies.
群体基因组研究表明，遗传漂变和背景选择可以深刻影响分子变异的全基因组模式。我们在现实的基因结构和选择情景下进行了正向模拟，以研究这种连锁效应对麦克唐纳-克里坦（MK）检验从多态性和分歧数据推断正选择率（α）的能力是否有影响。我们发现，即使排除所有频率低于 50%的多态性，在存在轻微有害突变的情况下，MK 对α的估计严重低估了真正的适应速率。此外，即使在适应率中等的情况下，遗传漂变也会使中性和功能位点的座位频率谱从突变-选择-漂变平衡的预期中发生严重扭曲。MK 型方法首先从同义位点推断种群动态，然后用推断出的种群动态来校正对α的估计，在我们的模拟中几乎得到了正确的α。然而，这些方法通常推断出过去存在严重的种群扩张，尽管在模拟中没有这种扩张，这使得从同义多态性数据推断种群动态的方法的准确性受到质疑。我们提出了一种简单的 MK 检验的渐近扩展，在我们的模拟中得到了准确的α估计，这应该为未来的研究提供一个有成果的方向。
