Genetic Epidemiology and Bioinformatics, Faculty of Medicine, University of Southampton, Duthie Building (808), Tremona Road, Southampton, SO16 6YD, UK.
Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
Heredity (Edinb). 2019 Dec;123(6):774-783. doi: 10.1038/s41437-019-0272-5. Epub 2019 Oct 1.
Purifying selection tends to reduce nucleotide and haplotype diversity leading to increased linkage disequilibrium. However, detection of evidence for selection is difficult as the signature is confounded by wide variation in the recombination rate which has a complex relationship with selection. The effective bottleneck time (the ratio of the linkage disequilibrium map to the genetic map in Morgans) controls for variability in the recombination rate. Reduced effective bottleneck times indicate stronger residual linkage disequilibrium, consistent with increased selection. Using whole genome sequence data from one European and three Sub-Saharan African human populations we find, in the African samples, strong correlations between high gene densities and reduced effective bottleneck time for autosomal chromosomes. This suggests that gene-dense autosomes have been subject to increased purifying selection reducing effective bottleneck times compared to gene-poor autosomes. Although previous studies have shown unusually strong linkage disequilibrium for the sex chromosomes variation within the autosomes has not been recognised. The strongest relationship is between effective bottleneck time and the density of essential genes, which are likely targets of greater selective pressure (p = 0.006, for the 22 autosomes). The magnitude of the reduction in chromosome-specific effective bottleneck times from the least to the most gene-dense autosomes is ~17-21% for Sub-Saharan African populations. The effect size is greater in Sub-Saharan African populations, compared to a European sample, consistent with increased efficiency of selection in populations with larger effective population sizes which have not been subject to intense population bottlenecks as experienced by populations of European ancestry. The findings highlight the value of deeper analyses of selection within Sub-Saharan African populations.
纯化选择往往会降低核苷酸和单倍型多样性，导致连锁不平衡增加。然而，由于重组率的广泛变化与选择有复杂的关系，选择的特征受到混淆，因此很难检测到选择的证据。有效瓶颈时间（连锁不平衡图谱与摩尔根遗传图谱的比值）控制着重组率的可变性。有效瓶颈时间减少表明残余连锁不平衡更强，与选择增强一致。利用来自一个欧洲人和三个撒哈拉以南非洲人类群体的全基因组序列数据，我们发现，在非洲样本中，高基因密度与常染色体的有效瓶颈时间减少之间存在强烈的相关性。这表明，与基因稀少的常染色体相比，基因密集的常染色体受到了更强的净化选择，从而降低了有效瓶颈时间。尽管先前的研究表明性染色体的连锁不平衡异常强烈，但常染色体内部的变异尚未得到承认。最强的关系是有效瓶颈时间与必需基因密度之间的关系，必需基因很可能是更大选择性压力的目标（22 条常染色体中，p=0.006）。从基因密度最低到最高的常染色体，特定染色体的有效瓶颈时间减少幅度约为 17-21%，在撒哈拉以南非洲人群中。与欧洲样本相比，撒哈拉以南非洲人群的效应大小更大，这与更大的有效种群大小的选择效率更高一致，这些人群没有经历过欧洲血统人群所经历的强烈人口瓶颈。这些发现强调了对撒哈拉以南非洲人群内部选择进行更深入分析的价值。
