Department of Biology, Stanford University, California 94305.
Department of Genetics, Stanford University, California 94305.
Genetics. 2019 Feb;211(2):757-772. doi: 10.1534/genetics.118.301833. Epub 2018 Dec 15.
Gene expression variation is a major contributor to phenotypic variation in human complex traits. Selection on complex traits may therefore be reflected in constraint on gene expression. Here, we explore the effects of stabilizing selection on -regulatory genetic variation in humans. We analyze patterns of expression variation at copy number variants and find evidence for selection against large increases in gene expression. Using allele-specific expression (ASE) data, we further show evidence of selection against smaller-effect variants. We estimate that, across all genes, singletons in a sample of 122 individuals have ∼2.2× greater effects on expression variation than the average variant across allele frequencies. Despite their increased effect size relative to common variants, we estimate that singletons in the sample studied explain, on average, only 5% of the heritability of gene expression from -regulatory variants. Finally, we show that genes depleted for loss-of-function variants are also depleted for -eQTLs and have low levels of allelic imbalance, confirming tighter constraint on the expression levels of these genes. We conclude that constraint on gene expression is present, but has relatively weak effects on most -regulatory variants, thus permitting high levels of gene-regulatory genetic variation.
基因表达的变化是人类复杂性状表型变异的主要原因。因此，对复杂性状的选择可能反映在对基因表达的约束上。在这里，我们探讨了稳定选择对人类 - 调节遗传变异的影响。我们分析了拷贝数变异的表达变异模式，并发现了对基因表达大量增加的选择证据。使用等位基因特异性表达 (ASE) 数据，我们进一步证明了对较小效应变异的选择。我们估计，在所有基因中，在 122 个人的样本中单倍体对表达变异的影响比等位基因频率下平均变异大约 2.2 倍。尽管它们相对于常见变异的效应大小增加了，但我们估计，在研究中样本中单倍体仅解释了 - 调节变异基因表达的遗传力的 5%。最后，我们表明，功能丧失变异体耗尽的基因也缺乏 -eQTL ，并且等位基因不平衡程度较低，这证实了这些基因的表达水平受到更严格的约束。我们的结论是，基因表达的约束是存在的，但对大多数 - 调节变异的影响相对较弱，从而允许高水平的基因调控遗传变异。
