Most rare missense alleles are deleterious in humans: Implications for complex disease and association studies
Most rare missense alleles are deleterious in humans: Implications for complex disease and association studies
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DOI：
10.1086/513473
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发表时间：
2007-04-01
影响因子：
9.8
通讯作者：
Sunyaev, Shamil R.
中科院分区：
文献类型：
--
作者：
Kryukov, Gregory V.;Pennacchio, Len A.;Sunyaev, Shamil R.
人类基因组中轻度有害错义突变的积累被认为是复杂疾病的遗传基础。这一假设的合理性取决于对人类中轻度有害的新生突变和多态性变体的流行率的定量估计，以及对它们的选择压力的强度。我们结合了对导致人类孟德尔疾病的突变、人类-黑猩猩分歧和人类遗传变异的系统数据的分析，发现人类中大约20%的新错义突变导致功能丧失，而大约27%的突变是有效的中性突变。因此，剩下的53%的新错义突变具有轻微的有害影响。这些突变在人群中产生了许多低频率的有害等位基因变异，这从11，500个人类染色体中测序的37个基因的新数据集中可以看出。令人惊讶的是，高达70%的低频错义等位基因是轻度有害的，并且与0.001-0.003范围内的杂合适合度损失相关。因此，氨基酸变体的低等位基因频率本身就可以作为其功能意义的预测因子。最近的几项研究报告了一个显着过量的罕见的错义变异的候选基因或途径的个体与极端值的数量表型。如果大多数罕见变异是中性的，或者如果罕见变异对表型遗传的遗传成分没有显著贡献，则这些研究不太可能产生结果。我们的研究结果为这些类型的候选基因（通路）关联研究提供了理由，并暗示突变选择平衡可能是一些常见疾病的潜在进化机制。
The accumulation of mildly deleterious missense mutations in individual human genomes has been proposed to be a genetic basis for complex diseases. The plausibility of this hypothesis depends on quantitative estimates of the prevalence of mildly deleterious de novo mutations and polymorphic variants in humans and on the intensity of selective pressure against them. We combined analysis of mutations causing human Mendelian diseases, of human-chimpanzee divergence, and of systematic data on human genetic variation and found that similar to 20% of new missense mutations in humans result in a loss of function, whereas similar to 27% are effectively neutral. Thus, the remaining 53% of new missense mutations have mildly deleterious effects. These mutations give rise to many low-frequency deleterious allelic variants in the human population, as is evident from a new data set of 37 genes sequenced in 11,500 individual human chromosomes. Surprisingly, up to 70% of low-frequency missense alleles are mildly deleterious and are associated with a heterozygous fitness loss in the range 0.001-0.003. Thus, the low allele frequency of an amino acid variant can, by itself, serve as a predictor of its functional significance. Several recent studies have reported a significant excess of rare missense variants in candidate genes or pathways in individuals with extreme values of quantitative phenotypes. These studies would be unlikely to yield results if most rare variants were neutral or if rare variants were not a significant contributor to the genetic component of phenotypic inheritance. Our results provide a justification for these types of candidate-gene (pathway) association studies and imply that mutation-selection balance may be a feasible evolutionary mechanism underlying some common diseases.