The mutational constraint spectrum quantified from variation in 141,456 humans.
The mutational constraint spectrum quantified from variation in 141,456 humans.
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DOI：
10.1038/s41586-020-2308-7
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发表时间：
2020-05-01
期刊：
影响因子：
64.8
通讯作者：
MacArthur, Daniel G
中科院分区：
文献类型：
--
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
遗传变异的蛋白质编码基因是一个强大的信息来源的表型基因破坏的后果：基因的功能是至关重要的生物体将耗尽这些变异在自然种群，而非必需基因将容忍他们的积累。然而，预测的功能丧失变体因注释错误而丰富，并且往往以极低的频率发现，因此它们的分析需要仔细的变体注释和非常大的样本量1。在这里，我们描述了来自人类测序研究的125，748个外显子组和15，708个基因组聚合到基因组聚合数据库（gnomAD）中。在过滤了由测序和注释错误引起的伪影后，我们在该队列中确定了443，769个高置信度预测的功能丧失变体。使用改进的人类突变率模型，我们将人类蛋白质编码基因沿着代表对失活的耐受性的谱进行分类，使用来自模型生物和工程化人类细胞的数据验证这种分类，并表明它可用于提高常见和罕见疾病的基因发现能力。
Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes1. Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases.