Identification of a large set of rare complete human knockouts
Identification of a large set of rare complete human knockouts
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DOI：
10.1038/ng.3243
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发表时间：
2015-05-01
期刊：
影响因子：
30.8
通讯作者：
Stefansson, Kari
中科院分区：
文献类型：
--
作者：
Sulem, Patrick;Helgason, Hannes;Stefansson, Kari
功能丧失突变导致许多孟德尔疾病。在这里，我们的目标是创建一个常染色体基因的目录，这些基因在人类中被罕见的功能丧失突变完全敲除。我们对2，636名冰岛人的全基因组进行了测序，并将这组中确定的序列变体估算到另外101，584名芯片基因分型和分相的冰岛人中。我们在4，924个基因中发现了6，795个常染色体功能缺失SNP和indel。在基因分型的冰岛人中，7.7%是纯合子或功能丧失突变的复合杂合子，在1，171个基因中的次要等位基因频率（MAF）低于2%（完全敲除）。在大脑中高度表达的基因比其他基因更少被完全敲除。两个杂合子亲本的纯合子功能丧失后代的发生频率低于预期（MAF变异的缺陷为136/10，000传播
Loss-of-function mutations cause many mendelian diseases. Here we aimed to create a catalog of autosomal genes that are completely knocked out in humans by rare loss-of-function mutations. We sequenced the whole genomes of 2,636 Icelanders and imputed the sequence variants identified in this set into 101,584 additional chip-genotyped and phased Icelanders. We found a total of 6,795 autosomal loss-of-function SNPs and indels in 4,924 genes. Of the genotyped Icelanders, 7.7% are homozygotes or compound heterozygotes for loss-offunction mutations with a minor allele frequency (MAF) below 2% in 1,171 genes (complete knockouts). Genes that are highly expressed in the brain are less often completely knocked out than other genes. Homozygous loss-of-function offspring of two heterozygous parents occurred less frequently than expected (deficit of 136 per 10,000 transmissions for variants with MAF