deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
Nat Genet. 2015 May;47(5):448-52. doi: 10.1038/ng.3243. Epub 2015 Mar 25.
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-of-function 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 <2%, 95% confidence interval (CI) = 10-261).
功能丧失性突变导致了许多孟德尔疾病。在这里，我们旨在创建一个目录，其中包含在人类中由罕见的功能丧失性突变完全敲除的常染色体基因。我们对 2636 名冰岛人的全基因组进行了测序，并将在该组中鉴定出的序列变体导入到 101584 名额外的芯片基因分型和相分型冰岛人中。我们在 4924 个基因中总共发现了 6795 个常染色体功能丧失性 SNPs 和 indels。在基因分型的冰岛人中，有 7.7%的个体是纯合子或复合杂合子，携带频率低于 2%的杂合子缺失突变，这些突变存在于 1171 个基因中（完全敲除）。在大脑中高度表达的基因比其他基因更不容易被完全敲除。两个杂合子父母的纯合子功能丧失性后代的发生频率低于预期（在 MAF <2%的情况下，每 10000 次传递中缺失 136 个，95%置信区间[CI]为 10-261）。
