Health and population effects of rare gene knockouts in adult humans with related parents.
Health and population effects of rare gene knockouts in adult humans with related parents.
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稀有基因敲除的健康和人口影响与相关父母的成年人。
DOI：
10.1126/science.aac8624
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发表时间：
2016-04-22
期刊：
影响因子：
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通讯作者：
van Heel DA
中科院分区：
文献类型：
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作者：
Narasimhan VM;Hunt KA;Mason D;Baker CL;Karczewski KJ;Barnes MR;Barnett AH;Bates C;Bellary S;Bockett NA;Giorda K;Griffiths CJ;Hemingway H;Jia Z;Kelly MA;Khawaja HA;Lek M;McCarthy S;McEachan R;O'Donnell-Luria A;Paigen K;Parisinos CA;Sheridan E;Southgate L;Tee L;Thomas M;Xue Y;Schnall-Levin M;Petkov PM;Tyler-Smith C;Maher ER;Trembath RC;MacArthur DG;Wright J;Durbin R;van Heel DA
在活生物体中检查完整的基因敲除可以了解基因的功能。我们对3,222名具有高亲本亲缘关系的英国巴基斯坦裔成年人的外显子组进行了测序，发现了1,111个罕见变异纯合基因型，其中781个基因预测存在基因功能缺失（敲除）。我们观察到纯合子敲除基因型比预期少13.7%，这意味着每个成年人平均携带1.6个隐性致死等效LOF变异。将基因数据与终身健康记录联系起来，基因敲除与临床咨询或处方率无关。在这个数据集中，我们确定了一位健康的PRDM9基因敲除母亲，并对她、她的孩子和对照组进行了分阶段基因组测序，结果显示减数分裂重组位点位于远离PRDM9依赖热点的地方。因此，天然的LOF变异告知了基本的遗传位点，并在人类中证明了PRDM9冗余。
Examining complete gene knockouts within a viable organism can inform on gene function. We sequenced the exomes of 3,222 British Pakistani-heritage adults with high parental relatedness, discovering 1,111 rare-variant homozygous genotypes with predicted loss of gene function (knockouts) in 781 genes. We observed 13.7% fewer than expected homozygous knockout genotypes, implying an average load of 1.6 recessive-lethal-equivalent LOF variants per adult. Linking genetic data to lifelong health records, knockouts were not associated with clinical consultation or prescription rate. In this dataset we identified a healthy PRDM9 knockout mother, and performed phased genome sequencing on her, her child and controls, which showed meiotic recombination sites localised away from PRDM9-dependent hotspots. Thus, natural LOF variants inform upon essential genetic loci, and demonstrate PRDM9 redundancy in humans.