近日，国际著名杂志Science在线刊登了国外研究人员的最新研究成果“A Systematic Survey of Loss-of-Function Variants in Human Protein-Coding Genes，”，文章中，研究者揭示了人类中灭活的基因惊人地常见。
那些阻止关键性蛋白质的制造或正常工作的突变常常与人类的疾病有关联。 但是，根据一项新的研究，这些“丧失功能”的突变在人类的基因组中实际上还是相对常见的。 基因组测序研究常常会发现丧失功能的突变，但这些常常是因为测序错误而非真正的遗传变异。 为了发现人类基因组中丧失功能的基因的真实程度，Daniel MacArthur及其同事对主要来自1000个基因组计划的185个个体的人类基因组进行了广泛的数据分析。
他们估计，人类的基因组通常含有大约100个丧失功能的等位基因。 有大约20个基因，它们的2个等位基因都为丧失功能的变异体，这意味着这些基因是完全灭活的。 尽管某些变异会有造成有害的影响，但大多数的其它变异似乎不管怎样都不会影响健康，而第三亚组的变异似乎还会提供某些裨益。文章的作者是根据等位基因频率来确定它的，它所反映的是自然选择的影响。这些发现意味着根据基因组测序所发现的突变需要有严格的分析以确认它们是真正的丧失功能的突变。这会与个性化医药有关，即某病人的个体基因组测序会被用来决定所用的治疗类型。Lluis Quintana-Murci在一则相关的《观点栏目》中对该研究进行了讨论。（生物谷Bioon.com）
doi:10.1126/science.1215040
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A Systematic Survey of Loss-of-Function Variants in Human Protein-Coding Genes
Daniel G. MacArthur1,2,*, Suganthi Balasubramanian3,4, Adam Frankish1, Ni Huang1, James Morris1, Klaudia Walter1, Luke Jostins1, Lukas Habegger3,4, Joseph K. Pickrell5, Stephen B. Montgomery6,7, Cornelis A. Albers1,8, Zhengdong D. Zhang9, Donald F. Conrad10, Gerton Lunter11, Hancheng Zheng12, Qasim Ayub1, Mark A. DePristo13, Eric Banks13, Min Hu1, Robert E. Handsaker13,14, Jeffrey A. Rosenfeld15, Menachem Fromer13, Mike Jin3, Xinmeng Jasmine Mu3,4, Ekta Khurana3,4, Kai Ye16, Mike Kay1, Gary Ian Saunders1, Marie-Marthe Suner1, Toby Hunt1, If H. A. Barnes1, Clara Amid1,17, Denise R. Carvalho-Silva1, Alexandra H. Bignell1, Catherine Snow1, Bryndis Yngvadottir1, Suzannah Bumpstead1, David N. Cooper18, Yali Xue1, Irene Gallego Romero1,5, 1000 Genomes Project Consortium, Jun Wang12, Yingrui Li12, Richard A. Gibbs19, Steven A. McCarroll13,14, Emmanouil T. Dermitzakis7, Jonathan K. Pritchard5,20, Jeffrey C. Barrett1, Jennifer Harrow1, Matthew E. Hurles1, Mark B. Gerstein3,4,21,†, Chris Tyler-Smith1,†
Genome-sequencing studies indicate that all humans carry many genetic variants predicted to cause loss of function (LoF) of protein-coding genes, suggesting unexpected redundancy in the human genome. Here we apply stringent filters to 2951 putative LoF variants obtained from 185 human genomes to determine their true prevalence and properties. We estimate that human genomes typically contain ~100 genuine LoF variants with ~20 genes completely inactivated. We identify rare and likely deleterious LoF alleles, including 26 known and 21 predicted severe disease–causing variants, as well as common LoF variants in nonessential genes. We describe functional and evolutionary differences between LoF-tolerant and recessive disease genes and a method for using these differences to prioritize candidate genes found in clinical sequencing studies
