近日，國(guó)際著名雜志Science在線刊登了國(guó)外研究人員的最新研究成果“A Systematic Survey of Loss-of-Function Variants in Human Protein-Coding Genes,，”,，文章中，研究者揭示了人類中滅活的基因驚人地常見(jiàn),。
那些阻止關(guān)鍵性蛋白質(zhì)的制造或正常工作的突變常常與人類的疾病有關(guān)聯(lián),。 但是，根據(jù)一項(xiàng)新的研究,，這些“喪失功能”的突變?cè)谌祟惖幕蚪M中實(shí)際上還是相對(duì)常見(jiàn)的,。 基因組測(cè)序研究常常會(huì)發(fā)現(xiàn)喪失功能的突變，但這些常常是因?yàn)闇y(cè)序錯(cuò)誤而非真正的遺傳變異,。 為了發(fā)現(xiàn)人類基因組中喪失功能的基因的真實(shí)程度,，Daniel MacArthur及其同事對(duì)主要來(lái)自1000個(gè)基因組計(jì)劃的185個(gè)個(gè)體的人類基因組進(jìn)行了廣泛的數(shù)據(jù)分析。
他們估計(jì),，人類的基因組通常含有大約100個(gè)喪失功能的等位基因,。 有大約20個(gè)基因，它們的2個(gè)等位基因都為喪失功能的變異體,，這意味著這些基因是完全滅活的,。 盡管某些變異會(huì)有造成有害的影響，但大多數(shù)的其它變異似乎不管怎樣都不會(huì)影響健康,，而第三亞組的變異似乎還會(huì)提供某些裨益,。文章的作者是根據(jù)等位基因頻率來(lái)確定它的,，它所反映的是自然選擇的影響。這些發(fā)現(xiàn)意味著根據(jù)基因組測(cè)序所發(fā)現(xiàn)的突變需要有嚴(yán)格的分析以確認(rèn)它們是真正的喪失功能的突變,。這會(huì)與個(gè)性化醫(yī)藥有關(guān),，即某病人的個(gè)體基因組測(cè)序會(huì)被用來(lái)決定所用的治療類型。Lluis Quintana-Murci在一則相關(guān)的《觀點(diǎn)欄目》中對(duì)該研究進(jìn)行了討論,。（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
