High-throughput discovery of novel developmental phenotypes.
High-throughput discovery of novel developmental phenotypes.
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DOI：
10.1038/nature19356
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发表时间：
2016-09-22
期刊：
影响因子：
64.8
通讯作者：
Murray SA
中科院分区：
文献类型：
--
作者：
Dickinson ME;Flenniken AM;Ji X;Teboul L;Wong MD;White JK;Meehan TF;Weninger WJ;Westerberg H;Adissu H;Baker CN;Bower L;Brown JM;Caddle LB;Chiani F;Clary D;Cleak J;Daly MJ;Denegre JM;Doe B;Dolan ME;Edie SM;Fuchs H;Gailus-Durner V;Galli A;Gambadoro A;Gallegos J;Guo S;Horner NR;Hsu CW;Johnson SJ;Kalaga S;Keith LC;Lanoue L;Lawson TN;Lek M;Mark M;Marschall S;Mason J;McElwee ML;Newbigging S;Nutter LM;Peterson KA;Ramirez-Solis R;Rowland DJ;Ryder E;Samocha KE;Seavitt JR;Selloum M;Szoke-Kovacs Z;Tamura M;Trainor AG;Tudose I;Wakana S;Warren J;Wendling O;West DB;Wong L;Yoshiki A;International Mouse Phenotyping Consortium;Jackson Laboratory;Infrastructure Nationale PHENOMIN, Institut Clinique de la Souris (ICS);Charles River Laboratories;MRC Harwell;Toronto Centre for Phenogenomics;Wellcome Trust Sanger Institute;RIKEN BioResource Center;MacArthur DG;Tocchini-Valentini GP;Gao X;Flicek P;Bradley A;Skarnes WC;Justice MJ;Parkinson HE;Moore M;Wells S;Braun RE;Svenson KL;de Angelis MH;Herault Y;Mohun T;Mallon AM;Henkelman RM;Brown SD;Adams DJ;Lloyd KC;McKerlie C;Beaudet AL;Bućan M;Murray SA
大约三分之一的哺乳动物基因是生命所必需的。小鼠敲除这些基因所产生的表型为基因功能和先天性疾病提供了巨大的洞察力。作为国际小鼠表型分析联盟努力产生和表型表征5000敲除小鼠品系的一部分，我们在产生第一个1751个独特基因敲除的过程中鉴定了410个致死基因。使用标准化的表型分析平台，结合高分辨率3D成像，我们确定了新的表型在多个时间点为以前未表征的基因和其他表型的基因与以前报告的突变表型。出乎意料的是，我们的分析表明，不完全的表达和可变的表达是常见的，即使在一个明确的遗传背景。此外，我们发现人类疾病基因富含我们筛选中鉴定的必需基因，从而提供了一个新的数据集，有助于对临床测序工作中鉴定的突变进行优先排序和验证。
Approximately one third of all mammalian genes are essential for life. Phenotypes resulting from mouse knockouts of these genes have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5000 knockout mouse lines, we have identified 410 lethal genes during the production of the first 1751 unique gene knockouts. Using a standardised phenotyping platform that incorporates high-resolution 3D imaging, we identified novel phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes identified in our screen, thus providing a novel dataset that facilitates prioritization and validation of mutations identified in clinical sequencing efforts.