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Essential mouse genes give insight into human disease

About a third of all genes in mammals are essential to life. Now an international, multi-institutional team, describes their discovery of which genes they are — and what impact they make on human development and disease.

The work was carried out by the International Mouse Phenotyping Consortium (IMPC) by researchers from 8 phenotyping centers representing more than 30 institutions world-wide. The IMPC assesses morphological and physiological characteristics of knockout mouse mutations (mice with genes turned OFF) for all protein-coding genes in the entire mouse genome. This information is now a catalog of mouse genes revealing what each gene does.

The Consortium aims to identify functions for the roughly 20,000 mouse genes shared with human genes — and make all of those mouse strains available for investigations of human disease.

The Nature article, published September 14, reports the results of the first 1,751 genes characterized by the IMPC — finding that nearly one third are essential for life.

Included were 410 lines that are fully lethal, and 198 — or fewer than half — of the mutations they expected to identify.

Using a new method for predicting a mouse strains' physical characteristics from a single genetic background, researchers established (1) time of embryo death and (2) nature of lethal features for that strain, all of which led to discovering many unique characteristics about the functions of each gene.

Identification of essential genes in the mouse provides a window on human disease. This includes the discovery of a number of cases where human disease genes overlap with human essential genes.

Human orthologs — genes that have a common ancestor with mouse genes — are significantly fewer in humans and present as loss-of-function mutations.

This makes these genes strong candidates for undiagnosed human genetic disorders.

"The work of the consortium will contribute significantly to our understanding of the genetic bases for human diseases including spina bifida and cardiovascular defects — amongst many others," adds co-first author Dr. Lydia Teboul, head of molecular and cellular biology at MRC Harwell Institute, in the UK.

Current estimates indicate only a small percentage of human genes are studied in research. Systematically studying characteristics of mouse genes — along with unrestricted access to that data and use of those mouse models, fills in the gap for human genes.

All data and images generated in the project are available for research, distributed via an open-source web portal in real time, and without embargo.

Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify 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, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.

These authors contributed equally to this work.
Mary E. Dickinson, Ann M. Flenniken, Xiao Ji, Lydia Teboul & Michael D. Wong

This work was supported by the National Institutes of Health's National Human Genome Research Institute and the Office of the Director's Common Fund (U42 OD011185, U54 HG006332, U54 HG006348-S1 and OD011174, HG006364-03S1 and U42 OD011175, U54 HG006370). Additional support was provided by the Wellcome Trust, Medical Research Council Strategic Award, Government of Canada through Genome Canada and Ontario Genomics (OGI-051), Wellcome Trust Strategic Award "Deciphering the Mechanisms of Developmental Disorders (DMDD)" (WT100160), National Centre for Scientific Research (CNRS), the French National Institute of Health and Medical Research (INSERM), the University of Strasbourg (UDS), the "Centre Européen de Recherche en Biologie et en Médecine", the "Agence Nationale de la Recherche" under the frame program "Investissements d'Avenir" labeled ANR-10-IDEX-0002-02, ANR-10-INBS- 07 PHENOMIN, the German Federal Ministry of Education and Research by Infrafrontier grant 01KX1012.

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Nov 4, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

International Mouse Phenotyping Consortium (IMPC) reveals mouse genes
essential for a mouse's life provide insights into human disease.
Image Credit:
National Cancer Institute


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