- MeSH
- delece genu * MeSH
- fenotyp MeSH
- genetické asociační studie * MeSH
- genom * MeSH
- genotyp * MeSH
- internet MeSH
- mezinárodní spolupráce MeSH
- mutageneze MeSH
- myší embryonální kmenové buňky cytologie metabolismus MeSH
- myši knockoutované MeSH
- myši MeSH
- šíření informací MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease.
- MeSH
- celogenomová asociační studie MeSH
- fenotyp MeSH
- genetická pleiotropie MeSH
- genotyp MeSH
- genová ontologie MeSH
- kostní denzita genetika MeSH
- mapy interakcí proteinů MeSH
- mutace MeSH
- myši transgenní MeSH
- myši MeSH
- osteoblasty metabolismus patologie MeSH
- osteoklasty metabolismus patologie MeSH
- osteoporóza genetika metabolismus MeSH
- pohlavní dimorfismus MeSH
- promotorové oblasti (genetika) MeSH
- regulace genové exprese genetika MeSH
- transkriptom MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery.
- MeSH
- esenciální geny MeSH
- genetické asociační studie metody MeSH
- genomika MeSH
- lidé MeSH
- myši knockoutované MeSH
- myši MeSH
- nemoc genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- hodnotící studie MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome.
- MeSH
- bazální metabolismus genetika MeSH
- celogenomová asociační studie MeSH
- diabetes mellitus 2. typu genetika MeSH
- fenotyp MeSH
- genové regulační sítě MeSH
- krevní glukóza metabolismus MeSH
- lidé MeSH
- metabolické nemoci genetika MeSH
- myši knockoutované MeSH
- myši MeSH
- obezita genetika MeSH
- plocha pod křivkou MeSH
- rychlé screeningové testy MeSH
- spotřeba kyslíku genetika MeSH
- tělesná hmotnost genetika MeSH
- triglyceridy metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
