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

• MeSH
• fenotyp MeSH
• genom * MeSH
• geny MeSH
• lidé MeSH
• mutace MeSH
• myši genetika   MeSH
• proteiny genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši genetika   MeSH
• zvířata MeSH
• Publikační typ
• úvodníky 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

Circadian systems provide a fitness advantage to organisms by allowing them to adapt to daily changes of environmental cues, such as light/dark cycles. The molecular mechanism underlying the circadian clock has been well characterized. However, how internal circadian clocks are entrained with regular daily light/dark cycles remains unclear. By collecting and analyzing indirect calorimetry (IC) data from more than 2000 wild-type mice available from the International Mouse Phenotyping Consortium (IMPC), we show that the onset time and peak phase of activity and food intake rhythms are reliable parameters for screening defects of circadian misalignment. We developed a machine learning algorithm to quantify these two parameters in our misalignment screen (SyncScreener) with existing datasets and used it to screen 750 mutant mouse lines from five IMPC phenotyping centres. Mutants of five genes (Slc7a11, Rhbdl1, Spop, Ctc1 and Oxtr) were found to be associated with altered patterns of activity or food intake. By further studying the Slc7a11tm1a/tm1a mice, we confirmed its advanced activity phase phenotype in response to a simulated jetlag and skeleton photoperiod stimuli. Disruption of Slc7a11 affected the intercellular communication in the suprachiasmatic nucleus, suggesting a defect in synchronization of clock neurons. Our study has established a systematic phenotype analysis approach that can be used to uncover the mechanism of circadian entrainment in mice.

• MeSH
• cirkadiánní rytmus genetika   MeSH
• komplexy ubikvitinligas genetika   MeSH
• mutace MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• proteiny vázající telomery genetika   MeSH
• receptory oxytocinu genetika   MeSH
• represorové proteiny genetika   MeSH
• serinové endopeptidasy genetika   MeSH
• strojové učení MeSH
• transportní systém aminokyselin y+ genetika   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH