Project description:This SuperSeries is composed of the following subset Series:; GSE6397: Comparison between gene expression in heart from Lmna H222P heterozygous and control mice; GSE6398: Comparison between gene expression in heart from Lmna H222P homozygous and control mice Experiment Overall Design: Refer to individual Series
Project description:SILAC based protein correlation profiling using size exclusion of protein complexes derived from Mus musculus tissues (Heart, Liver, Lung, Kidney, Skeletal Muscle, Thymus)
Project description:SILAC based protein correlation profiling using size exclusion of protein complexes derived from seven Mus musculus tissues (Heart, Brain, Liver, Lung, Kidney, Skeletal Muscle, Thymus)
Project description:To characterize the genetic basis of hybrid male sterility in detail, we used a systems genetics approach, integrating mapping of gene expression traits with sterility phenotypes and QTL. We measured genome-wide testis expression in 305 male F2s from a cross between wild-derived inbred strains of M. musculus musculus and M. m. domesticus. We identified several thousand cis- and trans-acting QTL contributing to expression variation (eQTL). Many trans eQTL cluster into eleven ‘hotspots,’ seven of which co-localize with QTL for sterility phenotypes identified in the cross. The number and clustering of trans eQTL - but not cis eQTL - were substantially lower when mapping was restricted to a ‘fertile’ subset of mice, providing evidence that trans eQTL hotspots are related to sterility. Functional annotation of transcripts with eQTL provides insights into the biological processes disrupted by sterility loci and guides prioritization of candidate genes. Using a conditional mapping approach, we identified eQTL dependent on interactions between loci, revealing a complex system of epistasis. Our results illuminate established patterns, including the role of the X chromosome in hybrid sterility.
Project description:We collected whole genome testis expression data from hybrid zone mice. We integrated GWAS mapping of testis expression traits and low testis weight to gain insight into the genetic basis of hybrid male sterility.
Project description:Dilated cardiomyopathy (DCM) is characterized by progressive ventricular dilation, systolic dysfunction, and an increased risk of arrythmias and sudden cardiac arrest. Variants in the LMNA gene, which encodesing for the nuclear lamins A and C, have been linked to familial form of the disease and the founder variant p.Ser143Pro is particularly common among Finnish DCM patients. To clarify elucidate the complex and poorly understood pathogenic mechanisms behind LMNA-related DCM, we generated a mouse model carrying the p.Ser143Pro mutation in the Lmna gene. All genetically modified mice appeared normal at birth. However, based on echocardiographyic, necropsy, B-type natriuretic peptide (Nppb) expression levels, and histopathological data, homozygous males developed progressive left ventricular dilatation, myocardial fibrosis, and cardiac failure after six months of age, with all succumbing before ten months. A reduced disease penetrance was observed in heterozygous male and homozygous female mice, with one-year survival rates of 40% and 60%, respectively. No signs of skeletal myopathy were observed in mice carrying the mutation. Whole-transcriptome RNA sequencing analysis of left ventricular cardiac tissue from asymptomatic two-month-old homozygous male mice revealed an upregulation of classical heart failure markers, such as atrial natriuretic peptide (Nppa ) and myosin heavy chain β (Myh7), and an elevated unfolded protein response signaling, as shown by elevated DNA damage-inducible transcript 3 (Ddit), Bcl-2-associated athanogene 3 (Bag3) and CCAAT/enhancer-binding protein beta (Cebpb) levels especially in the homozygous males compared to wild-type mice. In conclusion, p.Ser143Pro-Lmna mice closely mimic the clinical phenotype observed in patients with the p.Ser143Pro LMNA variant and offerserve as a valuablepotential in vivo model for investigatingstudying the underlying pathogenic mechanisms of LMNA-related DCM in greater detail.
