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: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. Gene expression was measured in whole testis from males aged 62-86 days. Samples include 190 first generation lab-bred male offspring of wild-caught mice from the Mus musculus musculus - M. m. domesticus hybrid zone.
Project description:Cancer-testis antigens are genes normally restricted to the germline but aberrantly activated in many cancers, where their role in tumorigenesis remains unclear. BORIS (CTCFL), a testis-specific paralog of the chromatin organizer CTCF, is one such antigen that shows limited conservation between humans and mice, complicating in vivo functional studies. Here, we generated humanized mice in which both alleles of the endogenous Boris locus are replaced with the full-length human BORIS gene, including its highly diverged cis-regulatory elements. These fully humanized mice maintain normal fertility, indicating accurate germline expression and preserved BORIS function despite evolutionary divergence. However, unlike the strictly testis-specific expression of mouse Boris, human BORIS escapes complete somatic silencing, producing mosaic expression in a minority of mouse somatic cells. This ectopic expression is associated with reduced survival, increased tumor incidence and a shift of tumor spectrum toward aggressive lymphomas. Transcriptomic and chromatin profiling revealed that ectopic human BORIS reactivates testes-specific genes in the soma, including regulators of meiosis and DNA repair, through direct chromatin binding. This transcriptional reprogramming was consistent across tissues and clonal cell lines, revealing a dominant tissue-independent gene activation program. These findings demonstrate that when human BORIS escapes epigenetic silencing in somatic cells, it connects aberrant germline gene activation with increased cancer susceptibility in vivo.
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:To identify differentially expressed genes in Boris KO testis, gene expression profilings were performed with NIAID mouse customized arrays. Gene expressions of five biological replicates of Boris KO testis were compared to those of wild type testis. Total RNAs from WT and BORIS KO testes prepared from P14 mice were labelled with Cy5 and Cy3, respectively. Five sets of each genotype were studied.
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 M-bM-^@M-^Xhotspots,M-bM-^@M-^Y 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 M-bM-^@M-^XfertileM-bM-^@M-^Y 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. Gene expression was measured in whole testis in males aged 70(M-BM-15) days. Samples include 294 WSB/EiJ x PWD/PhJ F2s, 11 PWD/PhJ x WSB/EiJ F2s, 8 WSB/EiJ, 8 PWD/PhJ, 6 PWD/PhJ x WSB/EiJ F1s and 4 WSB/EiJ x PWD/PhJ F1s.
Project description:To identify differentially expressed genes in Boris KO testis, gene expression profilings were performed with NIAID mouse customized arrays. Gene expressions of five biological replicates of Boris KO testis were compared to those of wild type testis.