Project description:Gene expression analysis of retinas from a mouse model of the mild form of Zellweger spectrum disorder (ZSD). Mice homozygous for the hypomorphic Pex1-G844D allele, the murine ortholog of the human PEX1-G843D mutation found in a subset of patients with autosomal recessive ZSD, develop phenotypes found in humans with a milder form of ZSD, including retinal degeneration and vision loss. Similar to humans, mice heterozygous for the hypomorphic Pex1-G844D allele do not display age-related retinal abnormalities. We conducted a comparative analysis of retinal gene expression profile from Pex1-G844D homozygous and heterozygous mice in order to investigate the pathomechanisms of vision loss in humans with mild forms of ZSD. Whole retinas were obtained from 4 mice homozygous and 4 mice heterozygous for the hypomorphic Pex1-G844D allele, the murine ortholog of the human PEX1-G843D mutation found in a subset of patients with autosomal recessive Zellweger spectrum disorder (ZSD). The former group of animals show abnormal age-related related retinal degeneration due to peroxisome assembly defect resulting from having two copies of the hypomorphic Pex1-G844D allele. The latter group of animals display no evidence of abnormal age-related retinal degeneration due to the presence of one wild type copy of the Pex1 gene. The overall goal was to identify differentially expressed genes between mice homozygous and heterozygous for the hypomorphic Pex1-G844D allele that are informative of the pathomechanisms of age-related retinal degeneration in the former group.
Project description:In mammals, retinal damage is followed by Müller glia cell activation and proliferation. While retinal gliosis persists in adult mammals after an insult or disease, some vertebrates, including zebrafish, have the capacity to regenerate. We believe we are the first group to show that gliosis is a fibrotic-like process in mammals’ eyes caused by differential activation of canonical and non-canonical TGFβ signaling pathways.
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.
