Project description:We combined a mouse model of Abeta accumulation and transcriptomics, and identified Klc1 as an Abeta accumulation modifier in vivo. For this transcriptomics analysis, we used 12 arrays (one mouse mRNA sample per array) for inbred mice analyses and 28 arrays for the APP Tg mice of mixed genetic backgrounds. First, 13309 probes whose signals were reliably detectable in all 40 arrays were selected from 25967 probes on the Illumina mouse Ref-8 Expression BeadChip. Second, to select the probes whose expression levels were affected by the DBA genetic background, we compared the expression levels of the 13309 probes in DBA, B6 and SJL inbred (non-Tg) mice (unpaired t-test).M-cM-^@M-^@Using inbred mice means that any change in gene expression is based on their genetic background, not the secondary effects of Abeta accumulation. To minimize the chance of false positives, we applied strict criteria in this selection: the fold change was equal to or more than 1.5 and the false discovery rate (FDR) was set to 0.001. In total 54 probes were identified, with the signals of 47 probes being lower and 7 probes being higher in DBA mice than those in either B6 or SJL. In the final step, we examined the correlation between the expression levels of these 54 probes and Abeta40 levels in the GuHCl fraction in APP Tg mice. Using strict selection criteria (PearsonM-bM-^@M-^Ys product-moment correlation FDR=0.001), we identified a total of four probes which correlated with Abeta levels. Two of these probes were higher in DBA and negatively correlated with the levels of Abeta accumulation. The other two probes were lower in DBA and positively correlated with the levels of Abeta accumulatio. Notably, the two probes (probe ID 4050133 and 6130468) that positively correlated with Abeta accumulation both detected the same transcript: kinesin light chain 1 (Klc1; also known as Kns2).
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:Oligomeric forms of amyloid-beta peptide (Abeta) are presumed to play a pivotal role in the pathogenesis of Alzheimer’s disease (AD). However, it is still unclear how Abeta oligomers contribute to AD pathogenesis in patient neural cells. We generated induced pluripotent stem cells (iPSCs) from a familial AD patient and differentiated them into neural cells. Abeta oligomers were accumulated in neural cells of AD bearing amyloid precursor protein (APP)-E693delta mutation. To uncover Abeta oligomers in AD(APP-E693delta) neural cells, we analyzed gene expression profiles of control and the AD neural cells
Project description:We used TALEN editing to insert a direct expression cassette of either Abeta42 or Abeta 40 eliminating any requirement for amyloidogenic processing of APP to produce Abeta.
Project description:Introgressed variants from other species can be an important source of genetic variation because they may arise rapidly, can include multiple mutations on a single haplotype, and have often been pretested by selection in the species of origin. Although introgressed alleles are generally deleterious, several studies have reported introgression as the source of adaptive alleles-including the rodenticide-resistant variant of Vkorc1 that introgressed from Mus spretus into European populations of Mus musculus domesticus. Here, we conducted bidirectional genome scans to characterize introgressed regions into one wild population of M. spretus from Spain and three wild populations of M. m. domesticus from France, Germany, and Iran. Despite the fact that these species show considerable intrinsic postzygotic reproductive isolation, introgression was observed in all individuals, including in the M. musculus reference genome (GRCm38). Mus spretus individuals had a greater proportion of introgression compared with M. m. domesticus, and within M. m. domesticus, the proportion of introgression decreased with geographic distance from the area of sympatry. Introgression was observed on all autosomes for both species, but not on the X-chromosome in M. m. domesticus, consistent with known X-linked hybrid sterility and inviability genes that have been mapped to the M. spretus X-chromosome. Tract lengths were generally short with a few outliers of up to 2.7 Mb. Interestingly, the longest introgressed tracts were in olfactory receptor regions, and introgressed tracts were significantly enriched for olfactory receptor genes in both species, suggesting that introgression may be a source of functional novelty even between species with high barriers to gene flow.
Project description:The importance of unanchored Ub in innate immunity has been shown only for a limited number of unanchored Ub-interactors. We investigated what additional cellular factors interact with unanchored Ub and whether unanchored Ub plays a broader role in innate immunity. To identify unanchored Ub-interacting factors from murine lungs, we used His-tagged recombinant poly-Ub chains as bait. These chains were mixed with lung tissue lysates and protein complexes were isolated with Ni-NTA beads. Sample elutions were subjected to mass spectrometry (LC-MSMS) analysis.
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.