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Brain transcriptional variation is a heritable trait that mediates complex behaviors, including addiction. Expression quantitative trait locus (eQTL) mapping reveals genomic regions harboring genetic variants that influence transcript abundance. In this study, we profiled transcript abundance in the striatum of 386 Diversity Outbred (J:DO) mice of both sexes using RNA-Seq. All mice were characterized using a behavioral battery of widely-used exploratory and risk-taking assays prior to transcriptional profiling. We performed eQTL mapping, incorporated the results into a browser-based eQTL viewer, and deposited co-expression network members in GeneWeaver. The eQTL viewer allows researchers to query specific genes to obtain allelic effect plots, analyze SNP associations, assess gene expression correlations, and apply mediation analysis to evaluate whether the regulatory variant is acting through the expression of another gene. GeneWeaver allows multi-species comparison of gene sets using statistical and combinatorial tools. This data resource allows users to find genetic variants that regulate differentially expressed transcripts and place them in the context of other studies of striatal gene expression and function in addiction-related behavior. [ABSTRACT FROM AUTHOR]

Epidermolysis Bullosa (EB) is a group of rare genetic disorders that compromise the structural integrity of the skin such that blisters and subsequent erosions occur after minor trauma. While primary genetic risk of all subforms of EB adhere to Mendelian patterns of inheritance, their clinical presentations and severities can vary greatly, implying genetic modifiers. The Lamc2jeb mouse model of non-Herlitz junctional EB (JEB-nH) demonstrated that genetic modifiers can contribute substantially to the phenotypic variability of JEB and likely other forms of EB. The innocuous changes in an 'EB related gene', Col17a1, have shown it to be a dominant modifier of Lamc2jeb. This work identifies six additional Quantitative Trait Loci (QTL) that modify disease in Lamc2jeb/jeb mice. Three QTL include other known 'EB related genes', with the strongest modifier effect mapping to a region including the epidermal hemi-desmosomal structural gene dystonin (Dst-e/Bpag1-e). Three other QTL map to intervals devoid of known EB-associated genes. Of these, one contains the nuclear receptor coactivator Ppargc1a as its primary candidate and the others contain related genes Pparg and Igf1, suggesting modifier pathways. These results, demonstrating the potent disease modifying effects of normally innocuous genetic variants, greatly expand the landscape of genetic modifiers of EB and therapeutic approaches that may be applied. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is the most common degenerative motor neuron disorder. Although most cases of ALS are sporadic, 5–10% of cases are familial, with mutations associated with over 40 genes. There is variation of ALS symptoms within families carrying the same mutation; the disease may develop in one sibling and not in another despite the presence of the mutation in both. Although the cause of this phenotypic variation is unknown, it is likely related to genetic modifiers of disease expression. The identification of ALS causing genes has led to the development of transgenic mouse models of motor neuron disease. Similar to families with familial ALS, there are background-dependent differences in disease phenotype in transgenic mouse models of ALS suggesting that, as in human ALS, differences in phenotype may be ascribed to genetic modifiers. These genetic modifiers may not cause ALS rather their expression either exacerbates or ameliorates the effect of the mutant ALS causing genes. We have reported that in both the G93A-hSOD1 and G59S-hDCTN1 mouse models, SJL mice demonstrated a more severe phenotype than C57BL6 mice. From reciprocal intercrosses between G93A-hSOD1 transgenic mice on SJL and C57BL6 strains, we identified a major quantitative trait locus (QTL) on mouse chromosome 17 that results in a significant shift in lifespan. In this study we generated reciprocal intercrosses between transgenic G59S-hDCTN1 mice on SJL and C57BL6 strains and identified survival QTLs on mouse chromosomes 17 and 18. The chromosome 17 survival QTL on G93A-hSOD1 and G59S-hDCTN1 mice partly overlap, suggesting that the genetic modifiers located in this region may be shared by these two ALS models despite the fact that motor neuron degeneration is caused by mutations in different proteins. The overlapping region contains eighty-seven genes with non-synonymous variations predicted to be deleterious and/or damaging. Two genes in this segment, NOTCH3 and Safb/SAFB1, have been associated with motor neuron disease. The identification of genetic modifiers of motor neuron disease, especially those modifiers that are shared by SOD1 and dynactin-1 transgenic mice, may result in the identification of novel targets for therapies that can alter the course of this devastating illness. [ABSTRACT FROM AUTHOR]

Testis weight is a genetically mediated trait associated with reproductive efficiency across numerous species. We sought to evaluate the genetically diverse, highly recombinant Diversity Outbred (DO) mouse population as a tool to identify and map quantitative trait loci (QTLs) associated with testis weight. Testis weights were recorded for 502 male DO mice and the mice were genotyped on the GIGAMuga array at ~ 143,000 SNPs. We performed a genome-wide association analysis and identified one significant and two suggestive QTLs associated with testis weight. Using bioinformatic approaches, we developed a list of candidate genes and identified those with known roles in testicular size and development. Candidates of particular interest include the RNA demethylase gene Alkbh5, the cyclin-dependent kinase inhibitor gene Cdkn2c, the dynein axonemal heavy chain gene Dnah11, the phospholipase D gene Pld6, the trans-acting transcription factor gene Sp4, and the spermatogenesis-associated gene Spata6, each of which has a human ortholog. Our results demonstrate the utility of DO mice in high-resolution genetic mapping of complex traits, enabling us to identify developmentally important genes in adult mice. Understanding how genetic variation in these genes influence testis weight could aid in the understanding of mechanisms of mammalian reproductive function. [ABSTRACT FROM AUTHOR]

Abstract: Heritable genetic factors contribute significantly to inflammatory nociception. To determine candidate genes underlying inflammatory nociception, the current study used a mouse model of abdominal inflammatory pain. BXD recombinant inbred (RI) mouse strains were administered the intraperitoneal acetic acid test, and genome-wide quantitative trait locus (QTL) mapping was performed on the mean number of abdominal contraction and extension movements in 3 distinct groups of BXD RI mouse strains in 2 separate experiments. Combined mapping results detected 2 QTLs on chromosomes (Chr) 3 and 10 across experiments and groups of mice; an additional sex-specific QTL was detected on Chr 16. The results replicate previous findings of a significant QTL, Nociq2, on distal Chr 10 for formalin-induced inflammatory nociception and will aid in identification of the underlying candidate genes. Comparisons of sensitivity to intraperitoneal acetic acid in BXD RI mouse strains with microarray mRNA transcript expression profiles in specific brain areas detected covarying expression of candidate genes that are also found in the detected QTL confidence intervals. The results indicate that common and distinct genetic mechanisms underlie heritable sensitivity to diverse inflammatory insults, and provide a discrete set of high-priority candidate genes to investigate further in rodents and human association studies. Novel genomic regions linked to inflammatory nociception were detected, a previously reported locus was confirmed, and high-priority candidate genes for inflammatory nociception and pain were identified. [Copyright &y& Elsevier]