Recla, J. M. | bioRxiv Science

bioRxiv2022

The Molecular Signatures Database Revisited: Extending Support for Mouse Data

The Molecular Signatures Database (MSigDB) serves as the primary repository of biological signature gene sets for performing Gene Set Enrichment Analysis (GSEA). In the more than 15 years since its creation, MSigDB has served over 290,000 users in their use of GSEA to perform statistically rigorous analysis of coordinated patterns of gene expression changes by leveraging the prior knowledge of tens of thousands of deposited signatures. In that time, the sets provided in MSigDB have been offered exclusively in the human gene space and only minimally supporting analysis of mouse model data through mapping to human genes. Here we present two substantial improvements to MSigDB: first, by providing gene sets from widely used resources in the mouse gene space; and second, by offering substantially improved orthology mapping resources for comparative analysis of both mouse and human datasets.

bioinformatics↗

bioRxiv2018

Genetic mapping in Diversity Outbred mice identifies a Trpa1 variant influencing late phase formalin response

Identification of genetic variants that influence susceptibility to chronic pain is key to identifying molecular mechanisms and targets for effective and safe therapeutic alternatives to opioids. To identify genes and variants associated with chronic pain, we measured late phase response to formalin injection in 275 male and female Diversity Outbred (DO) mice genotyped for over 70 thousand SNPs. One quantitative trait locus (QTL) reached genome-wide significance on chromosome 1 with a support interval of 3.1 Mb. This locus, Nociq4 (nociceptive sensitivity inflammatory QTL 4; MGI:5661503), harbors the well-known pain gene Trpa1 (transient receptor potential cation channel, subfamily A, member 1). Trpa1 is a cation channel known to play an important role in acute and chronic pain in both humans and mice. Analysis of DO founder strain allele effects revealed a significant effect of the CAST/EiJ allele at Trpa1, with CAST/EiJ carrier mice showing an early, but not late, response to formalin relative to carriers of the seven other inbred founder alleles (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HlLtJ, PWK/PhJ, and WSB/EiJ). We characterized possible functional consequences of sequence variants in Trpa1 by assessing channel conductance, Trpa1/Trpv1 interactions, and isoform expression. The phenotypic differences observed in CAST/EiJ relative to C57BL/6J carriers were best explained by Trpa1 isoform expression differences, implicating a splice junction variant as the causal functional variant. This study demonstrates the utility of advanced, high-precision genetic mapping populations in resolving specific molecular mechanisms of variation in pain sensitivity.

bioinformatics↗