Identification of a QTL in Mus musculus for Alcohol Preference, Withdrawal and Ap3m2 Expression Using Integrative Functional Genomics and Precision Genetics
Jason A. Bubier, Jeremy J. Jay, Christopher L. Baker, Susan E. Bergeson, Hiroshi Ohno, Pamela Metten, John C. Crabbe, Elissa J. Chesler

Abstract

Extensive genetic and genomic studies of the relationship between alcohol drinking preference and withdrawal severity have been performed using animal models. Data from multiple such publications and public data resources have been incorporated in GeneWeaver's database of over 60,000 gene sets including 285 alcohol withdrawal and preference related gene sets. Among these are evidence for positional candidates regulating these behaviors in overlapping quantitative trait loci (QTL) mapped in distinct mouse populations. Combinatorial integration of functional genomics experimental results revealed a single QTL positional candidate gene in one of the loci common to both preference and withdrawal. Functional validation studies in Ap3m2 knock-out mice confirmed these relationships. Genetic validation involves confirming the existence of segregating polymorphisms that could account for the phenotypic effect. By exploiting recent advances in mouse genotyping, sequence and phylogeny resources we confirmed that Ap3m2 resides in an appropriately segregating genomic region. We have demonstrated genetic and alcohol induced regulation of Ap3m2 expression. Although sequence analysis revealed no polymorphisms in the Ap3m2 coding region that could account for all phenotypic differences, there are several upstream SNPs that could. We have identified one of these to be an H3K4me3 site that exhibits strain differences in methylation. Thus, by making cross-species functional genomics readily computable we identified a common QTL candidate for two related bio-behavioral processes via functional evidence and demonstrate sufficiency of the genetic locus as a source of variation underlying two traits.

  • Received January 23, 2014.
  • Accepted May 30, 2014.