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 Jr Crabbe, Elissa J. Chesler

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 the GeneWeaver database with >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 knockout 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, epigenetics, 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.

Original languageEnglish (US)
Pages (from-to)1377-1393
Number of pages17
JournalGenetics
Volume197
Issue number4
DOIs
StatePublished - 2014

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Quantitative Trait Loci
Genomics
Alcohols
Genes
Genetic Loci
Validation Studies
Phylogeny
Epigenomics
Knockout Mice
Alcohol Drinking
Methylation
Single Nucleotide Polymorphism
Sequence Analysis
Publications
Animal Models
Databases
Population

Keywords

  • Behavioral genetics
  • Complex traits
  • Data integration

ASJC Scopus subject areas

  • Genetics

Cite this

Identification of a QTL in Mus musculus for alcohol preference, withdrawal, and Ap3m2 expression using integrative functional genomics and precision genetics. / Bubier, Jason A.; Jay, Jeremy J.; Baker, Christopher L.; Bergeson, Susan E.; Ohno, Hiroshi; Metten, Pamela; Crabbe, John Jr; Chesler, Elissa J.

In: Genetics, Vol. 197, No. 4, 2014, p. 1377-1393.

Research output: Contribution to journalArticle

Bubier, Jason A. ; Jay, Jeremy J. ; Baker, Christopher L. ; Bergeson, Susan E. ; Ohno, Hiroshi ; Metten, Pamela ; Crabbe, John Jr ; Chesler, Elissa J. / Identification of a QTL in Mus musculus for alcohol preference, withdrawal, and Ap3m2 expression using integrative functional genomics and precision genetics. In: Genetics. 2014 ; Vol. 197, No. 4. pp. 1377-1393.
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