High Resolution Genomic Scans Reveal Genetic Architecture Controlling Alcohol Preference in Bidirectionally Selected Rat Model

Chiao Ling Lo, Amy C. Lossie, Tiebing Liang, Yunlong Liu, Xiaoling Xuei, Lawrence Lumeng, Feng Zhou, William M. Muir

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Investigations on the influence of nature vs. nurture on Alcoholism (Alcohol Use Disorder) in human have yet to provide a clear view on potential genomic etiologies. To address this issue, we sequenced a replicated animal model system bidirectionally-selected for alcohol preference (AP). This model is uniquely suited to map genetic effects with high reproducibility, and resolution. The origin of the rat lines (an 8-way cross) resulted in small haplotype blocks (HB) with a corresponding high level of resolution. We sequenced DNAs from 40 samples (10 per line of each replicate) to determine allele frequencies and HB. We achieved ~46X coverage per line and replicate. Excessive differentiation in the genomic architecture between lines, across replicates, termed signatures of selection (SS), were classified according to gene and region. We identified SS in 930 genes associated with AP. The majority (50%) of the SS were confined to single gene regions, the greatest numbers of which were in promoters (284) and intronic regions (169) with the least in exon's (4), suggesting that differences in AP were primarily due to alterations in regulatory regions. We confirmed previously identified genes and found many new genes associated with AP. Of those newly identified genes, several demonstrated neuronal function involved in synaptic memory and reward behavior, e.g. ion channels (Kcnf1, Kcnn3, Scn5a), excitatory receptors (Grin2a, Gria3, Grip1), neurotransmitters (Pomc), and synapses (Snap29). This study not only reveals the polygenic architecture of AP, but also emphasizes the importance of regulatory elements, consistent with other complex traits.

Original languageEnglish (US)
Article numbere1006178
JournalPLoS Genetics
Volume12
Issue number8
DOIs
StatePublished - Aug 1 2016

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alcohol
genomics
alcohols
animal models
Alcohols
gene
Genes
genes
Haplotypes
haplotypes
Nucleic Acid Regulatory Sequences
etiology
ion channels
synapse
alcohol abuse
neurotransmitters
Reward
Ion Channels
Gene Frequency
reproducibility

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

High Resolution Genomic Scans Reveal Genetic Architecture Controlling Alcohol Preference in Bidirectionally Selected Rat Model. / Lo, Chiao Ling; Lossie, Amy C.; Liang, Tiebing; Liu, Yunlong; Xuei, Xiaoling; Lumeng, Lawrence; Zhou, Feng; Muir, William M.

In: PLoS Genetics, Vol. 12, No. 8, e1006178, 01.08.2016.

Research output: Contribution to journalArticle

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