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

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          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.

          Author Summary

          Alcohol Used Disorder (AUD) or Alcoholism extracts a great societal cost in terms of human suffering. Understanding the genetic basis is critical to comprehend, treat and prevent this disease, but difficult in humans, as choice is influenced by nature and nurture. To discover its genetic basis, we used an animal model system that controlled for genetic and non-genetic factors through randomization, study replication, long-term divergent selection, and a controlled environment. We conducted whole genome sequencing in breeds that were either compulsive excessive drinkers or completely abstinent. We discovered consistent alterations in several genes and neurological pathways previously unassociated with alcoholism. These results strengthened our understanding of the genetic basis of alcoholism and revealed potential genetic- and neurological-based treatments.

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          Most cited references52

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          Molecular signatures of natural selection.

          There is an increasing interest in detecting genes, or genomic regions, that have been targeted by natural selection. The interest stems from a basic desire to learn more about evolutionary processes in humans and other organisms, and from the realization that inferences regarding selection may provide important functional information. This review provides a nonmathematical description of the issues involved in detecting selection from DNA sequences and SNP data and is intended for readers who are not familiar with population genetic theory. Particular attention is placed on issues relating to the analysis of large-scale genomic data sets.
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            PROMO: detection of known transcription regulatory elements using species-tailored searches.

            We have developed a set of tools to construct positional weight matrices from known transcription factor binding sites in a species or taxon-specific manner, and to search for matches in DNA sequences.
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              The hitch-hiking effect of a favourable gene.

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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, CA USA )
                1553-7390
                1553-7404
                4 August 2016
                August 2016
                : 12
                : 8
                : e1006178
                Affiliations
                [1 ]Indiana Alcohol Research Center, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
                [2 ]Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
                [3 ]Department of Animal Sciences, Purdue University, West Lafayette, Indiana, United States of America
                [4 ]Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
                [5 ]Department of Medical Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
                [6 ]Department of Biochemistry, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
                [7 ]Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
                Georgia Institute of Technology, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: ACL FCZ WMM. Performed the experiments: CLL TL. Analyzed the data: WMM. Contributed reagents/materials/analysis tools: TL XX YL FCZ WMM. Wrote the paper: CLL ACL TL LL FCZ WMM.

                [¤]

                Current address: Genetics, Epigenetics, and Developmental Neuroscience Branch, Division of Neuroscience and Behavior, National Institute on Drug Abuse, NIH, Bethesda, Maryland, United States of America

                Author information
                http://orcid.org/0000-0001-5078-7743
                http://orcid.org/0000-0002-4143-2024
                Article
                PGENETICS-D-16-00489
                10.1371/journal.pgen.1006178
                4973992
                27490364
                6dcf6539-232b-4dea-87e1-4fc071547ae8

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 3 March 2016
                : 15 June 2016
                Page count
                Figures: 6, Tables: 2, Pages: 23
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000027, National Institute on Alcohol Abuse and Alcoholism;
                Award ID: P60 AA07611
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000027, National Institute on Alcohol Abuse and Alcoholism;
                Award ID: P60 AA07611
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000027, National Institute on Alcohol Abuse and Alcoholism;
                Award ID: AA016698
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000027, National Institute on Alcohol Abuse and Alcoholism;
                Award ID: AA016698
                Award Recipient :
                This work was supported by the National Institute of Health P60 AA07611 and AA016698. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Nutrition
                Diet
                Alcohol Consumption
                Medicine and Health Sciences
                Nutrition
                Diet
                Alcohol Consumption
                Biology and Life Sciences
                Biochemistry
                Neurochemistry
                Neurotransmitters
                Glutamate
                Biology and Life Sciences
                Neuroscience
                Neurochemistry
                Neurotransmitters
                Glutamate
                Biology and Life Sciences
                Psychology
                Addiction
                Alcoholism
                Social Sciences
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                Addiction
                Alcoholism
                Medicine and Health Sciences
                Mental Health and Psychiatry
                Substance-Related Disorders
                Alcoholism
                Medicine and Health Sciences
                Public and Occupational Health
                Substance-Related Disorders
                Alcoholism
                Biology and Life Sciences
                Evolutionary Biology
                Population Genetics
                Haplotypes
                Biology and Life Sciences
                Genetics
                Population Genetics
                Haplotypes
                Biology and Life Sciences
                Population Biology
                Population Genetics
                Haplotypes
                Biology and Life Sciences
                Computational Biology
                Genome Complexity
                Introns
                Biology and Life Sciences
                Genetics
                Genomics
                Genome Complexity
                Introns
                Biology and Life Sciences
                Genetics
                Genetic Loci
                Biology and Life Sciences
                Evolutionary Biology
                Evolutionary Processes
                Genetic Drift
                Biology and Life Sciences
                Evolutionary Biology
                Population Genetics
                Genetic Drift
                Biology and Life Sciences
                Genetics
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                Genetic Drift
                Biology and Life Sciences
                Population Biology
                Population Genetics
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                Custom metadata
                The data is available from the NIH Sequence Read Archive as BAM files ( http://trace.ncbi.nlm.nih.gov/Traces/study/) under accession SRP078592.

                Genetics
                Genetics

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