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Hypothalamic transcriptomes of 99 mouse strains reveal trans eQTL hotspots, splicing QTLs and novel non-coding genes

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Cite this article as: eLife 2016;5:e15614 doi: 10.7554/eLife.15614

Abstract

Previous studies had shown that integration of genome wide expression profiles, in metabolic tissues, with genetic and phenotypic variance, provided valuable insight into the underlying molecular mechanisms. We used RNA-Seq to characterize hypothalamic transcriptome in 99 inbred strains of mice from the Hybrid Mouse Diversity Panel (HMDP), a reference resource population for cardiovascular and metabolic traits. We report numerous novel transcripts supported by proteomic analyses, as well as novel non coding RNAs. High resolution genetic mapping of transcript levels in HMDP, reveals both local and trans expression Quantitative Trait Loci (eQTLs) demonstrating 2 trans eQTL 'hotspots' associated with expression of hundreds of genes. We also report thousands of alternative splicing events regulated by genetic variants. Finally, comparison with about 150 metabolic and cardiovascular traits revealed many highly significant associations. Our data provides a rich resource for understanding the many physiologic functions mediated by the hypothalamus and their genetic regulation.

Article and author information

Author details

  1. Yehudit Hasin-Brumshtein

    Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    For correspondence
    yehudit.hasin@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7528-603X
  2. Arshad H Khan

    Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Farhad Hormozdiari

    Department of Computer Science, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Calvin Pan

    Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Brian W Parks

    Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Vladislav A Petyuk

    Biological Sciences Division, Pacific Northwest National Laboratory, Richland, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Paul D Piehowski

    Biological Sciences Division, Pacific Northwest National Laboratory, Richland, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Anneke Bruemmer

    Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Matteo Pellegrini

    Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Xinshu Xiao

    Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Eleazar Eskin

    Department of Computer Science, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Richard D Smith

    Biological Sciences Division, Pacific Northwest National Laboratory, Richland, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Aldons J Lusis

    Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Desmond J Smith

    Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Institutes of Health (R01HG006264)

  • Xinshu Xiao

National Institutes of Health (R01GM098273)

  • Yehudit Hasin-Brumshtein
  • Arshad H Khan
  • Calvin Pan
  • Vladislav A Petyuk
  • Paul D Piehowski
  • Richard D Smith
  • Aldons J Lusis
  • Desmond J Smith

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: The animal protocol for the study was approved by the Institutional Animal Care and Use Committee (IACUC) at University of California, Los Angeles.

Reviewing Editor

  1. Joel K Elmquist, University of Texas Southwestern Medical Center, United States

Publication history

  1. Received: February 27, 2016
  2. Accepted: September 12, 2016
  3. Accepted Manuscript published: September 13, 2016 (version 1)
  4. Version of Record published: October 6, 2016 (version 2)

Copyright

© 2016, Hasin-Brumshtein et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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