Genetic basis of thermal nociceptive sensitivity and brain weight in a BALB/c reduced complexity cross

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Creator
  • Beierle, Jacob A
  • Yao, Emily J
    • Other Affiliation: Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, MA, USA
  • Goldstein, Stanley I
    • Other Affiliation: Program in Biomolecular Pharmacology, Boston University School of Medicine, Boston, MA, USA
  • Scotellaro, Julia L
    • Other Affiliation: Department of Biology and Biochemistry, Center for Network Systems Biology, Boston University School of Medicine, Boston, MA, USA
  • Sena, Katherine D
    • Other Affiliation: Department of Biology and Biochemistry, Center for Network Systems Biology, Boston University School of Medicine, Boston, MA, USA
  • Linnertz, Colton A
    • Affiliation: School of Medicine, Department of Genetics
  • Willits, Adam B
    • Other Affiliation: Neuroscience Program, University of Kansas Medical Center, Kansas City, KS, USA
  • Kader, Leena
    • Other Affiliation: Neuroscience Program, University of Kansas Medical Center, Kansas City, KS, USA
  • Young, Erin E
    • Other Affiliation: Department of Anesthesiology, University of Kansas Medical Center, Kansas City, KS, USA
  • Peltz, Gary
    • Other Affiliation: Department of Anesthesiology, Pain, and Preoperative Medicine, Stanford University School of Medicine, Stanford, CA, USA
  • Emili, Andrew
    • Other Affiliation: Department of Biology and Biochemistry, Center for Network Systems Biology, Boston University School of Medicine, Boston, MA, USA
  • Ferris, Martin T
    • Affiliation: School of Medicine, Department of Genetics
  • Bryant, Camron D
    • Other Affiliation: Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, MA, USA
Abstract
  • Thermal nociception involves the transmission of temperature-related noxious information from the periphery to the CNS and is a heritable trait that could predict transition to persistent pain. Rodent forward genetics complement human studies by controlling genetic complexity and environmental factors, analysis of end point tissue, and validation of variants on appropriate genetic backgrounds. Reduced complexity crosses between nearly identical inbred substrains with robust trait differences can greatly facilitate unbiased discovery of novel genes and variants. We found BALB/cByJ mice showed enhanced sensitivity on the 53.5°C hot plate and mechanical stimulation in the von Frey test compared to BALB/cJ mice and replicated decreased gross brain weight in BALB/cByJ versus BALB/cJ. We then identified a quantitative trait locus (QTL) on chromosome 13 for hot plate sensitivity (LOD = 10.7; p < 0.001; peak = 56 Mb) and a QTL for brain weight on chromosome 5 (LOD = 8.7; p < 0.001). Expression QTL mapping of brain tissues identified H2afy (56.07 Mb) as the top transcript with the strongest association at the hot plate locus (FDR = 0.0002) and spliceome analysis identified differential exon usage within H2afy associated with the same locus. Whole brain proteomics further supported decreased H2AFY expression could underlie enhanced hot plate sensitivity, and identified ACADS as a candidate for reduced brain weight. To summarize, a BALB/c reduced complexity cross combined with multiple-omics approaches facilitated identification of candidate genes underlying thermal nociception and brain weight. These substrains provide a powerful, reciprocal platform for future validation of candidate variants.
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  • Article
Rights statement
  • In Copyright
Rights holder
  • SAGE Publications Inc., unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses
License
  • Attribution-NonCommercial 4.0 International
Journal title
  • Molecular Pain
Journal volume
  • 18
Funder
  • National Institute on Drug Abuse
  • National Institute of General Medical Sciences
  • Burroughs Wellcome Fund
ISSN
  • 1744-8069
Copyright date
  • 2022
Publisher
  • SAGE Publications

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