Journal
NATURE BIOTECHNOLOGY
Volume 31, Issue 4, Pages 342-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nbt.2519
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Funding
- Human Frontiers Science Program postdoctoral fellowships
- Howard Hughes Medical Institute
- US National Institutes of Health
- Burroughs-Wellcome Fund Career Award at the Scientific Interface
- Center for Excellence in Genome Science from the National Human Genome Research Institute [5P50HG006193-02]
- Klarman Cell Observatory at the Broad Institute
- New England Regional Center for Excellence/Biodefense and Emerging Infectious Disease [U54 AI057159]
- Israeli Centers of Research Excellence (I-CORE) Gene Regulation in Complex Human Disease [41/11]
- Human Frontiers Science Program Career Development Award
- Israeli Science Foundation Bikura Institutional Research Grant Program
- Edmond J. Safra Center for Bioinformatics at Tel-Aviv University
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Individual genetic variation affects gene responsiveness to stimuli, often by influencing complex molecular circuits. Here we combine genomic and intermediate-scale transcriptional profiling with computational methods to identify variants that affect the responsiveness of genes to stimuli (responsiveness quantitative trait loci or reQTLs) and to position these variants in molecular circuit diagrams. We apply this approach to study variation in transcriptional responsiveness to pathogen components in dendritic cells from recombinant inbred mouse strains. We identify reQTLs that correlate with particular stimuli and position them in known pathways. For example, in response to a virus-like stimulus, a trans-acting variant responds as an activator of the antiviral response; using RNA interference, we identify Rgs16 as the likely causal gene. Our approach charts an experimental and analytic path to decipher the mechanisms underlying genetic variation in circuits that control responses to stimuli.
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