A quantitative framework for characterizing the evolutionary history of mammalian gene expression

  1. Aviv Regev4,8,9
  1. 1Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;
  2. 2Division of Health Science and Technology, MIT, Cambridge, Massachusetts 02139, USA;
  3. 3Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts 02115, USA;
  4. 4Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;
  5. 5Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, 752 36 Uppsala, Sweden;
  6. 6Earlham Institute, Norwich NR4 7UZ, United Kingdom;
  7. 7Department of Biological and Medical Sciences, University of East Anglia, Norwich NR4 7TJ, United Kingdom;
  8. 8Department of Biology and Koch Institute, MIT, Cambridge, Massachusetts 02142, USA;
  9. 9Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA
  • Corresponding author: aregev{at}broadinstitute.org
  • Abstract

    The evolutionary history of a gene helps predict its function and relationship to phenotypic traits. Although sequence conservation is commonly used to decipher gene function and assess medical relevance, methods for functional inference from comparative expression data are lacking. Here, we use RNA-seq across seven tissues from 17 mammalian species to show that expression evolution across mammals is accurately modeled by the Ornstein–Uhlenbeck process, a commonly proposed model of continuous trait evolution. We apply this model to identify expression pathways under neutral, stabilizing, and directional selection. We further demonstrate novel applications of this model to quantify the extent of stabilizing selection on a gene's expression, parameterize the distribution of each gene's optimal expression level, and detect deleterious expression levels in expression data from individual patients. Our work provides a statistical framework for interpreting expression data across species and in disease.

    Footnotes

    • Received March 27, 2018.
    • Accepted November 27, 2018.

    This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

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