Journal Articles

The Genetic Landscape of Hematopoietic Stem Cell Frequency in Mice

June 03, 2015

The Genetic Landscape of Hematopoietic Stem Cell Frequency in Mice, 2015 Jun 3, Stem Cell Reports. Zhou X1, Crow AL2, Hartiala J2, Spindler TJ1, Ghazalpour A3, Barsky LW1, Bennett BB4, Parks BW3, Eskin E5, Jain R6, Epstein JA6, Lusis AJ3, Adams GB7,Allayee H8.

Author information

  • 1Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
  • 2Department of Preventive Medicine and Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
  • 3Departments of Human Genetics, Medicine, and Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
  • 4Department of Genetics and Nutrition Research Institute, University of North Carolina, Chapel Hill, Kannapolis, NC 28081, USA.
  • 5Department of Computer Science and Inter-Departmental Program in Bioinformatics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 6Department of Cell and Developmental Biology and Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 7Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. Electronic address: gregorad@med.usc.edu.
  • 8Department of Preventive Medicine and Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. Electronic address: hallayee@usc.edu.

Abstract

Prior efforts to identify regulators of hematopoietic stem cell physiology have relied mainly on candidate gene approaches with genetically modifiedmice. Here we used a genome-wide association study (GWAS) strategy with the hybrid mouse diversity panel to identify the genetic determinants ofhematopoietic stem/progenitor cell (HSPC) frequency. Among 108 strains, we observed ∼120- to 300-fold variation in three HSPC populations. A GWAS analysis identified several loci that were significantly associated with HSPC frequency, including a locus on chromosome 5 harboring the homeodomain-only protein gene (Hopx). Hopx previously had been implicated in cardiac development but was not known to influence HSPC biology. Analysis of the HSPC pool in Hopx-/- mice demonstrated significantly reduced cell frequencies and impaired engraftment in competitive repopulation assays, thus providing functional validation of this positional candidate gene. These results demonstrate the power of GWAS in mice to identifygenetic determinants of the hematopoietic system.

Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

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