The Genetic Landscape of Hematopoietic Stem Cell Frequency in Mice

Xiaoying Zhou; Amanda L. Crow; Jaana Hartiala; Tassja J. Spindler; Anatole Ghazalpour; Lora W. Barsky; Brian J. Bennett; Brian W. Parks; Eleazar Eskin; Rajan Jain; Jonathan A. Epstein; Aldons J. Lusis; Gregor B. Adams; Hooman Allayee

doi:10.1016/j.stemcr.2015.05.008

Stem Cell Reports (Jul 2015)

The Genetic Landscape of Hematopoietic Stem Cell Frequency in Mice

Xiaoying Zhou,
Amanda L. Crow,
Jaana Hartiala,
Tassja J. Spindler,
Anatole Ghazalpour,
Lora W. Barsky,
Brian J. Bennett,
Brian W. Parks,
Eleazar Eskin,
Rajan Jain,
Jonathan A. Epstein,
Aldons J. Lusis,
Gregor B. Adams,
Hooman Allayee

Affiliations

Xiaoying Zhou: Eli 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
Amanda L. Crow: Department of Preventive Medicine and Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Jaana Hartiala: Department of Preventive Medicine and Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Tassja J. Spindler: Eli 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
Anatole Ghazalpour: Departments of Human Genetics, Medicine, and Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
Lora W. Barsky: Eli 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
Brian J. Bennett: Department of Genetics and Nutrition Research Institute, University of North Carolina, Chapel Hill, Kannapolis, NC 28081, USA
Brian W. Parks: Departments of Human Genetics, Medicine, and Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
Eleazar Eskin: Department of Computer Science and Inter-Departmental Program in Bioinformatics, University of California, Los Angeles, Los Angeles, CA 90095, USA
Rajan Jain: Department of Cell and Developmental Biology and Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Jonathan A. Epstein: Department of Cell and Developmental Biology and Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Aldons J. Lusis: Departments of Human Genetics, Medicine, and Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
Gregor B. Adams: Eli 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
Hooman Allayee: Department of Preventive Medicine and Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA

DOI: https://doi.org/10.1016/j.stemcr.2015.05.008
Journal volume & issue: Vol. 5, no. 1
pp. 125 – 138

Abstract

Read online

Prior efforts to identify regulators of hematopoietic stem cell physiology have relied mainly on candidate gene approaches with genetically modified mice. Here we used a genome-wide association study (GWAS) strategy with the hybrid mouse diversity panel to identify the genetic determinants of hematopoietic 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 identify genetic determinants of the hematopoietic system.

Published in Stem Cell Reports

ISSN: 2213-6711 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General); Science: Biology (General)
Website: http://www.cell.com/stem-cell-reports/home

About the journal