title: The Genetic Landscape of Hematopoietic Stem Cell Frequency in Mice.
abstract: 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.
authors.affiliation: 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.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Preventive Medicine and Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Crow
authors.affiliation: Department of Preventive Medicine and Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Jaana
authors.initials: J
authors.lastname: Hartiala
authors.affiliation: 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.
authors.forename: Tassja J
authors.initials: TJ
authors.lastname: Spindler
authors.affiliation: Departments of Human Genetics, Medicine, and Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Anatole
authors.initials: A
authors.lastname: Ghazalpour
authors.affiliation: 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.
authors.forename: Lora W
authors.initials: LW
authors.lastname: Barsky
authors.affiliation: Department of Genetics and Nutrition Research Institute, University of North Carolina, Chapel Hill, Kannapolis, NC 28081, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bennett
authors.affiliation: Departments of Human Genetics, Medicine, and Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Parks
authors.affiliation: Department of Computer Science and Inter-Departmental Program in Bioinformatics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Eleazar
authors.initials: E
authors.lastname: Eskin
authors.affiliation: Department of Cell and Developmental Biology and Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Rajan
authors.initials: R
authors.lastname: Jain
authors.affiliation: Department of Cell and Developmental Biology and Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Epstein
authors.affiliation: Departments of Human Genetics, Medicine, and Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.affiliation: 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. Electronic address: gregorad@med.usc.edu.
authors.forename: Gregor B
authors.initials: GB
authors.lastname: Adams
authors.affiliation: Department 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.
authors.forename: Hooman
authors.initials: H
authors.lastname: Allayee
mesh_terms: D000818:Animals; D019070:Cell Lineage / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D055106:Genome-Wide Association Study; D006412:Hematopoietic Stem Cells; D018398:Homeodomain Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout
chemical_list: C473013:Hod protein, mouse; D018398:Homeodomain Proteins