Abstract

Identification of the genetic regulators of hematopoietic stem cell (HSC) physiology has relied mainly on candidate gene approaches with genetically modified mice. However, the majority of these analyses can be constrained by the experimental procedures used to interrogate the gene of interest, the strain of mouse used, or the fact that candidate gene approaches are inherently biased towards the hypothesis that is being tested. Here we used a genome-wide association study (GWAS) strategy in a recently developed panel of classic inbred and recombinant inbred mouse strains, termed the Hybrid Mouse Diversity Panel (HMDP) to identify the genetic determinants of hematopoietic stem/progenitor cell (HSPC) frequency in adult bone marrow.  Among the 111 different strains of mice characterized, we observed 25 to 80-fold variation in three HSPC populations  A GWAS analysis identified variants at several loci that were significantly associated with HSPC frequency, including a locus on chromosome 5 containing homeodomain only protein (Hopx).  Hopx had previously been implicated in cardiac development but is otherwise not known to influence HSPC biology. Analysis of the HSPC pool in Hopx-/- mice demonstrated significantly reduced cell frequencies, thus providing functional validation of this positional candidate gene. These results demonstrate the power of GWAS in mice to identify novel genetic determinants of the hematopoietic system.