Submitted March 4, 2009
Accepted April 28, 2009
A chromosome 16 quantitative trait locus regulates allogeneic bone marrow engraftment in non-myeloablated mice
Thai M. Cao*, Alun Thomas, Yuanyuan Wang, Schickwann Tsai, Kathryn Logronio, and Judith A. Shizuru
Blood and Marrow Transplantation Program, Department of Medicine, University of Utah, Salt Lake City, UT, United States
Department of Biomedical Informatics, University of Utah, Salt Lake City, UT, United States
Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
* Corresponding author; email: thai.cao{at}hsc.utah.edu.
Identifying genes that regulate bone marrow (BM) engraftment may reveal molecular targets for overcoming engraftment barriers. To achieve this aim, we applied a forward genetic approach in a mouse model of non-myeloablative BM transplantation. We evaluated engraftment of allogeneic and syngeneic BM in BALB.K and B10.BR recipients. This allowed us to partition engraftment resistance into its intermediate phenotypes, which are firstly the immune-mediated resistance and secondly the non-immune rejection of donor BM cells. We observed that BALB.K and B10.BR mice differed with regards to each of these resistance mechanisms, thereby providing evidence that both are under genetic control. We then generated a segregating backcross (n = 200) between the BALB.K and B10.BR strains to analyze for genetic linkage to the allogeneic BM engraftment phenotype using a 127-marker genome scan. This analysis identified a novel quantitative trait locus (QTL) on chromosome 16, termed Bmgr5 (LOD 6.4, at 11.1 cM). The QLT encodes susceptibility alleles, from the BALB.K strain, that are permissive for allogeneic BM engraftment. Further identification of Bmgr5 genes by positional cloning may reveal new and effective approaches for overcoming BM engraftment obstacles.
