The International Complex Trait Consortium

A genetic and genomic analysis identifies a cluster of genes associated with hematopoietic cell turnover

Gerald de Haan, Leonid V. Bystrykh, Ellen Weersing, Bert Dontje, Hartmut Geiger, Natalia Ivanova, Ihor R. Lemischka, Edo Vellenga, Gary Van Zant

Dept. of Stem Cell Biology, University of Groningen, the Netherlands
Dept. of Hematology, University Hospital Groningen, the Netherlands
Dept of Molecular Biology, Princeton University
Dept of Hematology/Oncology, University of Kentucky, Lexington, KY

Hematopoietic stem cells from different strains of mice vary widely with respect to their cell cycle activity. In the present study we used complementary genetic and genomic approaches to identify molecular pathways affecting this complex trait. We identified a major quantitative trait locus (QTL) associated with variation in cell proliferation in C57BL/6 and DBA/2 mice to a 10 cM region on chromosome 11. A congenic mouse model confirmed that a genomic interval on chromosome 11 in isolation confers the proliferation phenotype. To detect candidate genes we performed subtractive hybridizations and gene arrays using cDNA from highly enriched stem cells from parental strains. Intriguingly, a disproportionate number of differentially expressed genes mapped to chromosome 11 and, more specifically, these transcripts occurred in three distinct clusters. The largest cluster co-localized exactly with the cell cycling QTL. Such clustering suggested the involvement of genetic variation that affects higher order chromosomal organization. This hypothesis was reinforced by the fact that differentially expressed genes mapped to recombination "coldspots", as a consequence of which clustered genes are collectively inherited. These findings suggest the functional interdependence of these closely linked genes. Our data are consistent with the hypothesis that this isolated cell cycle QTL does not result from a mutation in a single gene, but rather is a consequence of variable expression of a collection of highly linked genes.