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
ABSTRACT
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.