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Prepublished online as a Blood First Edition Paper on May 24, 2002; DOI 10.1182/blood-2002-03-0808.
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Blood, 15 September 2002, Vol. 100, No. 6, pp. 2056-2062
HEMATOPOIESIS
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, and
Gary Van Zant
From the Department of Stem Cell Biology, University of
Groningen, and Department of Hematology, University Hospital
Groningen; both of The Netherlands; Division of
Hematology/Oncology, Blood and Marrow Transplant Program, Markey
Cancer Center, University of Kentucky; and Department of Physiology,
University of Kentucky Medical Center; both of Lexington; and
Department of Molecular Biology, Princeton University, NJ.
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 centimorgan (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 3 distinct clusters. The
largest cluster colocalized 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.
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