Abstract
Differences in frequencies of blood cell subpopulations were reported to influence the course of infections, atopic and autoimmune diseases, and cancer. We have discovered a unique mouse strain B10.O20 containing extremely high frequency of myeloid-derived cells (MDC) in spleen. B10.O20 carries 3.6% of genes of the strain O20 on the C57BL/10 genetic background. It contains much higher frequency of CD11b+Gr1+ cells in spleen than both its parents. B10.O20 carries O20-derived segments on chromosomes 1, 15, 17, and 18. Their linkage with frequencies of blood cell subpopulations in spleen was tested in F2 hybrids between B10.O20 and C57BL/10. We found 3 novel loci controlling MDC frequencies: Mydc1, 2, and 3 on chromosomes 1, 15, and 17, respectively, and a locus controlling relative spleen weight (Rsw1) that co-localizes with Mydc3 and also influences proportion of white and red pulp in spleen. Mydc1 controls numbers of CD11b+Gr1+ cells. Interaction of Mydc2 and Mydc3 regulates frequency of CD11b+Gr1+ cells and neutrophils (Gr1+Siglec-F- cells from CD11b+ cells). Interestingly, Mydc3/Rsw1 is orthologous with human segment 6q21 that was shown previously to determine counts of white blood cells. Bioinformatics analysis of genomic sequence of the chromosomal segments bearing these loci revealed polymorphisms between O20 and C57BL/10 that change RNA stability and genes’ functions, and we examined expression of relevant genes. This identified potential candidate genes Smap1, Vps52, Tnxb, and Rab44. Definition of genetic control of MDC can help to personalize therapy of diseases influenced by these cells.
Highlights
IntroductionDisruption of the normal hematological phenotypes is directly related to multiple diseases [1]
For characterization of myeloid cell population, we examined markers F4/80, CD11b, and CD14 to characterize macrophage lineage, co-expression of CD11b and Gr1 to characterize granulocytes, and CD40 as a marker leukocyte with antigen-presenting function
Our results suggest a possible role for Rab44 in influencing the splenic architecture of mice by modifying frequencies of myeloid-derived cells (MDC) cells
Summary
Disruption of the normal hematological phenotypes is directly related to multiple diseases [1]. Hematological traits have been associated with an increased risk for a number of clinical disorders such as cancer, autoimmune diseases, and total mortality [2]. White blood cell (WBC) numbers are partly under genetic control, with heritability approximately 40%– 60% [3, 4]. Peripheral WBC levels vary among ethnic groups, with neutrophil number levels higher in European Americans than in African Americans [2, 5] due to mutation in Duffy antigen/chemokine receptor (DARC) gene [6]. Different strains of mice exhibited different numbers of WBC [7–9], indicating that the resting state WBC counts are under genetic control. It is essential to identify genes controlling the elements of homeostasis of normal human and animal immune systems, including the relative frequencies of WBC subsets [10]
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