QTL influencing baseline hematocrit in the C57BL/6J and DBA/2J lineage: age-related effects

Abstract

Baseline serum hematocrit varies substantially in the population. While additive genetic factors account for a large part of this variability, little is known about the genetic architecture underlying the trait. Because hematocrit levels vary with age, it is plausible that quantitative trait loci (QTL) that influence the phenotype also show an age-specific profile. To investigate this possibility, hematocrit was measured in three different age cohorts of mice (150, 450, and 750 days) of the C57BL/6J (B6) and the DBA2/J (D2) lineage. QTL were searched in the B6D2F(2) intercross and the BXD recombinant inbred (RI) strains. The effects of these QTL were explored across the different age groups. On the phenotypic level, baseline serum hematocrit declines with age in a sex-specific manner. In the B6D2F(2) intercross, suggestive QTL that influence the phenotype were located on Chromosomes (Chr) 1, 2, 7, 11, 13, and 16. With the exception of the QTL on Chr 2, all of these QTL exerted their largest effect at 750 days. The QTL on Chr 1, 2, 7, 11 and 16 were confirmed in the BXD RIs in a sex- and age-specific manner. Linkage analysis in the BXD RIs revealed an additional significant QTL on Chr 19. Baseline serum hematocrit is influenced by several QTL that appear to vary with the age and sex of the animal. These QTL primarily overlap with QTL that have been shown to regulate hematopoietic stem cell phenotypes.

Quantitative Trait Loci Analysis for Peripheral Blood Parameters in a (BALB/cW * C57BL/6J-Mpl hlb219/J) F2 Mice

“…In the proximal region of Chr 11, we found highly significant QTL influencing RBC (D11Mit78, 10.44cM). Although QTLRbcq3 (Chr 11, 42.88cM), detected by Peters et al [26], is situated outside the confidence interval (25cM), QTLs for other erythrocyte parameters, Mcvq2 (7.3cM [26]) for MCV and Hemq4 (9.92cM [16]) for HCT, are localized in close proximity to the detected QTL. Simultaneously, we cannot exclude the possibility that the same gene causes the effect of all these QTLs.…”

“…The research began at the turn of the 21st century and has been continued by several groups of scientists. Until now, analyses of QTL influencing blood cells parameters have been conducted on groups of laboratory animals [1,7,12,14,16,21,26,27,39], but the same results have been obtained from examination of other mammals, such as swine [31,42] and baboons [3].…”

“…The highly significant QTL for RBC on chromosome 1, locus D1Mit218 (55.76cM, CI=19cM), is close to Rbcqtl1 [27], Pbrbc2 [14], or Rbcqtl2 [8]. Moreover, QTL for HCT, Hemq1 [16] situated in the vicinity (5cM) of QTL locus D1Mit218, and QTL for MCV, Mcvqtl1 [8], are in the determined confidence interval. In our study, we detected that this locus is also connected with MCH and MCV.…”

“…The peak marker was D7Nds1 (43.46cM). Data from the literature indicates a QTL for cell hemoglobin concentration mean (CHCM) Chcmq3 (Chr 7, 55cM) [28], and QTLs for morphological parameters of erythrocytes, Mcvq1 (32.84cM) for MCV [27] and Hemq3 (61.37cM) for HCT [16], which were mapped in this region of chromosome 7. The QTL for HGB on chromosome 16 (10.09cM) can be compared with Hgbq1(23.27cM) [27], and this locus seems to be responsible only for the functional parameters of the erythrocytes, as there is no correlation between this location and RBC or MCV.…”

Mapping Temporally Varying Quantitative Trait Loci in Time-to-Failure Experiments

“…These changes are in part driven by the temporal regulation of the genes or quantitative trait loci (QTL) underlying these phenotypes. Simple experiments in which the same trait was measured across several age cohorts of mice, for instance, have revealed different sets of QTL in each cohort (e.g., Cheverud et al 1996;Henckaerts et al 2002;Lionikas et al 2005;Johannes et al 2006), suggesting that these genetic regions operate in a time-dependent manner. Recent methods (Ma et al 2002;W.…”