A dominant X-linked QTL regulating pubertal timing in mice found by whole genome scanning and modified interval-specific congenic strain analysis.

BACKGROUND: Pubertal timing in mammals is triggered by reactivation of the hypothalamic-pituitary-gonadal (HPG) axis and modulated by both genetic and environmental factors. Strain-dependent differences in vaginal opening among inbred mouse strains suggest that genetic background contribute significantly to the puberty timing, although the exact mechanism remains unknown. METHODOLOGY/PRINCIPAL FINDINGS: We performed a genome-wide scanning for linkage in reciprocal crosses between two strains, C3H/HeJ (C3H) and C57BL6/J (B6), which differed significantly in the pubertal timing. Vaginal opening (VO) was used to characterize pubertal timing in female mice, and the age at VO of all female mice (two parental strains, F1 and F2 progeny) was recorded. A genome-wide search was performed in 260 phenotypically extreme F2 mice out of 464 female progeny of the F1 intercrosses to identify quantitative trait loci (QTLs) controlling this trait. A QTL significantly associated was mapped to the DXMit166 marker (15.5 cM, LOD = 3.86, p<0.01) in the reciprocal cross population (C3HB6F2). This QTL contributed 2.1 days to the timing of VO, which accounted for 32.31% of the difference between the original strains. Further study showed that the QTL was B6-dominant and explained 10.5% of variation to this trait with a power of 99.4% at an alpha level of 0.05.The location of the significant ChrX QTL found by genome scanning was then fine-mapped to a region of approximately 2.5 cM between marker DXMit68 and rs29053133 by generating and phenotyping a panel of 10 modified interval-specific congenic strains (mISCSs). CONCLUSIONS/SIGNIFICANCE: Such findings in our study lay a foundation for positional cloning of genes regulating the timing of puberty, and also reveal the fact that chromosome X (the sex chromosome) does carry gene(s) which take part in the regulative pathway of the pubertal timing in mice.

Effects of maternal nuclear genome on the timing of puberty in mice offspring.

The timing of puberty is a complex trait which is regulated by environmental and genetic factors, but the detailed regulatory mechanism remains elusive. Maternal nutrition administration during late gestation in rats revealed that the time of onset of puberty in daughter rats was influenced by the mother's nutritional and physiological status during the embryonic development period. In this study, the potential effects of the maternal nuclear genome on the timing of puberty of offspring were investigated. Two inbred strains of mice (C3H/HeJ (C3H) and C57BL/6J (B6)) were used to set up two pedigrees (direct and reciprocal crosses), and the timing of puberty in all these mice (parent, F1 and F2) was recorded (the females were assessed by vaginal opening (VO) and the males by balano preputial separation (BPS)). The results from data of 822 mice showed that: 1) in female mice, the heritability of the timing of puberty in direct and reciprocal crosses is 68.51% and 63.97% respectively; 2) in female mice, a significant difference in the timing of puberty is observed between B6 and C3H (P = 3.7 x 10(-13)) mice as well as between direct and reciprocal F1 hybrids (P = 5.4 x 10(-3)), but not between direct and reciprocal F2 hybrids (P = 0.0941); 3) in male mice, direct and reciprocal F1 hybrids differ significantly from each other in the timing of BPS (P = 2.7 x 10(-7)), while such differences vanish in their male progenitor and progeny. The significant discrepancy between direct and reciprocal crosses in F1 but not in either cross of F2 hybrids reveals that the maternal nuclear genome has effects on the timing of puberty in mice progeny, probably through imprinting genes or the genes associated with intra-uterine physiological status.