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Chromosomes 6 and 13 Harbor Genes that Regulate Pubertal Timing in Mouse Chromosome Substitution Strains

Division of Pediatric Endocrinology and Metabolism (T.D.K., P.J.S., M.R.P.), Rainbow Babies and Children’s Hospital, and Center for Human Genetics (J.H.N.), University Hospitals of Cleveland, and Departments of Pediatrics (T.D.K., P.J.S., M.R.P.) and Genetics (A.E.H., J.H.N., M.R.P.), Case Western Reserve University School of Medicine, Cleveland, Ohio 44106; The Broad Institute of MIT and Harvard (J.B.S., E.S.L.), Cambridge, Massachusetts 02141; The Whitehead Institute for Biomedical Research (J.B.S., E.S.L.), Cambridge, Massachusetts 02142; and Massachusetts Institute of Technology (E.S.L.), Cambridge, Massachusetts 02139

Address all correspondence and requests for reprints to: Mark R. Palmert, M.D., Ph.D, Division of Pediatric Endocrinology and Metabolism, Rainbow Babies and Children’s Hospital, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, Ohio 44106. E-mail: mark.palmert{at}case.edu.

Variation in the onset of puberty among inbred strains of mice suggests that quantitative trait loci (QTLs) affect neurological and hormonal aspects of sexual maturation. Taking a novel approach toward identifying factors that regulate the hypothalamic-pituitary-gonadal (HPG) axis, we evaluated pubertal timing [as assessed by vaginal opening (VO)] in two inbred strains of mice, A/J and C57BL/6J (B6), and in a panel of chromosome substitution strains (CSSs) generated from A/J and B6 mice. In each CSS, a single chromosome from A/J has been substituted in a homozygous fashion for the corresponding chromosome in B6, partitioning the A/J genome into 22 strains with a common host (B6) background. VO occurred significantly earlier in A/J compared with B6 mice. Although the majority of the CSSs assessed had a timing of VO that was similar to the progenitor B6 strain, CSSs for chromosomes 6 and 13 each displayed significantly earlier time of VO than B6 mice. F1 (B6 x CSS) mice for chromosomes 6 and 13 displayed phenotypes that were intermediate between the CSS and B6 strains, suggesting that the trait was inherited in a codominant manner. These findings demonstrate that chromosomes 6 and 13 harbor QTLs that control the timing of VO. Identification of the responsible genes may reveal factors that regulate the maturation of the HPG axis and determine the timing of puberty.

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