The goal of the subaward is to perform resequencing and association tests of candidate genes suggested by human and mouse data to identify genes that regulate the timing of puberty. Through analysis of a unique panel of chromosome substitution strains (CSS), we have recently demonstrated that chromosomes 6 and 13 harbor genes that contribute to differences in the timing of vaginal opening between two inbred mouse strains (C57BL/6J and A/J). This finding lays the foundation for our studies designed to fine map individual quantitative trait loci (QTL) and identify responsible genes. In a complementary series of studies, a candidate gene approach will be used to identify genes that regulate the onset of puberty in humans. Initially these studies will focus on biological candidates and pathways drawn from the literature and informed by the mouse data (i.e. chromosomal location). Once mouse genes have been identified, subsequent studies will focus on analysis of the homologous human pathways. A unique set of resources and individuals has been assembled for this proposal. These include the CSS, existing populations of trios (probands with late pubertal development and their parents), and a cohort of women with timing of menarche within the earliest or latest 10% of the population. The investigative team includes a PI with the required experience in mouse and human studies and world renowned experts in the study of complex traits in mice and in humans. Together we propose to: (1) Identify small regions of the mouse genome that modulate the timing of vaginal opening using the CSS and congenic mice for QTL mapping; (2) Identify causative genes within the QTLs through analysis of sequence differences between the two progenitor strains combined with the generation and phenotyping of bacterial artificial chromosome transgenic mice; and (3) Evaluate whether sequence variation within candidate genes from selected biological and mouse-derived pathways modulates the timing of puberty in humans by performing association studies among populations with pubertal onset at the extremes of normal timing.
