This project focuses on the human Y. chromosome in the context of the Human Genome Project's 5-year goals as recently stated by Collins et al. (Science 282:682-689, 1998). The principal long-term objective of this project is systematic cataloguing, and interpretation, of natural variation in genes in the NRY (the Non-Recombining portion of the Y chromosome, comprising 95% of the chromosome). The NRY differs from the remainder of the nuclear genome in two respects: it is found in only one sex, and it does not participate in meiotic recombination. Thus, one might expect that variation in NRY genes would differ systematically from that on autosomes or the X chromosome. This project aims to explore this preposition in detail at the nucleotide level. The central aim of the present three-year proposal is to assembly a nearly comprehensive catalog of coding sequence variation in NRY genes. Specifically, coding sequence variants will be identified in 48 diverse Y haplotypes representing the great majority of US males. As a control for these studies of NRY genes, variants in the coding sequences of X-linked or autosomal homologs (of NRY genes) will also be catalogued. To place this survey of human sequence variation in context, parallel studies of NRY (and homologous) gene variation will be conducted in non-human primates. In collaboration with other investigations, we will systematically catalog polymorphism in human NRY gene order or copy number among the 48 Y haplotypes mentioned previously. The resulting catalog of NRY gene variation will provide a foundation for elucidating the roles of the Y chromosome in health and disease.
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