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This is a revised application requesting five years of support to continue Bishop's research on the identification and functional characterization of genes that reside on the mouse Y chromosome. During the past five to six years, Bishop's laboratory has established a long range physical map of the Sxr and Sxrb deletion mutant regions and has constructed a YAC contig covering nine of thirteen deletion intervals defined in the Sxr region by mapping studies conducted in collaboration E. Eicher, D. Roopinian (Jackson labs) and E. Simpson (CRC).

The first Specific Aim of the revised application proposes to complete the structural map of the mouse Y chromosome short arm and to establish a saturation transcription map for this region. Mouse bacterial and yeast artificial chromosome libraries will be screened to close existing gaps in the map. Transcription maps will be produced using BAC and YAC DNAs as templates for cDNA selection, large fragment exon trapping, and hybridization to subtractive cDNAs. Using cDNA selection, Bishop's group identified Smcy and its homologue on the X chromosome, Smcx. These genes encode members of a family of putative transcription factors that includes the human retinoblastoma binding protein-2 (RBP-2). Smcx is of interest as Bishop has shown that it escapes X-inactivation, the only gene known to do so in the mouse.

The objective of the second Specific Aim of the revised application is to determine the biological function of Smcx using gene targeting via homologous recombination in ES cells. The Smcy gene was found by Bishop's group to encode the male specific minor histocompatibility antigen, H-Y, in both man and mouse.

The potential function of Smcy, and also of the Ube1y gene, will be investigated the third Specific Aim. The Ube1y gene was discovered by Bishop's group using conserved sequences as probes to identify genes within the Sxrb deletion region. This work revealed that Ube1y is the Y chromosome homologue of Ube1x, the X-linked gene encoding Ubiquitin activating enzyme E1. Based on its chromosomal location and testis specific germ cell dependent expression, Bishop has proposed that Ube1y is a candidate for Spy, the Y-linked spermatogenesis factor required for post-natal mitotic proliferation. The biological roles of Ube1y and Smcy will be investigated using large genomic cosmid, BAC, or YAC fragments to complement the loss of spermatogenesis in XOSxrb male mice. Sxrb is an interstitial deletion within Sxr that removes Smcy, Ube1y, and potentially unknown genes as well. Whereas XOSxr germ cells show most stages of spermatogenesis, the germ cells in the XOSxrb testis are blocked prior to the first meiotic metaphase.
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