Hybrid sterility in male mouse F1 hybrids obtained by crossing different species or subspecies is genetically determined. Hybrid sterility in (C57BL/6J x M. spretus)F1 males involves a locus in the pseudoautosomal region (PAR) were obligatory pairing between the X and Y chromosome takes place during meiosis. In these sterile males X//Y dissociation occurs and the sex chromosomes cannot segregate normally. In the pervious funding period two new loci associated with hybrid sterility on proximal Chr X were identified. One of these loci, Ihtw1, was found in a congenic strain C57BL/6J.Hprts, containing 14 map units from the M. spretus Chr X on a C57BL/6 background. Ihtw1 is associated with small testis weight and allows partial fertility, but only half of the testicular tubules are filled with meiotic cells and developing sperm, while the other tubules are empty. The second new locus also on proximal Chr X, prevents entry into male meiosis I and was found using the male progeny of the backcross, (C57BL/6J x M. macedonicus) x C57BL/6J. Some backcross males carrying M. Macedonicus alleles at the distal end of Chr X enter meiosis but show X//Y dissociation. This study also identified a locus on proximal Chr 17, that may be identical to the previously described Hst loci. This proposal has two major goals. The first goal is to extend the genetic analysis of the mouse PAR and to initiate a physical analysis of this region, using a number of resources already generated by earlier work on this grant and by new resources described in this proposal. The physical structure of the PAR will be correlated with recombination frequency and with the positions of recombination that have occurred in both male and female F1 animals. Second, Ihtw1 will be fine mapped and additional congenic strains will be made to isolate the genes controlling the phenotypes discovered in the recently analyzed M. macedonicus backcross. The genetic isolation of the phenotypes in congenic strains is a necessary first step toward identification and cloning of the genes. Each of these genes has at least one suppressor, and genetic experiments are described to map the suppressors for the loci affecting hybrid sterility and to determine whether they act in a dominant or recessive manner. The loci found on proximal Chr X and their suppressor may play a significant role in causing sterility in the human male.
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