A tau haplotype is a variant form of the proximal portion of mouse chromosome 17 that has evolved the ability to propagate itself at the expense of wild-type meiotic partners. Males that are heterozygous for a tau haplotype can transmit it as an intact genetic unit to 95% or more of their off spring. This phenotype, known as transmission ration distortion (TRD), results from the genetic interaction of a series of tau-specific alleles at loci distributed along the 15 cM region of a tau haplotype. Two types of TRD loci have been defined. One is the tau complex responder (Tcr) locus which acts in a haploid-specific manner to determine which homolog of chromosome 17 will be transmitted at a high ratio. The second is the class tau complex disorder (Tcd) loci which can act in cis or trans configuration to Tcr and are defined by their ability to control the absolute level at which transmission ratios are distorted. The goal of the first three specific aims of this proposal is an increased understanding of the TRD phenotype and tau haplotype effects on sperm function. In particular, the first specific aim is directed toward a further analysis of the expression & function of a recently-cloned gene family that includes a strong candidate for the Tcr locus. Three types of experiments are proposed: (1) PCR analysis of patterns of expression and transcript processing during sequential stages of haploid germ cell differentiation; (2) transgenic studies of the functionality of the candidate Tcr gene; and (3) analysis of polypeptide products from the candidate Tcr gene. The second specific aim is directed toward studies of the Tcd loci. Experiments similar to those described above will be performed on a cloned candidate for one of the Tcd loci, and additional Tcd loci will be cloned based on the genetics and molecular biology of the tau system. The third specific aim is directed toward a genetic analysis of a tau haplotype-induced sterility phenotype. Finally, the goal of the fourth specific aim is a better understanding of the evolutionary history of tau haplotypes. This will be accomplished through the construction of phylogenetic trees (by a maximum parsimony algorithm) for loci distributes along the tau region. The ultimate objective of the research described in this proposal is to use the tau haplotype system as a vehicle with which to gain insight towards (1) general principles of germ cell differentiation & the role played in this process by haploid gene expression, and (2) general principles of chromosomal evolution in mice.
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