The major objective of this proposal is the identification and characterization of human analogues of mouse t complex genes expressed in a testes-specific manner (referred to generically as Tcte genes). Variant forms of the t complex, known as t haplotypes, carry a set of mutant Tcte genes that interact to the detriment of sperm function. To date, a total of 16 t-complex testes-expressed gene have been defined by cloning or phenotypic expression. Six independent Tcte genes/gene families have been cloned, and four of these show cross-hybridization to human DNA and map to human chromosome 6. We will determine if the untested mouse Tcte genes also hybridize with human DNA. Our working hypothesis is that most, if not all, Tcte genes will be localized to human chromosome 6, and that a subset of male sterilities are a result of mutation in these genes. Representative clones for each human Tcte gene will be obtained and sequenced for comparison with the known mouse sequences (both wild-type and mutant). DNA will be obtained from a random population of individual for a survey of the type and frequency of polymorphisms associated with each Tcte gene. Three independent methods - in situ hybidization, somatic cell hybrid analysis, and pedigree studies - will be used for high resolution mapping of all chromosome 6-associated Tcte genes. The gene order of human chromosome 6 will be compared with that of mouse chromosome 17 to formulate models for chromosomal evolution. Since there is evidence for at least two separate clusters of Tcte genes in the mouse, we will use the techniques of pulse field gel electrophoresis and yeast artificial chromosome cloning to determine the possible presence of Tcte gene clusters in humans. Finally, once we have completed a basic characterization of the human Tcte system, our long-range goal will be to analyze the segregation of chromosome 6 alleles with familial cases of male infertility.
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