The DNA sequence of the human genome provides the foundation for elucidating the functions of genes on a large scale, and understanding the consequences of genetic perturbations on human health. We propose to continue studies using the mouse as a model for uncovering gene functions in mammals, concentrating on a particularly fascinating region of the genome known as the t complex on chromosome 17. Variant alleles or mutations of genes within the t complex cause a variety of phenotypes, including embryonic lethality, male infertility, segregation distortion, hybrid sterility, parent-of-origin (imprinting) effects, and sex reversal. Most of these phenotypes are associated with naturally-occurring, variant forms of the t complex known as t haplotypes. Classical genetic analyses of these mutations are largely ineffective, due to inversions in the t haplotypes that prevent recombination. Other phenotypes are only revealed in the context of segmental aneuploidy, and thus the underlying genes are also refractory to meiotic mapping. To identify genes underlying these t complex phenomena and to identify new functions along this region of the genome, we have developed a series of overlapping chromosomal deletion complexes that overlap in an interdigitated fashion. In the proposed work, this collection of deletions and other molecular genetic approaches will be used to: 1) Characterize and clone newly discovered haplolethal and imprinted loci; 2) Identify the T associated sex reversal locus (Tas); 3) Identify the gene or genes underlying the tw18 mutation, which disrupts gastrulation due to defective mesoderm migration and survival; and 4) Identify new genetic functions in the t complex by systematically generating mice that are nullizygous for various t complex intervals, using combinations of deletions.
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