This application requests renewed funding for a project to develop reagents for testing specific genes for association with cancer predisposition. In the initially funded application, efforts were focused on development of genomic sequence data from numerous genes with known or suspected involvement in cancer predisposition, and on the development of reagents capable of detecting variation at these loci in pilot studies. The initial request was for three years of funding. The rationale for the short time frame was in part due to the rapid changes in human genome sequencing program (HGP), such that the utility of the proposed sequencing efforts might be diminished by the rapid advancement of the HGP. Moreover, the ability to develop and characterize SNPs at the loci of interest, and their potential utility in defining haplotypes were both unknown. In this request for renewed funding, the role of genomic sequencing has been reduced to """"""""finishing"""""""" clones in order to provide high quality, contiguous sequence for genes with suspected cancer involvement. Improved methods for the identification and typing of SNPs are proposed in order to accelerate these efforts. Finally, subcontracts with experts in population and statistical genetics are included that will provide improved approaches to the design and execution of association studies based on complex haplotypes. This addition to the project is essential for the final aim of pilot association studies. The project is composed of the following aims: 1. Sequencing of the target genes initiated in the project will be completed. 2. Identification of SNPs will continue, through the use of publicly accessible database entries, and by direct identification, resulting in genetic reagents available for association studies for 25 additional genes. 3. Methods will be developed to improve detection and typing of SNPs in the targeted loci. 4. Methods for improved haplotype inferences from multiple SNP site genotype data will be developed. 5. Methods will be developed to utilize haplotypes associated with phenotype to locate and identify possible site of variation responsible for the phenotype. 6. Pilot association studies with the markers and haplotypes developed will be initiated.
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