Hotspots, the chromosomal regions where meiotic crossovers tend to localize, limit mapping resolution in experimental organisms and confound the use of linkage disequilibrium to map disease genes in humans. The goal of the proposed project is to generate the first high-resolution, large-scale map of recombination hotspots for an entire chromosome. This information will provide a resource for identifying and characterizing hotspots anywhere in the genome, and for understanding the relationship between hotspots and the functional and structural organization of the genome. To generate the map, we will first map an estimated 500-1,000 hotspots on mouse Chr 1 at 50-kb resolution in each of two crosses involving genetically distinct mouse strains. Three thousand female meioses and three thousand male meioses will be used in each cross. Recombination activity in the two crosses will then be compared, allowing testing of hotspots for genetic variation, sex specificity, and imprinting effects. Hotspots found to be sex- or strain- specific will then be mapped to 3-kb resolution, followed by performance of sperm assays on a broad pool of F1 samples from 16 strains to identify, for each hotspot, the parental strains in which recombination is initiated. Relevance to Public Health: The proposed work will have significant, immediate applications in mapping genes underlying any disease with a significant genetic component, both in humans and experimental animals, and will help to improve our understanding of processes leading to development of genetically influenced human diseases, such as cancer and infertility.
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