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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM078452-04
Application #
7771708
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Hagan, Ann A
Project Start
2007-03-01
Project End
2012-02-29
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
4
Fiscal Year
2010
Total Cost
$440,466
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Parvanov, Emil D; Tian, Hui; Billings, Timothy et al. (2017) PRDM9 interactions with other proteins provide a link between recombination hotspots and the chromosomal axis in meiosis. Mol Biol Cell 28:488-499
Walker, Michael; Billings, Timothy; Baker, Christopher L et al. (2015) Affinity-seq detects genome-wide PRDM9 binding sites and reveals the impact of prior chromatin modifications on mammalian recombination hotspot usage. Epigenetics Chromatin 8:31
Didion, John P; Morgan, Andrew P; Clayshulte, Amelia M-F et al. (2015) A multi-megabase copy number gain causes maternal transmission ratio distortion on mouse chromosome 2. PLoS Genet 11:e1004850
Baker, Christopher L; Petkova, Pavlina; Walker, Michael et al. (2015) Multimer Formation Explains Allelic Suppression of PRDM9 Recombination Hotspots. PLoS Genet 11:e1005512
Baker, Christopher L; Kajita, Shimpei; Walker, Michael et al. (2015) PRDM9 drives evolutionary erosion of hotspots in Mus musculus through haplotype-specific initiation of meiotic recombination. PLoS Genet 11:e1004916
Baker, Christopher L; Walker, Michael; Kajita, Shimpei et al. (2014) PRDM9 binding organizes hotspot nucleosomes and limits Holliday junction migration. Genome Res 24:724-32
Billings, Timothy; Parvanov, Emil D; Baker, Christopher L et al. (2013) DNA binding specificities of the long zinc-finger recombination protein PRDM9. Genome Biol 14:R35
Billings, Timothy; Sargent, Evelyn E; Szatkiewicz, Jin P et al. (2010) Patterns of recombination activity on mouse chromosome 11 revealed by high resolution mapping. PLoS One 5:e15340
Paigen, Kenneth; Petkov, Petko (2010) Mammalian recombination hot spots: properties, control and evolution. Nat Rev Genet 11:221-33
Parvanov, Emil D; Petkov, Petko M; Paigen, Kenneth (2010) Prdm9 controls activation of mammalian recombination hotspots. Science 327:835

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