Genetic recombination is responsible for the re-assortment of alleles at each generation;for our own species, this means the assortment of disease susceptibility alleles across generations and populations, and for all organisms, generating the substrates of evolutionary change. While there has been considerable progress in understanding the molecular details underlying recombination processes, especially in yeast species, among mammalian organisms we are still relatively ignorant of many aspects of recombination biology, including the factors determining the location and relative activity of individual recombination hotspots, and the choice between the crossover and non-crossover (gene conversion) pathways as outcomes of the recombination process. We have now discovered the existence of a trans-acting regulatory system whose products control the behavior of individual hotspots. We compared the hotspot recombination maps of mice heterozygous C57BL/6J and CAST/EiJ for the distal half of Chr 1 when the remaining genomic regions were either homozygous B6 or heterozygous B6/CAST. The activities of some hotspots in this region are dependent on the presence of CAST alleles at distant genes and others are suppressed by such alleles. CAST activated hotspots are controlled in an all-or-none fashion;we do not know about suppressed hotspots. This discovery opens the possibility of new approaches to understanding hotspot behavior by characterizing the genetic architecture of the control system and whether it regulates the formation of the double strand DNA breaks that initiate recombination or regulates the choice between crossover and noncrossover pathways. These findings will eventually open the way to identifying a new class of molecules involved in recombination processes and elucidating recombination control mechanisms. We will determine the number and the location of the trans-acting genes and how they interact;the dependence of hotspot activity on the dosage of trans-acting gene alleles, and, using a new cloning assay for characterizing recombination events at individual hotspots, determine whether the various trans-acting genes control both gene conversion and crossing over, or are specific to crossing over.

Public Health Relevance

Our genetic heritage has a strong influence on our susceptibility to all of the common diseases that afflict us. Mapping the genes responsible for these susceptibilities provides a means of identifying targets for intervention, both preventive and therapeutic, and for developing a personalized medicine adapted to our individual constitutions. The proposed experiments will help us understand how combinations of genes are transmitted from one generation to the next and how we can improve our ability to identify the genes underlying disease susceptibility. Our project thus has relevance to all issues of health and disease that have any genetic component, and specifically to problems of tumorigenesis and infertility that involve DNA rearrangements and repair.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Genomics, Computational Biology and Technology Study Section (GCAT)
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Hagan, Ann A
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Jackson Laboratory
Bar Harbor
United States
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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
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
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
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Parvanov, Emil D; Petkov, Petko M; Paigen, Kenneth (2010) Prdm9 controls activation of mammalian recombination hotspots. Science 327:835