Complex dynamics of meiotic recombination initiation in laboratory mouse strains. K. Brick1, F. Smagulova2, R. D. Camerini-Otero1, G. Petukhova2 1) Genetics & Biochemistry Branch, NIDDK, National Institutes of Health, Bethesda, MD, USA; 2) Deparment of Biochemistry and Molecular Biology, Uniformed Services University of Health Sciences, Bethesda, MD, USA.

   In mouse and in other mammals, the DNA double strand breaks (DSBs) that initiate meiotic recombination are directed to a subset of genomic loci called hotspots by the PRDM9 protein. The C-terminal zinc finger (ZnF) array of PRDM9 is responsible for directing sequence specific DNA binding of PRDM9, yet this ZnF-array is highly polymorphic with over 100 alleles described in mouse. We have previously developed the first method to directly map the sites of meiotic DSBs genome-wide and here, we exploit this technique to categorize the recombination initiation landscape in six common laboratory mouse strains with different PRDM9 alleles and in their F1 hybrids.

We find that DSB hotspots defined by the six different alleles of the PRDM9 protein occur mostly at mutually exclusive loci. Furthermore, even very similar PRDM9 alleles that differ by only a single zinc finger (C57Bl/6J and C3H/HeJ) define mostly different hotspots. In addition to clear dominance of some PRDM9 alleles over others, a striking finding in F1 mice is that of the appearance of novel DSB hotspots, not present in either parental genome. In some cases, such sites constitute 30% of all hotspots. By analyzing the DNA sequence pulled down from DMC1 ChIP-Seq in B6xCAST F1 mice we found that the vast majority of novel hotspots are formed by the PRDM9 allele from one parental strain on the chromosome of the other parental strain (non-self chromosome). A straightforward explanation is that novel hotspots arise due to the presence of new PRDM9 binding sites on the non-self chromosome, however we can only find evidence for this at ~50% of novel hotspots. Biased DSB initiation on the non-self chromosome is also observed at other hotspots and results in hotspots that are relatively stronger than in the parental genome. We will also discuss curiously frequent instances of hotspots that coincide with the sites where DSBs form in the absence of PRDM9 and will provide evidence for broad domains of DSB formation across mouse strains that agree with crossover data. Together, these findings elucidate some of the complex dynamics of DSB formation in mammalian meiosis.

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