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The ability to examine all chromatids from a single meiosis in yeast tetrads has been indispensable for defining the mechanisms of homologous recombination initiated by DNA double-strand breaks (DSBs). Using a broadly applicable strategy for the analysis of chromatids from a single meiosis at two recombination hotspots in mouse oocytes and spermatocytes, we demonstrate here the unidirectional transfer of information-gene conversion-in both crossovers and noncrossovers. Whereas gene conversion in crossovers is associated with reciprocal exchange, the unbroken chromatid is not altered in noncrossover gene conversion events, providing strong evidence that noncrossovers arise from a distinct pathway. Gene conversion frequently spares the binding site of the hotspot-specifying protein PRDM9, with the result that erosion of the hotspot is slowed. Thus, mouse tetrad analysis demonstrates how unique aspects of mammalian recombination mechanisms shape hotspot evolutionary dynamics.
Sexual reproduction requires the formation of haploid gametes from diploid precursors through meiosis, which comprises two divisions following a single round of genome duplication. During the first meiotic prophase, recombination establishes physical connections between homologous chromosomes (homologs), essential for proper chromosome segregation1-3.
Recombination is best understood in yeast, in part because all four chromatids from a single meiosis-a tetrad-can be recovered4. Tetrad analysis demonstrated that recombination can occur with an exchange of chromatid arms, as a crossover, or without an exchange, as a noncrossover5. Importantly, both crossovers and noncross- overs are often associated with gene conversion, the non-reciprocal transfer of information from a donor chromatid to a recipient. A model to account for this transmission, confirmed later by molecular approaches, holds that recombination initiated by DSBs leads to gene conversion at the DSB site using information from the uncut donor chromatid6. This model posited the formation of a double- Holliday junction intermediate that is resolved as a crossover or a noncrossover, such that either resolution type can lead to conversion of markers on the donor. Work in budding yeast supports this model for crossovers but demonstrated that most noncrossovers arise by pathways that do not involve the resolution of a double Holliday junction or alteration of the donor chromatid7-11.
In mammals, crossovers are detected by genetic mapping in pedi- grees and by sperm and oocyte typing, and they can be inferred from population diversity analysis12-17. Events involving the transfer of...