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Genetics, Vol. 178, 1937-1945, April 2008, Copyright © 2008
doi:10.1534/genetics.107.084798

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Distinct Functions of MLH3 at Recombination Hot Spots in the Mouse

Anton Svetlanov*,1, Frederic Baudat{dagger},1, Paula E. Cohen*,1 and Bernard de Massy{dagger},1,2

* Department of Biomedical Sciences, Cornell University, Ithaca, New York 14850 and {dagger} Institute of Human Genetics, Centre National de la Recherche Scientifique, UPR1142, 34396 Montpellier, Cedex 5, France

2 Corresponding author: Institute of Human Genetics, Centre National de la Recherche Scientifique, UPR1142, 141 rue de la Cardonille, 34396 Montpellier, Cedex 5, France.
E-mail: bdemassy{at}igh.cnrs.fr

The four mammalian MutL homologs (MLH1, MLH3, PMS1, and PMS2) participate in a variety of events, including postreplicative DNA repair, prevention of homeologous recombination, and crossover formation during meiosis. In this latter role, MLH1–MLH3 heterodimers predominate and are essential for prophase I progression. Previous studies demonstrated that mice lacking Mlh1 exhibit a 90% reduction in crossing over at the Psmb9 hot spot while noncrossovers, which do not result in exchange of flanking markers but arise from the same double-strand break event, are unaffected. Using a PCR-based strategy that allows for detailed analysis of crossovers and noncrossovers, we show here that Mlh3–/– exhibit a 85–94% reduction in the number of crossovers at the Psmb9 hot spot. Most of the remaining crossovers in Mlh3–/– meiocytes represent simple exchanges similar to those seen in wild-type mice, with a small fraction (6%) representing complex events that can extend far from the initiation zone. Interestingly, we detect an increase of noncrossovers in Mlh3–/– spermatocytes. These results suggest that MLH3 functions predominantly with MLH1 to promote crossovers, while noncrossover events do not require these activities. Furthermore, these results indicate that ~10% of crossovers in the mouse are independent of MLH3, suggesting the existence of alternative crossover pathways in mammals.






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Copyright © 2008 by the Genetics Society of America.