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Histone methyltransferase PRDM9 is not essential for meiosis in male mice

ABSTRACT: A hallmark of meiosis is the rearrangement of parental alleles to assure genetic diversity in gametes. These chromosome rearrangements are mediated by the repair of programmed DNA double-strand-breaks (DSBs) as genetic crossovers between parental homologs. In mice, humans, and many other mammals, meiotic DSB occur primarily at hotspots, determined by sequence-specific binding of the PRDM9 protein. Without PRDM9, meiotic DSBs occur near gene promoters and other functional sites. Studies in a limited number of mouse strains showed that functional PRDM9 is required to complete meiosis, but despite its apparent importance, Prdm9 has been repeatedly lost across many animal lineages. Both the reason for mouse sterility in the absence of PRDM9 and the mechanism by which Prdm9 can be lost remain unclear. Here, we explore if mice can tolerate the loss of Prdm9. By generating Prdm9 functional knockouts in an array of genetic backgrounds, we observe a wide range of fertility phenotypes and ultimately demonstrate that PRDM9 is not required for completion of meiosis. Although DSBs still form at a common subset of functional sites in all mice lacking PRDM9, meiotic outcomes differ substantially. We speculate that DSBs at functional sites are difficult to repair as a crossover and that by increasing the efficiency of crossover formation at these sites, genetic modifiers of recombination rates can allow for meiotic progression. This model implies that species with a sufficiently high recombination rate may lose Prdm9 yet remain fertile.

ORGANISM(S): Mus musculus

PROVIDER: GSE109874 | GEO | 2019/06/07

REPOSITORIES: GEO

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Recombination initiation maps of individual human genomes

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2014-11-17 | E-GEOD-59836 | biostudies-arrayexpress

Recombination initiation maps of individual human genomes

2014-11-17 | GSE59836 | GEO

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Cataloging human PRDM9 variability utilizing long-read sequencing technologies reveals PRDM9 population-specificity and two distinct groupings of related alleles

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Genetic recombination is directed away from functional genetic sites in mice.

Project description:Genetic recombination occurs during meiosis, the key developmental program of gametogenesis. Recombination in mammals has been recently linked to the activity of a histone H3 methyl-transferase, PRDM9, the product of the only known speciation gene in mammals. PRDM9 is thought to determine the preferred recombination sites - recombination hotspots - through sequence-specific binding of its highly polymorphic multi-Zn-finger domain. Nevertheless, Prdm9 knockout mice are proficient at initiating recombination. Here we map and analyze the genome-wide distribution of recombination initiation sites in Prdm9 knockout mice and in two mouse strains with different Prdm9 alleles and their F1 hybrid. We show that PRDM9 determines the positions of practically all hotspots in the mouse genome, with the remarkable exception of the pseudoautosomal region – the only area of the genome that undergoes recombination in 100% of cells. Surprisingly, hotspots are still observed in Prdm9 knockout mice and as in wild-type, these hotspots are found at H3K4 trimethylation marks. However, in the absence of PRDM9, the majority of recombination is initiated at promoters and at other sites of PRDM9-independent H3K4 trimethylation. Such sites are rarely targeted in wild-type mice indicating an unexpected role of the PRDM9 protein in sequestering the recombination machinery away from gene promoter regions and other functional genomic elements.

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