Abstract
BackgroundHomologous recombination is the key process that generates genetic diversity and drives evolution. SPO11 protein triggers recombination by introducing DNA double stranded breaks at discreet areas of the genome called recombination hotspots. The hotspot locations are largely determined by the DNA binding specificity of the PRDM9 protein in human, mice and most other mammals. In budding yeast Saccharomyces cerevisae, which lacks a Prdm9 gene, meiotic breaks are formed opportunistically in the regions of accessible chromatin, primarily at gene promoters. The genome-wide distribution of hotspots in this organism can be altered by tethering Spo11 protein to Gal4 recognition sequences in the strain expressing Spo11 attached to the DNA binding domain of the Gal4 transcription factor. To establish whether similar re-targeting of meiotic breaks can be achieved in PRDM9-containing organisms we have generated a Gal4BD-Spo11 mouse that expresses SPO11 protein joined to the DNA binding domain of yeast Gal4.ResultsWe have mapped the genome-wide distribution of the recombination initiation sites in the Gal4BD-Spo11 mice. More than two hundred of the hotspots in these mice were novel and were likely defined by Gal4BD, as the Gal4 consensus motif was clustered around the centers in these hotspots. Surprisingly, meiotic DNA breaks in the Gal4BD-Spo11 mice were significantly depleted near the ends of chromosomes. The effect is particularly striking at the pseudoautosomal region of the X and Y chromosomes – normally the hottest region in the genome.ConclusionsOur data suggest that specific, yet-unidentified factors influence the initiation of meiotic recombination at subtelomeric chromosomal regions.
Highlights
Homologous recombination is the key process that generates genetic diversity and drives evolution
Expression of the alpha isoform in males predominantly occurs in late prophase, beginning in early pachynema [11], and lack of SPO11α correlates with a reduction in the number of late-forming Double stranded DNA breaks (DSB) in the pseudoautosomal region (PAR) [12]
This domain recognizes the CGGN11CCG consensus sequence and, when attached to the yeast Spo11 protein, it is able to tether Spo11 to Gal4 recognition sites leading to the formation of Gal4BD-Spo11 specific recombination hotspots [26,27,28]
Summary
Homologous recombination is the key process that generates genetic diversity and drives evolution. Homologous recombination is initiated by the generation of DNA double stranded breaks (DSBs) by the SPO11 protein [1]. Subsequent repair of these breaks culminates in the formation of crossing overs (COs) between homologous chromosomes that, in turn, are required for faithful chromosomal segregation [2,3]. The beta isoform appears early and maintains a relatively constant level throughout the first meiotic prophase [11] This form is sufficient for the production of the majority of meiotic DSBs [12]. Since mice expressing only the SPO11β isoform are deficient in X/Y synapsis SPO11α is thought to be required for efficient recombination in the PAR [12]
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