Cis- and Trans-Acting Elements Regulate the Mouse Psmb9 Meiotic Recombination Hotspot

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Abstract
In most eukaryotes, the prophase of the first meiotic division is characterized by a high level of homologous recombination between homologous chromosomes. Recombination events are not distributed evenly within the genome, but vary both locally and at large scale. Locally, most recombination events are clustered in short intervals (a few kilobases) called hotspots, separated by large intervening regions with no or very little recombination. Despite the importance of regulating both the frequency and the distribution of recombination events, the genetic factors controlling the activity of the recombination hotspots in mammals are still poorly understood. We previously characterized a recombination hotspot located close to the Psmb9 gene in the mouse major histocompatibility complex by sperm typing, demonstrating that it is a site of recombination initiation. With the goal of uncovering some of the genetic factors controlling the activity of this initiation site, we analyzed this hotspot in both male and female germ lines and compared the level of recombination in different hybrid mice. We show that a haplotype-specific element acts at distance and in trans to activate about 2,000-fold the recombination activity at Psmb9. Another haplotype-specific element acts in cis to repress initiation of recombination, and we propose this control to be due to polymorphisms located within the initiation zone. In addition, we describe subtle variations in the frequency and distribution of recombination events related to strain and sex differences. These findings show that most regulations observed act at the level of initiation and provide the first analysis of the control of the activity of a meiotic recombination hotspot in the mouse genome that reveals the interactions of elements located both in and outside the hotspot. In most sexually reproducing species, during meiosis a high level of recombination between homologous chromosomes is induced. These events are not evenly distributed in the genome but clustered in small regions called hotspots. The genetic factors controlling their activity in mammals are still poorly understood. We have performed experiments to identify factors that influence the recombination activity of a hotspot in the mouse genome. By detecting the recombination products by a PCR-based method, we show that the variation of hotspot activity (up to 2,000-fold) is mainly due to differences of initiation frequencies, rather than differences at later steps of recombination. In addition, we identify several levels of controls. First, the initiation of recombination is activated by a haplotype-specific element, localized outside the hotspot and acting in trans (when heterozygous, this element allows for recombination initiation on both homologous chromosomes). This suggests a unique type of regulation requiring the presence of a diffusible factor and/or of communications between homologous chromosomes before recombination. A second element represses the recombination initiation in cis, which might indicate the influence of local polymorphisms affecting initiation events. Our results provide the first functional analysis of the control of recombination initiation sites for meiotic recombination in mammals.