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Is the Control of Recombination Conserved Among Diverse Eukaryotes&Quest; Heredity (2011) 106, 710–711 & 2011 Macmillan Publishers Limited All rights reserved 0018-067X/11 www.nature.com/hdy NEWS AND COMMENTARY .....................Positioning of recombination in yeast..................... and mammals ..................... DSB formation, and whether these histone signals for hotspots are con- Is the control of recombination served across Eukarya. For example, the apparent pre-eminent role of methyla- conserved among diverse tion in determining budding yeast recombination hotspots has yet to be supported in fission yeast. Even in eukaryotes? Saccharomyces cerevisiae, H3K4me3 can- L Goodstadt and CP Ponting not be a sufficient code for DSB hotspot ........................................................... initiation because this histone mark also Heredity (2011) 106, 710–711; doi:10.1038/hdy.2010.88; published online 7 July 2010 reflects an active transcriptional state of genes (Berger, 2007). Moreover, DSBs still occur in the absence of H3K4me3 ate in 2009, several research groups sequence motifs being present in 60% (Borde et al., 2009). independently alighted on a his- of randomly generated DSB hotspots for Second, the currently identified DNA- L tone 3 lysine 4 (H3K4) trimethylase, Schizosaccharomyces pombe (Steiner et al., binding proteins that determine DSB PRDM9, as the first known determinant 2009). Across the eukaryotic lineage, positioning show no signs of being of meiotic recombination hotspots in meiotic DNA cleavage activity is cata- conserved between fission and budding metazoa (Cheung et al., 2010, and lysed by orthologous Spo11 enzymes, yeasts, or between these yeasts and references therein). Earlier, hotspot ac- thereby placing a conserved enzymatic metazoans. The extremely rapid evolu- tivity in budding yeast was found to be activity at the heart of this fundamental tion of Prdm9’s DNA-binding determi- regulated by its only H3K4 trimethy- cellular process. nants is strikingly different to the lase, encoded by the Set1 gene (Sollier Are molecular processes controlling situation in yeast. Moreover, although et al., 2004). This apparent conservation recombination, other than Spo11- there is little evidence for turnover of mechanism across diverse eukaryotes mediated DNA cleavage, also broadly either among yeast hotspots or the led Wahls and Davidson (2010), in a conserved over eukaryotic evolution? consensus sequences that define them recent opinion article, to propose a Wahls and Davidson (2010) present evi- (Tsai et al., 2010), primate recombination ‘unifying model’ of recombination. dence that this is, indeed, the case. They hotspots are extremely short lived, They suggest that the positioning of point to associations between histone with the Prdm9 zinc-fingers that bind recombination in eukaryotic species as H3K4 trimethylation and recombination them changing at a correspondingly different as fungi and humans is deter- at hotspots that are seen in both mouse rapid pace (Oliver et al., 2009; Myers mined by the transcription factor recog- and yeast (Borde et al., 2009; Buard et al., et al., 2010). nition of specific DNA sites followed by 2009). Furthermore, most yeast hotspots The rapidity by which mammalian histone modification and chromatin might be bound by zinc-finger or other hotspots are turned over might resolve remodelling (Figure 1). transcription factors, as they are in the ‘recombination hotspot paradox’ In mammals and in yeast, meiotic mammals (by PRDM9). Could the par- (Boulton et al., 1997) and may explain recombination is essential for the reg- ticipation of histone H3K4 trimethylases the extreme positive selection driving ular segregation of homologous chro- and transcription factors in recombina- Prdm9 sequence change. As DSBs are mosomes during meiotic cell divisions tion for organisms as different as yeasts repaired using the homologous chromo- (Coop and Przeworski, 2007). For ex- and mammals be mere coincidence? some as a template, ‘hot’ alleles with ample, if meiotic recombination is re- Not at all, argue Wahls and Davidson. high recombination-initiation activity duced or positioned suboptimally, this They instead propose that these mole- are constantly being replaced by ‘cold’ may result in congenital trisomatic birth cules contribute to a phyletically con- low-activity homologues. Once hotspots defects. Recombination is nonrandomly served process, which requires first become substantially depleted, new concentrated at ‘hotspots’ that together the binding of transcription factors to Prdm9 alleles with altered DNA-bind- occupy only a small fraction of the hotspot motifs, which then induces ing specificity will be favoured, redir- genome. This has profound implications histone modifications, and is followed ecting recombination to newly ‘hot’ for gene and genome evolution. For by the recruitment of the recombina- sites, and thus ensuring a necessary example, meiotic recombination is cor- tion molecular machinery to the hotspot number of crossover events to support related with increases in mutation rate (Figure 1). disjunction. These rapid changes, how- and in GC content, and it disrupts the Their model is attractive both in its ever, come with an evolutionary cost, co-inheritance of physically linked al- simplicity and its relevance to a broad as combinations of incompatible Prdm9 leles, thereby generating diversity and swathe of cellular life. It is also consis- alleles apparently result in male infertility promoting efficient response to natural tent with the conservation of many (Vyskocilova et al., 2009). This, presum- selection. other fundamental cellular processes ably, is the basis for why Prdm9 is In mammalian meiosis, double- across single- and multicellular euka- a species-incompatibility gene (Mihola stranded breaks (DSBs), which precede ryotic life. Nevertheless, they acknow- et al., 2009). recombination, cluster at these hotspots. ledge that problems remain, two of By contrast to this situation in mam- The zinc-finger domains of human which we discuss here. mals, recombination hotspots appear to PRDM9 bind preferentially to a minor- First, although histone modification be highly conserved between Saccharo- ity (B40%) of such hotspots through has been associated with recombination, myces paradoxus and S. cerevisiae (Tsai a degenerate 13-bp consensus motif it is yet unclear which particular histone et al., 2010), species that are consider- (Myers et al., 2008). Hotspots are also marks (for example, acetylation, ubiqui- ably more divergent than are chimpan- evident in yeast, with one or more tylation, dimethylation or trimethyla- zees and humans that do not share of five classes of degenerate DNA tion) facilitate Spo11 recruitment and hotspots. The low frequency of sex and News and Commentary 711 Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK. e-mail: [email protected] Berger SL (2007). The complex language of chromatin regulation during transcription. Nature 447: 407–412. Borde V, Robine N, Lin W, Bonfils S, Geli V, Nicolas A (2009). Histone H3 lysine 4 trimethy- lation marks meiotic recombination initiation sites. EMBO J 28: 99–111. Boulton A, Myers RS, Redfield RJ (1997). The hotspot conversion paradox and the evolution of meiotic recombination. Proc Natl Acad Sci USA 94: 8058–8063. Buard J, Barthes P, Grey C, de Massy B (2009). Distinct histone modifications define initiation and repair of meiotic recombination in the mouse. EMBO J 28: 2616–2624. Cheung VG, Sherman SL, Feingold E (2010). Genetics. Genetic control of hotspots. Science 327: 791–792. Coop G, Przeworski M (2007). An evolutionary view of human recombination. Nat Rev Genet 8: 23–34. Mihola O, Trachtulec Z, Vlcek C, Schimenti JC, Forejt J (2009). A mouse speciation gene encodes a meiotic histone H3 methyltransfer- ase. Science 323: 373–375. Myers S, Bowden R, Tumian A, Bontrop RE, Figure 1 A simplified representation of Wahls and Davidson’s pan-eukaryotic model for Freeman C, MacFie TS et al. (2010). Drive recombination positioning. (a) Consensus DNA recognition sites (dark segment) within against hotspot motifs in primates implicates recombination hotspots are recognized by a transcription factor (TF), such as Prdm9 in the PRDM9 gene in meiotic recombination. mammals or Atf1-Pcr1 in yeast. Identifiable sequence motifs near hotspots fall into many Science 327: 876–879. classes, each presumably recognized by a separate TF. (b) In yeast, TFs recruit histone Myers S, Freeman C, Auton A, Donnelly P, modification enzymes that add, or subtract, methyl, acetyl or ubiquitin marks (circles or McVean G (2008). A common sequence motif associated with recombination hot spots and stars), for example, to adjacent nucleosomes. In mammals, the hotspot-recognizing Prdm9 is genome instability in humans. Nat Genet 40: itself a H3K4 trimethylase. (c) These histone modifications then recruit further elements of 1124–1129. the recombination machinery, including Spo11, presumably to more open chromatin. This Oliver PL, Goodstadt L, Bayes JJ, Birtle Z, Roach catalyses DSBs in the vicinity of the hotspot. KC, Phadnis N et al. (2009). Accelerated evolution of the Prdm9 speciation gene across diverse metazoan taxa. PLoS Genet 5: e1000753. Sollier J, Lin W, Soustelle C, Suhre K, Nicolas A, Geli V et al. (2004). Set1 is required for meiotic outcrossing (estimated as 1 in 10 000 humans, has either lost its DNA-bind- S-phase onset, double-strand break formation and generations in S. paradoxus), and hence ing specificity or protein-coding func- middle gene expression. EMBO J 23: 1957–1967.
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