Sticky fingers

Sticky fingers A single protein recognizes different sequences in different organisms and drives speciation. Computer graphic of a two zinc-finger peptide (yellow) binding to a DNA (red and blue) molecule. © KEN EWARD / BIOGRAFX / SCIENCE PHOTO LIBRARY Homologous recombination physically links together chromosomes at the first division in meiosis by sharing DNA strands between chromosomes. This creates genetic variation in organisms that reproduce sexually, and makes sure that homologous chromosomes segregate correctly into the daughter cells. But recombination does not appear to be random: it tends to cluster within specialized 1- to 2-kb-long sites called “hotspots.” It’s logical then to ask what specifies or controls hotspot location. Scientists have gathered evidence that three different mechanisms are involved in controlling location and activity. First, the genomic sequence around each hotspot seems to be important; for example, 40 percent of human hotspots are associated with a repeating 13-basepair motif. However, because only a portion of hotspots correlates with a specific sequence, other factors must be involved. For example, evidence is accumulating that hotspot locations are associated with certain histone modifications. The third proposed mechanism implies that a soluble factor or protein must control the location and distribution of hotspots. Remarkably, a single protein appears to satisfy all three conditions. PRDM9 is a soluble protein that not only binds to the human 13-basepair motif DNA with its zinc finger domain, but it can also methylate histone tails, suggesting it may be behind the histone modifications marking hotspots. Furthermore, PRDM9 is undergoing rapid evolution and may play a role not only in marking recombination events but also a broader role in speciation. Rapidly-evolving fingers Researchers have puzzled over the finding that chimps and humans share very few hotspots, given the level of genetic similarity between the two species (over 99 percent identity at aligned bases). Using a computational model, Simon Myers and colleagues at the University of Oxford1 scanned the chimp hotspots and failed to find the 13-basepair human motif. They then looked for candidate proteins that might bind to the motif in humans. They turned up just the one: PRDM9, a protein also found in chimpanzees. PRDM9 was initially thought to act as a transcription factor that controlled the cell’s entry into meiosis. Like other transcription factors, it binds to DNA, but can also bind other active proteins. However, transcription factors tend to be tightly conserved between species, and unlike the rest of the protein, the DNA-binding zinc fingers of PRDM9 vary widely between all species studied. The DNA that codes for PRDM9’s zinc fingers is a hypermutable cassette—that is, it evolves extraordinarily rapidly. This implies the sequence that PRDM9 binds to must also be changing rapidly, as the DNA hotspots erode over time through recombination. But because PRDM9 is evolving so quickly, new PRDM9 zinc fingers arise to match the recombined hotspot sequences and create a new family of hotspots—explaining why mice, humans and chimps all use PRDM9 but have different sequences marking their recombination hotspots.2 Interestingly, researchers had already discovered that PRMD9 is involved in hybrid sterility. An early sign of impending speciation is when a species that has accrued multiple recombination events and mutations produces infertile offspring when it mates with a closely related organism, an outcome known as hybrid sterility. This genetic shift is not only a consequence of species divergence, but also drives speciation by reducing gene flow and placing reproductive barriers between previously interbreeding populations. Over 35 years ago, Jiri Forejt of the Academy of Sciences of the Czech Republic mapped the cause of mouse hybrid sterility to a particular chromosomal locus, but its protein identity was only revealed last year as PRDM9.3 Recent surveys from multiple species suggest that it may have played a role in speciation on many occasions.4 Finding the link But how does PRDM9 drive recombination? An obvious possibility would be via its histone methyltransferase activity. Studies on mouse hotspots known to be controlled by PRDM9 showed that chromatids containing those hotspots become marked by histone methylation. But further studies will be needed to definitively prove that PRDM9 is responsible for these markings.5 It is unlikely that PRDM9 is the only protein involved in hotspot specification. First, 60 percent of human hotspots are not associated with the 13-basepair motif to which PRDM9 binds. Second, spermatocytes from PRDM9-null mice still have double-stranded breaks, suggesting that homologous recombination can occur at non-PRDM9 sites. Finally, the detailed mechanism by which PRDM9 contributes to hybrid sterility is unknown, and it is still unclear if there is a direct link between PRDM9’s role in hotspot specification, per se, and hybrid sterility. While the hybrid sterility phenotype attributed to PRDM9 depends on the zinc finger polymorphisms, the genes that presumably interfere with PRDM9’s normal function and hence make hybrid offspring infertile remain to be identified. Nonetheless, PRDM9 neatly wraps genetic, epigenetic and trans-acting factors of meiotic recombination hotspot specification into one intriguing package. This article is an adaptation of an article published in F1000 Biology Reports, a publication of the Faculty of 1000. For the full-length version, click here. F1000 Biology consists of more than 2,000 leading biologists (Faculty Members) who select and review the most important published papers in their respective fields (Faculties). References 1. S. Myers et al., “Drive against hotspot motifs in primates implicates the PRDM9 gene in meiotic recombination,” Science, 327:876–79, 2010. 2. F. Baudat et al., “PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice.,” Science, 327:836–40, 2010. F1000 Biology Factor 9.0 Article ID 1867956 3. O. Mihola et al., “A mouse speciation gene encodes a meiotic histone H3 methyltransferase,” Science, 323: 373–75, 2009. 4. P.L. Oliver et al., “Accelerated evolution of the Prdm9 speciation gene across diverse metazoan taxa,” PLoS Genet, 5:e1000753, 2009. F1000 Biology Factor 3.0 Article ID 1304956. 5. J. Buard et al., “Distinct histone modifications define initiation and repair of meiotic recombination in the mouse,” EMBO J, 28:2616–24, 2009.

Sticky fingers

Sticky fingers

A single protein recognizes different sequences in different organisms and drives speciation.

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Ionel Sandovici

Carmen Sapienza

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June 2010

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