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Conservation of Recombination Hotspots in Yeast Conservation of recombination hotspots in yeast Isheng J. Tsai1, Austin Burt2, and Vassiliki Koufopanou2,3 Division of Biology, Imperial College London, Silwood Park, Ascot, Berks SL5 7PY, United Kingdom Edited by Franklin Stahl, University of Oregon, Eugene, OR, and approved January 19, 2010 (received for review August 5, 2009) Meiotic recombination does not occur randomly along a chromo- between humans and chimpanzees), and they are about 13% some, but instead tendsto beconcentrated in smallregions, known as divergent from S. cerevisiae (19). “recombination hotspots.” Recombination hotspots are thought to be short-lived in evolutionary time due to their self-destructive Results and Discussion nature, as gene conversion favors recombination-suppressing alleles Identification and Distribution of Recombination Hotspots Along the over recombination-promoting alleles during double-strand repair. Chromosome. The alignment is 287 kb long and there are 464 Consistent with this expectation, hotspots in humans are highly nonsingleton SNPs in the European population and 232 in the Far dynamic, with little correspondence in location between humans East Asian, giving an average density of one SNP every 0.6 kb in and chimpanzees. Here, we identify recombination hotspots in two Europe and 1.2 kb in the Far East (Table S1). For each population lineages of the yeast Saccharomyces paradoxus, and compare their no more than two alternative nucleotides were found at each site. locations to those found previously in Saccharomyces cerevisiae.Sur- We estimated the population recombination parameter ρ between prisingly, we find considerable overlap between the two species, neighboring pairs of SNPs using the program rhomap (20) (Fig. despite the fact that they are at least 10 times more divergent than 1A). In an idealized population, ρ is equal to 4Ner(1−F)M, where humans and chimpanzees. We attribute this unexpected result to the Ne is the effective population size, r the rate of recombination low frequency of sex and outcrossing in these yeasts, acting to reduce between the two SNPs, F the inbreeding coefficient, and M the the population genetic effect of biased gene conversion. Traces from frequency of sex (18, 21). Both populations show heterogeneity in two other signatures of recombination, namely high mutagenicity the rate of recombination along the chromosome, particularly the and GC-biased gene conversion, are consistent with this interpreta- European population, which also shows higher rates on average. tion. Thus, recombination hotspots are not inevitably short-lived, but This difference is not simply because of the smaller sample size in rather their persistence through evolutionary timewill bedetermined the Far East population, as it persists when the European pop- by the frequency of outcrossing events in the life cycle. ulation is reduced to eight strains (Fig. S1). To assess our population-genomic estimates of recombination base composition | frequency of outcrossing | hotspot degeneration | rates, we tested whether two well-supported experimental results Saccharomyces | biased gene conversion from S. cerevisiae are replicated in our dataset. In S. cerevisiae, rates of recombination are relatively low between the centromere eiotic recombination is critical for generating diversity and, and mating-type locus, and also higher in intergenic regions con- Mhence, increasing the efficacy of selection. It also has an taining at least one promoter than in those with none (22, 23). We important structural role during meiosis, crossovers being necessary confirm both these results in S. paradoxus. Recombination in the for proper chromosome segregation (1). Meiotic recombination ∼100-kb region between the centromere (CEN) and the mating does not occur uniformly across the genome and, at least in some type (MAT) locus is about half that for the rest of the chromosome species, is predominantly localized in short regions, a few kilobases (ρ = 1.9 vs. 4.5 Morgans/kb in Europe and 0.9 vs. 2.0 in the Far long, known as recombination hotspots (reviewed in refs. 2 and 3). East). In addition, intergenic regions that are 5′ to at least one Recombination hotspots are thought to be evolutionarily unstable of the flanking genes have higher ρ than those that are 5′ to none because of an inherent self-destructive dynamic. Recombination is (P = 0.004 and P = 0.07 for Europe and Far East) (Table S2). This initiated by a double-strand break in one chromosome, which is then correspondence of results gives us confidence that our dataset is repaired using the homologous chromosome as a template. Alleles sufficient to detect major features of recombination. with high recombination-initiation activity are therefore continually To identify recombination hotspots, we tested for statistically fi ρ fl being replaced during their repair by the unbroken, low-activity signi cant increases in compared to anking regions, using the homologs (4–7). Consistent with this expectation, comparisons of program sequenceLDhot (24). For each 2-kb window (with a 1-kb ρ hotspot locations in humans and chimpanzees show little or no offset), the program tests the null hypothesis that in the window is ρ fl conservation of hotspot position (8–10). equal to in the anking 50-kb region (centered on that window). The brewer’syeastSaccharomyces cerevisiae has long been a Six recombination hotspots were found in each population (Fig. model system for studies of recombination, and experimental 1A and Table 1). They are 2 to 5 kb in length, similar to the 3 kb S. cerevisiae studies have identified multiple recombination hotspots throughout average found in chromosome III and the 1 to 2 kb the genome (3, 11–14). To study the conservation of recombination length of human hotspots (3, 12, 25). Exactly the same hotspots are found if each 2-kb window along the chromosome is tested against hotspots in yeast, we have analyzed recombination rates in the wild yeast Saccharomyces paradoxus. This species has recently emerged as an ideal model for population genomic studies because of its S. cerevisiae Author contributions: A.B. and V.K. designed research; I.J.T., A.B., and V.K. analyzed data; phylogenetic proximity to and nondomesticated status and I.J.T., A.B., and V.K. wrote the paper. – (15 17). In this article we identify recombination hotspots from The authors declare no conflict of interest. population genomic analyses of an alignment of nearly complete This article is a PNAS Direct Submission. S. paradoxus chromosome III sequences from 20 strains of ,12from Freely available online through the PNAS open access option. Europe and 8 from Far East Asia (18). The alignment has relatively 1Present address: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, few gaps and, hence, is ideal for analyzing recombination. The United Kingdom. S. paradoxus 2 European and Far East lineages of are phylogenetically A.B. and V.K. contributed equally to this work. independent (i.e., all isolates in one population are more closely 3To whom correspondence should be addressed. E-mail: [email protected]. EVOLUTION related to each other than to any isolate from the other population), This article contains supporting information online at www.pnas.org/cgi/content/full/ with about 1% sequence divergence (approximately the same as 0908774107/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.0908774107 PNAS | April 27, 2010 | vol. 107 | no. 17 | 7847–7852 Downloaded by guest on October 2, 2021 Europe A MAT 30 CEN 6 1 20 2 4 3 5 10 0 15 Far East 1 10 2 3 5 5 4 6 0 0 50 100 150 200 250 300 kb B S. paradoxus (average) 15 1 7 10 6 10 2 4 3 5 8 9 5 0 0 50 100 150 200 250 300 kb C S. paradoxus 1 2 3 4 5 6 7 8 9 10 S. cerevisiae DSBs Crossovers Crossovers + non-crossovers Fig. 1. Distribution of recombination on S. paradoxus chromosome III. (A) The population-recombination parameter ρ, calculated between consecutive pairs of SNPs along the chromosome, is shown for the European and Far East populations (the first and last genes in the alignment are VBA3 and HMRA1; SNPs are shown as dots along the lines). The hotspot regions identified in each population are highlighted in red, and the corresponding regions in the other population in blue (for visual clarity, these extend 2 kb on either side). Hotspot numbers correspond to those used in Table 1. Positions of the centromere (CEN) and mating type locus (MAT) are indicated by arrows. The distribution of haplotype blocks, representing regions with no evidence of recombination, is also shown (black lines) (see Methods). Haplotype blocks are longer in the Far East population, consistent with the finding of lower recombination rate. (B) The average ρ for the two populations of S. paradoxus is plotted and hotspots from the combined analysis shown in red. Diamonds indicate the position of DSB hotspots in S. cerevisiae (11). (C) Comparison of hotpsot locations. Vertical red bars show the position of hotspots in S. paradoxus. Diamonds again show the position of DSB hotspots in S. cerevisiae (11) and horizontal lines show the hotspots identified by Mancera et al. (12) in their “crossover” and “total” analyses. the flanking 6-kb region. We further evaluated the significance of rhomap estimates are not identified as statistically significant by these hotspots by calculating the number of hotspots expected by sequenceLDhot (Fig. 1A). Nevertheless, one region is identified as chance in chromosomes with constant recombination along their a hotspot in both populations independently (the IMG1-BUD23- length. Twenty simulated alignments were obtained by evolving ARE1 hotspot ∼9 kb to the right of MAT). Moreover, it is apparent chromosomes of the same length and level of polymorphism as the from Fig. 1A that hotspots in one population correspond to local original dataset, using the program ms (26).
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