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Title: The Many Landscapes of Recombination in Drosophila melanogaster}
Article:
Abstract:
Recombination is a fundamental biological process with profound evolutionary implications. Theory predicts that recombination increases the effectiveness of selection in natural populations. Yet, direct tests of this prediction have been restricted to qualitative trends due to the lack of detailed characterization of recombination rate variation across genomes and within species. The use of imprecise recombination rates can also skew population genetic analyses designed to assess the presence and mode of selection across genomes. Here we report the first integrated high-resolution description of genomic and population variation in recombination, which also distinguishes between the two outcomes of meiotic recombination: crossing over( CO) and gene conversion( GC). We characterized the products of 5, 860 female meioses in Drosophila melanogaster by genotyping a total of 139 million informative SNPs and mapped 106, 964 recombination events at a resolution down to 2 kilobases. This approach allowed us to generate whole-genome CO and GC maps as well as a detailed description of variation in recombination among individuals of this species. We describe many levels of variation in recombination rates. At a large-scale( 100 kb), CO rates exhibit extreme and highly punctuated variation along chromosomes, with hot and coldspots. We also show extensive intra-specific variation in CO landscapes that is associated with hotspots at low frequency in our sample. GC rates are more uniformly distributed across the genome than CO rates and detectable in regions with reduced or absent CO. At a local scale, recombination events are associated with numerous sequence motifs and tend to occur within transcript regions, thus suggesting that chromatin accessibility favors double-strand breaks. All these non-independent layers of variation in recombination across genomes and among individuals need to be taken into account in order to obtain relevant estimates of recombination rates, and should be included in a new generation of population genetic models of the interaction between selection and linkage.
Introduction:
Recombination is a fundamental biological process. Mechanistically, most sexual eukaryotes require recombination between homologous chromosomes for proper formation of haploid gametes from diploid germ cells[1]. Evolutionarily, recombination is predicted to increase the effectiveness of selection in natural populations, thus explaining the pervasiveness of recombination and sex[2]–[9]. In most species, recombination rates also vary among and along chromosomes. This intra-genomic variation provides a unique opportunity to evaluate the evolutionary consequences of recombination due to exposure to identical demographic and environmental factors; an all else being equal premise that is hardly ever warranted when comparing populations or species. Population genetic analyses across genomes have confirmed the profound effects that recombination imposes on the evolutionary process, shaping levels of genetic variation, limiting the accumulation of deleterious mutations and enhancing rates of adaptation in many species including Drosophila, Arabidopsis thaliana, Saccharomyces cerevisiae and nematodes[10]–[25]. Yet these studies have been hindered, at least in part, by three limitations associated with the lack of detailed characterization of natural variation in recombination across genomes and within species. First, population genomic analyses can now analyze patterns of selection at the scale of single genes, or even focus on specific gene regions, but most whole-genome genetic maps localize recombination events with much less detail[24],[26]–[31]. Second, most species' maps based on direct measures of recombination are obtained either from two specific, usually highly diverged, strains( e. g., Caenorhabditis elegans[30] or S. cerevisiae[32]), or compiled from crosses in different laboratory/natural conditions that can also influence recombination rates[13],[26],[28]. These genetic maps are customarily assumed to represent a monomorphic description of recombination for a given species, even when there is ample evidence of intra-specific natural variation. In species like A. thaliana, D. melanogaster, C. elegans, maize, mice or humans, variation has been reported for the number of recombination events at the level of whole chromosomes[28],[30],[33]–[35] or for specific chromosomal intervals[36]–[44], but a high-resolution whole-genome study of variation in genetic maps based on multiple natural strains is lacking. Third, the process of meiotic recombination associated with the repair of double strand breaks( DSB) has two possible outcomes with diverse evolutionary consequences: crossing over( CO) and non-crossing over( or gene conversion; GC). Although CO events also include a gene conversion tract, we will use GC to refer to recombination events that are not accompanied by crossing over( Figure S1). Unlike CO, GC results in the exchange of only small tracts of a chromosome, interrupting linkage disequilibrium in a much localized manner while having no effect on linkage disequilibrium at longer intervals, thus GC plays a stronger role than CO at short physical distances[45]–[48]. Corresponding high-resolution CO and GC maps based on direct experimental detection of recombination events however are only available for the unicellular yeast Saccharomyces cerevisiae[32]. In multicellular organisms, CO maps are used as proxy for total recombination, and the consequences of GC are overlooked, despite its potential influence on total recombination, particularly in regions or chromosomes with limited CO. To alleviate all these deficiencies, we generated high-resolution, whole-genome CO and GC maps from eight crosses between natural strains of D. melanogaster( see Materials and Methods for details). In order to obtain haploid genomes resulting from female meioses, we crossed heterozygous D. melanogaster females to males of D. simulans and genotyped the female hybrid progeny using whole-genome high-throughput Illumina sequencing. Reads corresponding to D. simulans were removed bioinformatically by mapping them to D. simulans genomic sequences. We then generated a whole-genome D. melanogaster haplotype per genotyped fly by mapping high-quality informative SNPs to one of the two parental D. melanogaster strains. Recombination events were detected, and directly assigned as CO or GC events, based on changes in parental identity along each D. melanogaster haplotype. Overall, we characterized the products of 5, 860 female meioses and genotyped an average of 49, 000 informative SNPs per fly, for a total of 139 million SNPs. We mapped more than 106, 000 recombination events( CO and GC combined) with a median distance to the nearest informative SNP of less than 2. 0 kb( 1. 83 kb). This resolution is almost equivalent to the high-resolution mapping of meiotic recombination in the unicellular S. cerevisiae[32], 15-fold higher than the linkage map in A. thaliana also based on recombinant inbred lines[27], and more than 50-fold more detailed than current high-resolution whole-genome CO maps in humans[28], C. elegans[30], C. briggsae[24], or D. pseudoobscura[29].
Discussion:
Our study provides the first coordinated high-resolution eukaryotic picture of genomic and population variation in recombination rates that distinguishes between CO and GC rates, the two outcomes of meiotic DSB repair. We report CO and GC maps that describe variation across the genome of D. melanogaster at the scale of 100-kb. We also obtained and analyzed eight whole-genome CO maps that provide insight into intra-specific variation at a resolution of 250-kb. The types of recombination variation detected in D. melanogaster are many-fold in nature. Along chromosomes, CO rates vary significantly at the scale of 100-kb in a highly punctuated manner with hot- and coldspots within regions traditionally associated with non-reduced recombination( see also[29]). This study of D. melanogaster also reveals a clear difference from traditional hotspots described in humans or mice[110],[111]. Human and mice hotspots are associated with highly delimited genomic regions and a restricted number of DNA motifs[42],[86],[87],[112]. Our data suggests a softer, more probabilistic and less discrete, landscape with an excess of recombination events within larger regions( i. e., annotated transcript regions) and a large and heterogeneous population of motifs. Our analysis of eight crosses within the same species has also allowed us to describe extensive and significant intra-specific variation in CO landscapes. The presence of polymorphic modifiers is at the core of models of the evolution of recombination([113] and references therein) but little is known about their actual frequency and genomic distribution in natural populations. Our collection of maps in D. melanogaster describing naturally occurring variation in recombination rates underscore the tremendous potential for selection to act on or be associated with recombination modifiers, and alter the landscape of recombination rates across the genome. Notably, the excess variance in recombination among crosses is mostly associated with CO hotspots at low frequency in our sample. Our results therefore emphasize the need for obtaining estimates of recombination based on several crosses rather than on a single or two crosses, even if highly detailed in resolution. Additionally, the presence of hotspots at low frequency suggests that estimates of recombination rate based on the average of several maps may not fully capture the relevant population dynamics either under neutrality or as a consequence of the interaction between selection and linkage. The observed pattern of hotspots at low frequency could be explained by mutation-selection balance but is also is congruent with neutral expectations where most derived mutations, in this case modifiers causing high recombination at specific genomic regions, are expected to be at low frequency( present as singletons or in two genotypes in our sample). For cis-controlled hotspots, their frequency might be also limited by the meiotic drive predicted when the initiating DSB sequence is converted into the allele of the non-initiating homologous chromosome during DSB repair[114]–[119]. Only a systematic study of populations and closely related species will allow us to assess the relative role of selection, mutation and drift acting on these modifiers. The existence of coldspots throughout the whole genome, monomorphic or coupled with low median values, has also direct implications for population genetic analyses of selection. A reduction in polymorphism levels in regions of non-reduced recombination is often explained by the action of positive selection and selective sweeps( the hitchhiking model, HH[120]–[124]). Similar population genetic patterns however could be explained by the steady elimination of deleterious mutations from populations( the background selection model, BGS[48],[125],[126]) if sufficiently reduced CO rates were operating. The use of our high-resolution CO maps( c) to investigate the predicted consequences of selection at linked sites( HH and/or BGS) across the D. melanogaster genome confirms the results of previous analyses[10],[13],[19],[21],[22],[127]–[130] and show a positive relationship between c and levels of nucleotide polymorphism( π) at noncoding sites( Figure 11; R = 0. 560, P<1×10−12). Notably, our CO maps reveal that the strong association between c and π is also observed after removing telomeric/centromeric regions( R = 0. 497, P<1×10−12). Our results therefore suggest that BGS should be considered across the whole D. melanogaster genome before invoking positive selection and selective sweeps. In this regard, strong local BGS caused by the presence of CO coldspots embedded in region of non-reduced recombination( what we call “coldspot effect”) would predict the presence of genomic regions with polymorphism and divergence patterns( e. g., reduced neutral polymorphism and an excess of amino acid substitutions) that could be also interpreted as evidence of adaptive evolution[131]. We observe that GC rates are more uniformly distributed than CO rates and are also detectable in regions with reduced or absent CO. Because GC is predicted to play a more important role in increasing effective recombination at short distances than CO[45],[48],[105], this result is specifically relevant for studies of variation in evolutionary patterns at physically close regions. Nested within large-scale recombination environments, total recombination and GC events in particular tend to occur within annotated transcript sequences. Our data therefore expose higher recombination within transcript regions relative to intergenic regions. Introns and/or synonymous sites thus might not be fully adequate to test evolutionary patterns at flanking regions of these same genes, and vice versa. For instance, if we accept the presence of conserved sites in transcribed regions( e. g., exons) and flanking regions( e. g., cis-regulatory sequences), local BGS together with variable effective recombination might generate patterns of lower polymorphism( and polymorphism to divergence) in noncoding flanking regions relative to intronic or synonymous sites. Current population genetic analyses use coalescent simulations to test alternatives to a neutral process or specific models of selection[132]–[138]. These coalescent simulations can use constant recombination rates( c and/or γ) or add flexibility by including variable rates between simulations, but assume nonetheless that recombination occurs with equal probability for different lineages or for adaptive and neutral alleles within a genealogy[139],[140]. Our data indicate that coalescent-based analyses should take into account the highly heterogeneous recombination environments at long- and local-scales across genomes but also incorporate recombination variation within genealogies in order to capture the dynamics associated with naturally occurring modifiers. An additional and intriguing possibility for models of selection and linkage is the support that our results provide for a heterozygosity-dependent GC∶CO repair of DSB in Drosophila( see also[46]), increasing the frequency of GC relative to CO events when heterozygosity is low. Under this scenario, selection would reduce nucleotide polymorphism at linked sites due to BGS or HH but this very same change in polymorphism levels would, in turn, alter the degree of future linkage effects due to the variable GC∶CO ratio[46]. Further studies are needed to understand and characterize the spatial and temporal dynamics across the genome generated under this model, with variable GC∶CO ratios and stochastic and/or selective processes associated with polymorphic modifiers of DSB formation. In conclusion, we have shown that there are many layers of variation in recombination rates in D. melanogaster: across genomes at a large-( >100-kb) and small-( i. e., single-gene) scales, among crosses and for GC and CO. Each of these levels is expected to play a role in shaping evolutionary patterns. We propose that these overlapping, non-independent and dynamic landscapes of recombination should be included in a new generation of population genetic models of selection and recombination.
Most sexual eukaryotes require recombination between homologous chromosomes for the proper formation of haploid gametes from diploid germ cells . Evolutionarily , recombination increases the effectiveness of selection in natural populations , thus explaining the pervasiveness of recombination and sex . Recombination is also a central parameter in population genetic studies designed to detect the presence of selection acting across genomes . Current evolutionary analyses are hindered , however , by the use of imprecise recombination rates that can influence the results and skew their interpretation . This limitation is associated with the lack of detailed characterization of natural variation in recombination across genomes and within species . Our study in Drosophila melanogaster represents the first integrated , whole-genome description of recombination that alleviates these deficiencies in any organism . Our results and conclusions will help to characterize the molecular basis of the observed variation in recombination across genomes and have an immediate impact on population genetic analyses of selection , laying the foundation for a new generation of population models that will better capture natural variation in recombination and its consequences .