Department of Ecology and Evolutionary Biology, University of Arizona
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Abstract |
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Key Words: evolutionary genomics nucleotide polymorphism SNP recombination rate genetic hitchhiking background selection Caenorhabditis elegans
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Introduction |
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Surveys of nucleotide variation in low-recombination regions in Drosophila melanogaster support these predictions. Reduced nucleotide polymorphism has been observed at the tip of the X chromosome (Aguadé, Miyashita, and Langley 1989; Begun and Aquadro 1991) and on the fourth chromosome (Berry, Ajioka, and Kreitman 1991; Jensen, Charlesworth, and Kreitman 2002; but see Wang et al. 2002), both genomic regions experiencing low recombination rates. Additionally, nucleotide polymorphism and recombination rate are positively correlated across the D. melanogaster genome (Begun and Aquadro 1992; Aquadro, Begun, and Kindahl 1994; Moriyama and Powell 1996).
Data from a variety of additional species suggest that the positive relationship between nucleotide polymorphism and recombination rate may be taxonomically widespread. Nucleotide diversity is reduced in low-recombination regions in a number of other Drosophila species, including D. ananassae (Stephan and Langley 1989; Chen, Marsh, and Stephan 2000), D. simulans (Begun and Aquadro 1991; Berry, Ajioka, and Kreitman 1991), D. mauritiana (Hilton, Kliman, and Hey 1994), and D. sechellia (Hilton, Kliman, and Hey 1994). Furthermore, there is evidence for a positive correlation between nucleotide variation and recombination rate in humans (Nachman et al. 1998; Przeworski, Hudson, and Di Rienzo 2000; Nachman 2001), and weaker support for such an association in house mice (Nachman 1997), sea beets (Kraft et al. 1998), tomatoes (Stephan and Langley 1998; Baudry et al. 2001), goatgrasses (Dvorak, Luo, and Yang 1998), and maize (Tenaillon et al. 2001).
The phylogenetic distribution of these patterns raises the question of what factors may be responsible for variation in the role of selection at linked sites in shaping genomic patterns within a species. Among other attributes, the breeding system may affect the dynamics and observed signature of selection at linked sites (Charlesworth and Wright 2001). Selfing reduces the "effective recombination rate" between selected and unselected loci within a genome because the effective recombination rate is controlled by both chromosomal crossovers and outcrossing (Nordborg 1997, 2000). In other words, like restricted recombination in outcrossing species, self-fertilization generates linkage disequilibrium between selected and neutral mutations, increasing the effects of selection on neutral polymorphism. Consequently, the predicted signature of selection at linked sites (e.g., the correlation between nucleotide polymorphism and recombination rate) depends on the level of self-fertilization (Baudry et al. 2001). In a purely selfing population, the effects of recombination are essentially eliminated, so no genomic pattern is expected for variation in neutral polymorphism levels due to selection at linked sites. Highly, but not obligately, selfing populations are expected to exhibit a positive correlation between neutral polymorphism and recombination rate over a greater range of recombination rates than populations with lower degrees of selfing (Baudry et al. 2001). Furthermore, Hedrick (1980) demonstrated that positive selection usually affects neutral variation more dramatically in self-fertilizing species than in regions of reduced recombination in outcrossing species. Provided that initial genotypic frequencies are not at Hardy-Weinberg equilibrium (a reasonable assumption in self-fertilizing species), this result holds for a range of self-fertilization rates. Theoretical work also suggests that background selection may be stronger in self-fertilizing species than in their outcrossing relatives (Charlesworth, Morgan, and Charlesworth 1993; Nordborg, Charlesworth, and Charlesworth 1996). Hence, selection at linked sites is likely to be an important determinant of neutral polymorphism patterns within partially self-fertilizing species.
Empirical studies of the association between nucleotide variation and recombination rate in tomatoes (Baudry et al. 2001), goatgrasses (Dvorak, Luo, and Yang 1998), and maize (Tenaillon et al. 2001) have provided mixed results regarding the potential importance of selection at linked sites in partially self-fertilizing organisms. In goatgrasses, nucleotide variation and recombination rate are weakly positively correlated in five self-fertilizing species, but not in the one outcrossing species investigated (Dvorak, Luo, and Yang 1998). Two self-compatible and three self-incompatible tomato species show a trend toward a correlation between nucleotide diversity and recombination rate, but none of these relationships is significant (although only five genes were surveyed; Baudry et al. 2001). In maize, nucleotide polymorphism and recombination rate appear to be positively correlated (Tenaillon et al. 2001), although this study estimated recombination rates indirectly from observed levels of linkage disequilibria.
Hence, theoretical studies suggest that selection at linked sites should be important in self-fertilizing species, but available evidence provides ambiguous support for this prediction. This incongruence indicates that further investigation of the relationship between nucleotide polymorphism and recombination rate in self-fertilizing species is warranted. To date, this relationship has not been evaluated in any animal that engages in self-fertilization.
The bacteriophagous, soil-dwelling nematode, Caenorhabditis elegans, provides a good system in which to assess the effect of reproductive mode on selection at linked sites. First, this androdioecious species reproduces primarily via self-fertilization of hermaphrodites and presumably outcrosses with males only rarely (Fitch and Thomas 1997). Second, availability of dense genetic maps (Barnes et al. 1995) and the complete genomic sequence (The C. elegans Sequencing Consortium 1998) allow estimation of recombination rates across the genome. Third, a large-scale study of SNP identification has recently been completed in C. elegans (Wicks et al. 2001). Finally, a recent study concluded that selection at linked sites may explain differences in levels of nucleotide polymorphism between Caenorhabditid species (Graustein et al. 2002). Here, we demonstrate that nucleotide polymorphism (as measured by SNP density) and recombination rate correlate strongly and positively across the genome of C. elegans. We also suggest that gene-dense regions may harbor lower polymorphism levels than gene-poor regions. Our results indicate that natural selection is an important determinant of genome-wide patterns of neutral DNA sequence variability in C. elegans. Finally, we discuss the ability of background selection and genetic hitchhiking models to explain our results, and we suggest that background selection is more compatible with observed patterns than is widespread genetic hitchhiking.
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Methods |
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We calculated estimates for genomic statistics (SNP density, gene density, recombination rate, base composition, mean coding region divergence) for nonoverlapping windows of sequence along each chromosome, starting at both the left and right ends of each chromosome. We varied the size of the windows from 500 kbp to 7 Mbp at 500-kbp intervals. We excluded some windows at the ends of chromosomes that were less than half the length of the window size under consideration. The appropriate scale at which to consider relationships between the genomic statistics was unclear, so we arbitrarily chose the forward-oriented 4 Mbp window size for more intensive analysis. Unless otherwise noted, our results refer to analyses of this 4 Mbp window size (n = 24, one of these points was excluded from analyses involving divergence due to insufficient numbers of homologous loci in C. briggsae). We calculated SNP density as the number of noncoding SNPs per Mbp of noncoding DNA and gene density as the number of coding genes (including alternative splicings) per Mbp of total DNA in the window. Because the SNPs were identified from random sequences of 5% of the worm genome (Wicks et al. 2001), the absolute magnitude of SNP density should be
20-fold higher than the values reported here, although relative density should remain unaffected. We estimated recombination rates (cM/Mbp) for each window based on the total genetic and physical lengths of the windows, using the flanking two mapped loci at each boundary to infer the position of the boundary in cM (from a set of 515 mapped loci among the six C. elegans chromosomes in WormBase). We estimated divergence rates across the genome for 1,326 locus pairs between C. elegans and C. briggsae using a calculation of ks on nucleotide sequences with Diverge from the Wisconsin Package Version 10.2 (Genetics Computer Group [GCG], Madison, Wis.) software based on the method of Li (Pamilo and Bianchi 1993; Li 1993). We selected the putative homologous loci based on top Blast scores of predicted coding sequences for the full C. elegans genome and
13 Mbp of sequence from C. briggsae in WormBase, and we aligned the sequence pairs based on predicted protein sequence. We adjusted the ks estimates by subtracting the residuals of a linear regression with the codon bias statistic Fop (Stenico, Lloyd, and Sharp 1994; Keightley and Eyre-Walker 2000; Marais and Duret 2001). We calculated the mean adjusted ks value (
s) of the available loci in each window as an estimator of local mutation rate. Windows of 4 Mbp size contained a mean of 53.9 loci from which average
s was calculated, and windows with fewer than two loci for mean
s estimation were excluded from analyses involving divergence. Recombination rate and SNP density were not normally distributed. We employed two approaches to address this issue. Although normality was not completely restored, we used logarithmic transformations of these variables in multiple regression analyses to better satisfy the assumptions of this method. Also, we used nonparametric correlation tests in bivariate analyses that included these variables.
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Results |
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Discussion |
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Gene Density
A prediction of models of selection at linked sites is that genomic regions with more selective targets will exhibit lower levels of polymorphism. If selection is mostly restricted to coding regions, local gene density may provide a useful index of selection intensity. Under this assumption, gene density should be negatively correlated with nucleotide variation. Nucleotide polymorphism and gene density may be negatively correlated in humans (Payseur and Nachman 2002; but see Lercher and Hurst 2002), although there is little evidence for such a relationship in D. melanogaster (Hey and Kliman 2002). As predicted by models of selection at linked sites, SNP density in C. elegans is negatively correlated with gene density independent of other variables (provided that chromosome identity is included in the multiple regression analysis; see below). An alternative interpretation for the negative association between polymorphism and gene density is that a higher fraction of noncoding SNP sites may experience stabilizing selection in gene-dense regions. This could occur if conserved regulatory elements are represented disproportionately in gene-dense regions. A comprehensive assignment of function to noncoding regions of the worm genome will clarify the relative contribution of these two possible alternatives.
Divergence
Multiple regression models show that, under some circumstances, the ks-based measure of divergence s is associated with SNP density independent of other variables. This result suggests that some of the variation in SNP density may be attributable to variation in the neutral mutation rate. However, the robustness of this conclusion depends on the ability of ks to characterize neutral mutation rates. Several factors affect the quality of ks (and therefore
s) as a measure of divergence. First, biased usage of codons in C. elegans indicates that many synonymous sites experience selection (Stenico, Lloyd, and Sharp 1994; Duret 2000), which complicates the use of ks as an estimator of the neutral mutation rate. We have attempted to account for this issue by adjusting ks for codon bias (see Methods), although this adjustment will suffice only to the extent to which the Fop codon usage statistic accurately captures selection on synonymous sites. Second, a potential problem arises from measuring polymorphism and ks at different loci. Estimates of divergence from the same noncoding regions where SNP density was measured might provide more appropriate estimates of the neutral mutation rate. Unfortunately, this is not feasible because noncoding regions of C. elegans and C. briggsae are difficult to align (Shabalina and Kondrashov 1999). Finally, estimating ks between highly divergent lineages is difficult. C. elegans and C. briggsae show evidence of saturation at synonymous sites (mean
s = 1.5). At this level of divergence, estimates of ks may be inaccurate. Consequently, the use of
s as an indicator of mutational heterogeneity may lead to underestimation of the effect of mutation on variation in SNP density. Additionally, if mutation rates have changed recently, relative to the divergence time between C. elegans and C. briggsae, ks may not accurately reflect the mutational environment under which the SNPs arose.
Previous work has suggested that recombination may be mutagenic in C. elegans (Marais, Mouchiroud, and Duret 2001). Consistent with this hypothesis, our bivariate analyses uncovered a positive correlation between recombination rate and s (Spearman's
= 0.80, P < 0.0001). Analyses in humans have also indicated that ks (measured by comparing human and mouse) and recombination rate are correlated (Lercher and Hurst 2002). Along with experimental evidence in yeast (Strathern, Shafer, and McGill 1995; Rattray et al. 2001), these observations collectively provide growing support for the notion that recombination may be mutagenic. Nevertheless, the observation that recombination rate and SNP density are strongly correlated independent of divergence suggests that natural selection shapes genomic patterns of SNP diversity in C. elegans.
Chromosome Identity
The inclusion of chromosome identity in multiple regression models does not influence the strong correlation between SNP density and recombination rate; however, its inclusion does affect the relative contribution of gene density and divergence to variation in SNP density (cf. fig. 3a and b). For example, gene density is not a significant predictor of variation in SNP density when chromosome identity is excluded from multiple regression analyses. It is difficult to construct a biological explanation for the effect of chromosome identity on SNP density. Ascertainment bias at the chromosomal level in the identification of SNPs or mutational differences among chromosomes could account for this effect. We find no evidence, however, that chromosomes differ in SNP density (F5,18 = 0.46, P = 0.8) or s (F5,1374 = 0.88, P = 0.5). If the effect of chromosome identity has a biological basis, then inclusion of this variable in our analyses is appropriate. Without knowledge of the true basis of this effect, interpretation of the relative roles of gene density and divergence as predictors of variation in SNP density requires caution. In contrast, our observation of the relationship between recombination rate and SNP density is unaffected by the inclusion or exclusion of chromosome identity in multiple regression analyses.
Background Selection and Genetic Hitchhiking Models
Is the observed positive correlation between SNP density and recombination rate in C. elegans primarily caused by positive or negative selection? A number of approaches have been proposed with the aim of distinguishing between genetic hitchhiking and background selection in outcrossing populations with even sex ratios (Aquadro, Begun, and Kindahl 1994; Andolfatto 2001). However, no theoretical treatments have thoroughly outlined the predictions of these selective models in the context of partial selfing and biased sex ratios. A greater effect of hitchhiking may be expected in partially selfing populations, because selfing rate exerts a much stronger influence on the fixation probability of recessive beneficial mutations than on the fixation probability of deleterious mutations (Charlesworth 1992), although few data are available regarding the average dominance of beneficial mutations. We cannot rigorously evaluate the relative abilities of the two models to explain our results, and both forces likely operate simultaneously (Kim and Stephan 2000). Here, we examine the parameter space that is consistent with each of them.
We can use estimates of the genomic deleterious mutation rate (U) in C. elegans to predict the effects of background selection on SNP density. Under background selection, an approximation of the expected level of neutral polymorphism () in a genomic region that takes into account partial self-fertilization is
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Conclusions
Outcrossing occurs with sufficient frequency within C. elegans to yield a significant signature of selection across the genome. In the absence of outcrossing, we would not expect selection at linked sites to induce a correlation between neutral polymorphism and recombination rate. However, we observe a clear correlation. If background selection accurately describes the process underlying the relationship between neutral polymorphism and recombination rate, then outcrossing may occur with a frequency of >1%. Two independent sources of evidence for the operation of outcrossing among populations come from mixed SNP profiles among 11 C. elegans strains (Koch et al. 2000) and mosaic distributions of transposable elements among strains (Egilmez, Ebert, and Reis 1995). These observations suggest that males may deserve a more prominent role in our understanding of the evolution of C. elegans populations. The intriguing question of how even a low level of outcrossing is maintained in this species, given that reproduction does not require the presence of males, remains open.
Reduced levels of genetic variation overall in partially or fully selfing species compared to outcrossing relatives have been observed in several plant clades (Miyashita, Innan, and Terauchi 1996; Liu, Zhang, and Charlesworth 1998; Liu, Charlesworth, and Kreitman 1999; Savolainen et al. 2000; Baudry et al. 2001), but this study provides one of the first unambiguous examples of a relationship between neutral polymorphism and recombination rate within the genome of a partially selfing organism (Dvorak, Luo, and Yang 1998; Baudry et al. 2001; Tenaillon et al. 2001). The strength of this relationship and the wealth of genetic information in C. elegans, together, suggest that the genus Caenorhabditis, in which species vary in mode of reproduction, may provide a more fertile system than previously recognized for studying the influence of breeding system on patterns of genomic diversity.
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Acknowledgements |
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Footnotes |
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Adam Eyre-Walker, Associate Editor
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