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Title: Patterns of Positive Selection in Six Mammalian Genomes}
Article:
Abstract:
Genome-wide scans for positively selected genes( PSGs) in mammals have provided insight into the dynamics of genome evolution, the genetic basis of differences between species, and the functions of individual genes. However, previous scans have been limited in power and accuracy owing to small numbers of available genomes. Here we present the most comprehensive examination of mammalian PSGs to date, using the six high-coverage genome assemblies now available for eutherian mammals. The increased phylogenetic depth of this dataset results in substantially improved statistical power, and permits several new lineage- and clade-specific tests to be applied. Of ∼16, 500 human genes with high-confidence orthologs in at least two other species, 400 genes showed significant evidence of positive selection( FDR<0. 05), according to a standard likelihood ratio test. An additional 144 genes showed evidence of positive selection on particular lineages or clades. As in previous studies, the identified PSGs were enriched for roles in defense/immunity, chemosensory perception, and reproduction, but enrichments were also evident for more specific functions, such as complement-mediated immunity and taste perception. Several pathways were strongly enriched for PSGs, suggesting possible co-evolution of interacting genes. A novel Bayesian analysis of the possible “selection histories” of each gene indicated that most PSGs have switched multiple times between positive selection and nonselection, suggesting that positive selection is often episodic. A detailed analysis of Affymetrix exon array data indicated that PSGs are expressed at significantly lower levels, and in a more tissue-specific manner, than non-PSGs. Genes that are specifically expressed in the spleen, testes, liver, and breast are significantly enriched for PSGs, but no evidence was found for an enrichment for PSGs among brain-specific genes. This study provides additional evidence for widespread positive selection in mammalian evolution and new genome-wide insights into the functional implications of positive selection.
Introduction:
Positive darwinian selection is an important source of evolutionary innovation and a major force behind the divergence of species. The Neutralist-Selectionist debate of the past 30 years has gradually given way to a general consensus that both neutral drift and positive selection play major roles in evolutionary change. Interest has therefore shifted to questions of which genes positive selection has affected, how strong was the effect, when did it occur, and what were its functional consequences. Heightening interest in these questions is a growing appreciation that methods for detecting positive selection can also be valuable tools for gaining insight into gene function[1]. Consequently, a wide variety of methods for detecting positively selected genes( PSGs) have been introduced, including comparative or phylogenetic methods, which make use of patterns of substitutions between species, and population genetic methods, which primarily rely on patterns of intraspecies polymorphism[2],[3]. Using these techniques, strong evidence of positive selection has been found for various genes in various organisms, including many genes involved in sensory perception, immunity, host-pathogen interactions, and reproduction( reviewed in[1],[3]). Phylogenetic and population genetic methods for detecting positive selection serve as complementary tools for functional and evolutionary analysis. These methods operate at different time scales, with phylogenetic methods being best suited for detecting selection that operates over relatively long periods in evolutionary history, and population genetic methods being best suited for detecting more recent selection. Population genetic methods can potentially detect selection operating at individual sites, through the effects of linkage with flanking alleles, while phylogenetic methods generally require multiple sites to have been affected in a sequence of interest. At the same time, decay of linkage disequilibrium at longer evolutionary time scales can allow phylogenetic methods to more accurately pinpoint the specific locations of functionally important substitutions. In some cases, phylogenetic methods also allow such substitutions to be mapped to particular branches of a phylogenetic tree, thereby providing useful insights about the evolutionary histories of the sequences in question. With the availability of multiple complete genome sequences, it has become possible to apply phylogenetic methods for the detection of positive selection at a genome-wide scale. Within mammals, several genome-wide scans for positive selection on protein-coding genes have been conducted, using both phylogenetic[4],[5],[6],[7],[8],[9] and population genetic[10],[11],[12],[13],[14],[15] methods( reviewed in[16]). These analyses have identified many new genes showing strong evidence of positive selection and have revealed striking differences in the prevalence of positive selection on different lineages and among different classes of genes. For example, it has been reported that PSGs are enriched for roles in sensory perception, immunity and defense, tumor suppression, apoptosis, and spermatogenesis[4],[5]; that PSGs are associated with known Mendelian disorders[4]; that PSGs often coincide with segmental duplications[8]; and that more genes have undergone positive selection in chimpanzee evolution than in human evolution[9]. Genome-wide scans for PSGs have also helped to stimulate interest in detecting positive selection on noncoding sequences and on gene expression[17],[18],[19],[20]. Nevertheless, much remains to be learned about positive selection in mammalian genomes, even within protein-coding regions. The most comprehensive scans for PSGs so far[4],[5],[7],[8],[9] have been based on at most three genome sequences—typically the highly similar human, chimpanzee, and/or rhesus macaque genomes( >97% average identity in orthologous coding regions[8]). As a result, the power for detection of PSGs has been relatively weak[5],[8]. In addition, in several of these studies, at least one genome was of draft quality, which reduced the number of genes that could be examined and required additional care in avoiding false positive predictions. Here we present a phylogenetic analysis of positive selection in the six eutherian mammalian genomes for which high-coverage, high-quality sequence assemblies are now available: the human[21], chimpanzee[6], macaque[8], mouse[22], rat[23], and dog[24] genomes. The phylogenetic depth of this data set helps considerably in addressing the problem of weak power. Indeed, these genomes have a near-optimal degree of divergence for PSG detection, being distant enough to produce a strong phylogenetic signal, yet close enough that gene structures are well conserved, alignment is fairly straightforward, and synonymous substitutions are not saturated( e. g.,[25]). In addition, our data set for the first time allows positive selection of mammalian genes to be examined genome-wide on a nontrivial phylogeny, so that insight can be gained into the particular “selection histories” of individual genes—that is, the branches of the phylogeny on which they experienced positive selection. In our analysis, we employ models of codon substitution that account for variation of selective pressure over branches on the tree and across sites in a sequence, which can capture signatures of molecular adaptation that affect small numbers of sites[26],[27]. Using a series of likelihood ratio tests( LRTs) based on these models, we identify more than four hundred genes that show strong signatures of positive selection during mammalian evolution. Our detailed analysis of the functional roles, selection histories, and expression patterns of these genes follows.
Discussion:
Since it first became possible to compare the sequences of complete mammalian genomes about five years ago, a number of genome-wide scans for positively selected genes( PSGs) have been conducted using phylogenetic methods[4],[5],[6],[7],[8],[9]. These studies have provided a valuable initial assessement of the genome-wide landscape of positive selection in mammals, but they have left many important questions unanswered. The analysis presented here, by incorporating non-primate mammalian genomes into a genome-wide scan for positive selection, represents a significant step forward. The larger, more divergent group of species improves power significantly, and the use of a nontrivial phylogeny provides insight into the particular patterns of positive selection that have helped to shape present-day genes. To our knowledge this is the largest and most detailed genome-wide analysis of positive selection to date, not only in mammals but in any group of organisms( although extensive analyses, similar in some respects, have been performed recently in Drosophila[75],[76]). One finding of particular interest was that several whole pathways are especially rich in PSGs. Examples include the classical and alternative pathways for complement-mediated immunity and the FAS/p53 apoptotic pathway( Figures S1, S4 and S5). These findings suggest that positive selection may frequently act directly on whole protein complexes or pathways( see[77],[78]). Alternatively, adaptive changes in one protein may sometimes have a cascade effect, leading to changes in other genes that bring a system back into equilibrium. Whether or not all changes affecting a pathway are driven by positive selection, one might expect to see similarities in the selection histories of gene with closely related functions. Indeed, we have found that genes with similar selection histories on average have substantially greater similarity in their GO categories than do genes with more divergent histories( Figure S6). The observations that multiple interacting genes often show evidence of positive selection and that positive selection is frequently episodic may well be connected. For example, in some cases a transient external force could induce a burst of changes in multiple genes that participate in the same pathway, either separately or by triggering a cascade of interdependent events. Further unraveling the( co-) evolutionary histories of interacting PSGs promises to be a fertile area for future work. Care will be required to distinguish between true co-evolution and correlations that can be explained by dependencies on expression levels or other covariates of evolutionary rate[79]. Our finding that PSGs are expressed at lower levels and in a more tissue-specific manner than non-PSGs is consistent with a well-known negative correlation ω with expression level, and a positive correlation of ω with tissue bias( τ or γ). Various explanations have been proposed for the observed decrease in ω among genes expressed at high levels and/or expressed broadly across tissues, including selection for translational efficiency, selection against misfolding, or increased selection due to pleiotropy[62],[68],[65]. In any case, these genes do appear to experience a reduction in their evolutionary “flexibility” compared with genes expressed at low levels and/or nonuniformly across tissues. Our observation of decreased rates of positive selection among these genes—and increased rates among low-expression/high-tissue-bias genes—is consistent with this characterization. Interestingly, however, we observe that correlations of ω with expression level and τ hold strongly within non-PSGs, but are much less pronounced within PSGs. Thus, expression levels and patterns are strongly correlated with both the strength of negative selection and the likelihood of positive selection, but they are only weakly correlated with the strength of positive selection. It appears that genes may be more likely to come under positive selection if they are in a state of evolutionary flexibility brought on by reduced or tissue-specific expression, but once positive selection has taken hold their subsequent evolutionary course is not strongly dependent on their expression patterns. As additional mammalian genomes become available, the statistical power to detect positive selection will improve. However, most forthcoming genomes are being sequenced at low coverage, and will inevitably exhibit increased levels of error in base calls, genome assemblies, ortholog identification( due to short contigs), and alignment—all of which can lead to spurious signals for positive selection.( The same errors tend to produce false negatives, rather than false positives, in the identification of conserved elements.) Thus, careful data quality controls will be needed to take advantage of these data. In addition, when considering the impact of additional sequences on statistical power, it is useful to distinguish between positive selection that acts continuously( or in recurrent episodes) over a long evolutionary period, and positive selection that acts transiently or in a lineage-specific manner. Deep phylogenetic sequencing should generally improve detection power for continuous or recurrent positive selection, but power for transient selection depends strongly on the sequenced species and the lineages of interest. For example, the genome sequences of a dozen non-primate mammals will likely have little effect on the power to detect human-specific selection, while the gorilla and neanderthal genomes could help considerably. There are fundamental limitations in the detection of weak, transient, or highly localized positive selection that will not be overcome by any amount of genome sequencing. Nevertheless, the availability of several new primate genomes, including those of the orangutan, marmoset, and gorilla, may significantly improve power for PSGs in primates. Our ability to connect positive selection with function remains rudimentary, but gradual progress is being made. As additional sequence data becomes available, it will become possible to associate selection with individual residues of proteins with greater accuracy. At the same time, more data is becoming available on the specific functional roles of individual amino acids, for example, from structural or mutagenesis studies. As a result, it will increasingly become possible to find direct links between selection and function. Often these links will initially be tentative, as in our site-specific analysis of the HAVCR1 gene. Nevertheless, they provide a valuable starting point for experimental follow-up. At the same time, more can be done to incorporate non-sequence data—such as structural and expression data—into computational methods for detecting positive selection. Thus, improvements in both computational and experimental methods will be needed to establish deeper and more informative connections between evolutionary dynamics and molecular function.
Populations evolve as mutations arise in individual organisms and , through hereditary transmission , gradually become “fixed” ( shared by all individuals ) in the population . Many mutations have essentially no effect on organismal fitness and can become fixed only by the stochastic process of neutral drift . However , some mutations produce a selective advantage that boosts their chances of reaching fixation . Genes in which new mutations tend to be beneficial , rather than neutral or deleterious , tend to evolve rapidly and are said to be under positive selection . Genes involved in immunity and defense are a well-known example; rapid evolution in these genes presumably occurs because new mutations help organisms to prevail in evolutionary “arms races” with pathogens . Many mammalian genes show evidence of positive selection , but open questions remain about the overall impact of positive selection in mammals . For example , which key differences between species can be attributed to positive selection ? How have patterns of selection changed across the mammalian phylogeny ? What are the effects of population size and gene expression patterns on positive selection ? Here we attempt to shed light on these and other questions in a comprehensive study of ∼16 , 500 genes in six mammalian genomes .