A scan for positively selected genes in the genomes of humans and chimpanzees

Since the divergence of humans and chimpanzees about 5 million years ago, these species have undergone a remarkable evolution with drastic divergence in anatomy and cognitive abilities. At the molecular level, despite the small overall magnitude of DNA sequence divergence, we might expect such evolutionary changes to leave a noticeable signature throughout the genome. We here compare 13,731 annotated genes from humans to their chimpanzee orthologs to identify genes that show evidence of positive selection. Many of the genes that present a signature of positive selection tend to be involved in sensory perception or immune defenses. However, the group of genes that show the strongest evidence for positive selection also includes a surprising number of genes involved in tumor suppression and apoptosis, and of genes involved in spermatogenesis. We hypothesize that positive selection in some of these genes may be driven by genomic conflict due to apoptosis during spermatogenesis. Genes with maximal expression in the brain show little or no evidence for positive selection, while genes with maximal expression in the testis tend to be enriched with positively selected genes. Genes on the X chromosome also tend to show an elevated tendency for positive selection. We also present polymorphism data from 20 Caucasian Americans and 19 African Americans for the 50 annotated genes showing the strongest evidence for positive selection. The polymorphism analysis further supports the presence of positive selection in these genes by showing an excess of high-frequency derived nonsynonymous mutations.     

Patterns of positive selection in six Mammalian genomes

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 approximately 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.     

Patterns of divergence among conifer ESTs and polymorphism in Pinus sylvestris identify putative selective sweeps

Finding genes that are under positive selection is a difficult task, especially in non-model organisms. Here, we have analyzed expressed sequence tag (EST) data from 4 species (Pinus pinaster, Pinus taeda, Picea glauca, and Pseudotsuga menziesii) to investigate selection patterns during their evolution and to identify genes likely to be under positive selection. To confirm selection, population samples of these genes have been sequenced in Pinus sylvestris, a species that was not included in the EST data set. The estimates of branch-specific Ka/Ks (nonsynonymous/synonymous substitution rates) across all genes in the EST data set were similar or smaller than estimates from other higher plant species. There was no evidence for the traditional indication of positive selection, Ka/Ks above 1. However, several lines of evidence based on polymorphism patterns suggest that genes with high Ka/Ks (0.20-0.52) in the EST data set are in fact more affected by positive selection in P. sylvestris than genes with low Ka/Ks (0.01-0.04). The high Ka/Ks genes have a lower level of polymorphism and more negative Tajima's D than the low Ka/Ks genes. Further, in the high Ka/Ks group, the Hudson-Kreitman-Aguade test is significant. This suggests that the EST data set is a good starting point for finding genes under positive selection in conifers and that even moderate Ka/Ks values could be indicative of selection. A group of 5 genes with high Ka/Ks collectively show evidence for positive selection within P. sylvestris.     

Evidence for positive selection on the leptin gene in Cetacea and Pinnipedia

The leptin gene has received intensive attention and scientific investigation for its importance in energy homeostasis and reproductive regulation in mammals. Furthermore, study of the leptin gene is of crucial importance for public health, particularly for its role in obesity, as well as for other numerous physiological roles that it plays in mammals. In the present work, we report the identification of novel leptin genes in 4 species of Cetacea, and a comparison with 55 publicly available leptin sequences from mammalian genome assemblies and previous studies. Our study provides evidence for positive selection in the suborder Odontoceti (toothed whales) of the Cetacea and the family Phocidae (earless seals) of the Pinnipedia. We also detected positive selection in several leptin gene residues in these two lineages. To test whether leptin and its receptor evolved in a coordinated manner, we analyzed 24 leptin receptor gene (LPR) sequences from available mammalian genome assemblies and other published data. Unlike the case of leptin, our analyses did not find evidence of positive selection for LPR across the Cetacea and Pinnipedia lineages. In line with this, positively selected sites identified in the leptin genes of these two lineages were located outside of leptin receptor binding sites, which at least partially explains why co-evolution of leptin and its receptor was not observed in the present study. Our study provides interesting insights into current understanding of the evolution of mammalian leptin genes in response to selective pressures from life in an aquatic environment, and leads to a hypothesis that new tissue specificity or novel physiologic functions of leptin genes may have arisen in both odontocetes and phocids. Additional data from other species encompassing varying life histories and functional tests of the adaptive role of the amino acid changes identified in this study will help determine the factors that promote the adaptive evolution of the leptin genes in marine mammals.     

Relating hybrid advantage and genome replacement in unisexual salamanders

Unisexual vertebrates are model systems for understanding the evolution of sex. Many predominantly clonal lineages allow occasional genetic recombination, which may be sufficient to avoid the accumulation of deleterious mutations and parasites. Introgression of paternal DNA into an all-female lineage represents a one-way flow of genetic material. Over many generations, this could result in complete replacement of the unisexual genomes by those of the donor species. The process of genome replacement may be counteracted by contemporary dispersal or by positive selection on hybrid nuclear genomes in ecotones. I present a conceptual model that relates nuclear genome replacement, positive selection on hybrids and biogeography in unisexual systems. I execute an individual-based simulation of the fate of hybrid genotypes in contact with a single host species. I parameterize these models for unisexual salamanders in the Ambystoma genus, for which the frequency of genome replacement has been a source of ongoing debate. I find that, if genome replacement occurs at a rate greater than 1/10,000 in Ambystoma, then there must be compensating positive selection in order to maintain observed levels of hybrid nuclei. Future researchers studying unisexual systems may use this framework as a guide to evaluating the hybrid superiority hypothesis.     

Effects of X-linkage and sex-biased gene expression on the rate of adaptive protein evolution in Drosophila

Patterns of polymorphism and divergence in Drosophila protein-coding genes suggest that a considerable fraction of amino acid differences between species can be attributed to positive selection and that genes with sex-biased expression, that is, those expressed predominantly in one sex, have especially high rates of adaptive evolution. Previous studies, however, have been restricted to autosomal sex-biased genes and, thus, do not provide a complete picture of the evolutionary forces acting on sex-biased genes across the genome. To determine the effects of X-linkage on sex-biased gene evolution, we surveyed DNA sequence polymorphism and divergence in 45 X-linked genes, including 17 with male-biased expression, 13 with female-biased expression, and 15 with equal expression in the 2 sexes. Using both single- and multilocus tests for selection, we found evidence for adaptive evolution in both groups of sex-biased genes. The signal of adaptive evolution was particularly strong for X-linked male-biased genes. A comparison with data from 91 autosomal genes revealed a "fast-X" effect, in which the rate of adaptive evolution was greater for X-linked than for autosomal genes. This effect was strongest for male-biased genes but could be seen in the other groups as well. A genome-wide analysis of coding sequence divergence that accounted for sex-biased expression also uncovered a fast-X effect for male-biased and unbiased genes, suggesting that recessive beneficial mutations play an important role in adaptation.     

Genomic analysis of closely related astroviruses

To understand astrovirus biology, it is essential to understand factors associated with its evolution. The current study reports the genomic sequences of nine novel turkey astrovirus (TAstV) type 2-like clinical isolates. This represents, to our knowledge, the largest genomic-length data set available for any one astrovirus type. The comparison of these TAstV sequences suggests that the TAstV species contains multiple subtypes and that recombination events have occurred across the astrovirus genome. In addition, the analysis of the capsid gene demonstrated evidence for both site-specific positive selection and purifying selection.     

Comparative genomics and the study of evolution by natural selection

Genomics profoundly affects most areas of biology, including ecology and evolutionary biology. By examining genome sequences from multiple species, comparative genomics offers new insight into genome evolution and the way natural selection moulds DNA sequence evolution. Functional divergence, as manifested in the accumulation of nonsynonymous substitutions in protein-coding genes, differs among lineages in a manner seemingly related to population size. For example, the ratio of nonsynonymous to synonymous substitution (d_N/d_S) is higher in apes than in rodents, compatible with Ohta's nearly neutral theory of molecular evolution, which suggests that the fixation of slightly deleterious mutations contributes to protein evolution at an extent negatively correlated with effective population size. While this supports the idea that functional evolution is not necessarily adaptive, comparative genomics is uncovering a role for positive Darwinian selection in 10–40% of all genes in different lineages, estimates that are likely to increase when the addition of more genomes gives increased power. Again, population size seems to matter also in this context, with a higher proportion of fixed amino acid changes representing advantageous mutations in large populations. Genes that are particularly prone to be driven by positive selection include those involved with reproduction, immune response, sensory perception and apoptosis. Genetic innovations are also frequently obtained by the gain or loss of complete gene sequences. Moreover, it is increasingly realized, from comparative genomics, that purifying selection conserves much more than just the protein-coding part of the genome, and this points at an important role for regulatory elements in trait evolution. Finally, genome sequencing using outbred or multiple individuals has provided a wealth of polymorphism data that gives information on population history, demography and marker evolution.     

Genome size evolution is associated with climate seasonality and glucosinolates,but not life history,soil nutrients or range size,across a clade of mustards

Background and AimsWe investigate patterns of evolution of genome size across a morphologically and ecologically diverse clade of Brassicaceae, in relation to ecological and life history traits. While numerous hypotheses have been put forward regarding autecological and environmental factors that could favour small vs. large genomes, a challenge in understanding genome size evolution in plants is that many hypothesized selective agents are intercorrelated.MethodsWe contribute genome size estimates for 47 species of Streptanthus Nutt. and close relatives, and take advantage of many data collections for this group to assemble data on climate, life history, soil affinity and composition, geographic range and plant secondary chemistry to identify simultaneous correlates of variation in genome size in an evolutionary framework. We assess models of evolution across clades and use phylogenetically informed analyses as well as model selection and information criteria approaches to identify variables that can best explain genome size variation in this clade.Key ResultsWe find differences in genome size and heterogeneity in its rate of evolution across subclades of Streptanthus and close relatives. We show that clade-wide genome size is positively associated with climate seasonality and glucosinolate compounds. Model selection and information criteria approaches identify a best model that includes temperature seasonality and fraction of aliphatic glucosinolates, suggesting a possible role for genome size in climatic adaptation or a role for biotic interactions in shaping the evolution of genome size. We find no evidence supporting hypotheses of life history, range size or soil nutrients as forces shaping genome size in this system.ConclusionsOur findings suggest climate seasonality and biotic interactions as potential forces shaping the evolution of genome size and highlight the importance of evaluating multiple factors in the context of phylogeny to understand the effect of possible selective agents on genome size.     

A neutral view of the evolving genomic architecture of speciation

Analyses of genomewide polymorphism data have begun to shed light on speciation and adaptation. Genome scans to identify regions of the genome that are unusually different between populations or species, possibly due to divergent natural or sexual selection, are widespread in speciation genomics. Theoretical and empirical work suggests that such outlier regions may grow faster than linearly during speciation with gene flow due to a rapid transition between low and high reproductive isolation. We investigate whether this pattern could be attributed to neutral processes by simulating genomes under neutral evolution with varying amounts and timing of gene flow. Under both neutral evolution and divergent selection, simulations with little or no gene flow, or with a long allopatric period after its cessation, resulted in faster than linear growth of the proportion of the genome lying in outlier regions. Without selection, higher recent gene flow erased differentiation; with divergent selection, these same scenarios produced nonlinear growth to a plateau. Our results suggest that, given a history of gene flow, the growth of the divergent genome is informative about selection during divergence, but that in many scenarios, this pattern does not easily distinguish neutral and non‐neutral processes during speciation with gene flow.     

Sexual Selection and the Molecular Evolution of ADAM Proteins

Rapid evolution has been identified for many reproductive genes and recent studies have combined phylogenetic tests and information on species mating systems to test sexual selection. Here we examined the molecular evolution of the ADAM gene family, a diverse group of 35 proteins capable of adhesion to and cleavage of other proteins, using sequence data from 25 mammalian genes. Out of the 25 genes analyzed, all those expressed in male reproductive tissue showed evidence of positive selection. Positively selected amino acids within the protein adhesion domain were only found in sperm surface ADAM proteins (ADAMs 1, 2, 3, 4, and 32) suggesting selection driven by male × female interactions. We tested heterogeneity in rates of evolution of the adhesion domain of ADAM proteins by using sequence data from Hominidae and macaques. The use of the branch and branch-site models (PAML) showed evidence of higher d _N/d _S and/or positive selection linked to branches experiencing high postmating selective pressures (chimpanzee and macaque) for Adams 2, 18, and 23. Moreover, we found consistent higher proportion of nonsynonymous relative to synonymous and noncoding sequence substitutions in chimpanzee and/or macaque only for Adams 2, 18, and 23. Our results suggest that lineage-specific sexual selection bouts might have driven the evolution of the adhesion sperm protein surface domains of ADAMs 2 and 18 in primates. Adams 2 and 18 are localized in chromosome 8 of primates and adjacent to each other, so their evolution might have also been influenced by their common genome localization.     

Adaptive Evolution and the Birth of CTCF Binding Sites in the Drosophila Genome

Changes in the physical interaction between cis-regulatory DNA sequences and proteins drive the evolution of gene expression. However, it has proven difficult to accurately quantify evolutionary rates of such binding change or to estimate the relative effects of selection and drift in shaping the binding evolution. Here we examine the genome-wide binding of CTCF in four species of Drosophila separated by between ∼2.5 and 25 million years. CTCF is a highly conserved protein known to be associated with insulator sequences in the genomes of human and Drosophila. Although the binding preference for CTCF is highly conserved, we find that CTCF binding itself is highly evolutionarily dynamic and has adaptively evolved. Between species, binding divergence increased linearly with evolutionary distance, and CTCF binding profiles are diverging rapidly at the rate of 2.22% per million years (Myr). At least 89 new CTCF binding sites have originated in the Drosophila melanogaster genome since the most recent common ancestor with Drosophila simulans. Comparing these data to genome sequence data from 37 different strains of Drosophila melanogaster, we detected signatures of selection in both newly gained and evolutionarily conserved binding sites. Newly evolved CTCF binding sites show a significantly stronger signature for positive selection than older sites. Comparative gene expression profiling revealed that expression divergence of genes adjacent to CTCF binding site is significantly associated with the gain and loss of CTCF binding. Further, the birth of new genes is associated with the birth of new CTCF binding sites. Our data indicate that binding of Drosophila CTCF protein has evolved under natural selection, and CTCF binding evolution has shaped both the evolution of gene expression and genome evolution during the birth of new genes.     

Lack of low frequency variants masks patterns of non-neutral evolution following domestication

Detecting artificial selection in the genome of domesticated species can not only shed light on human history but can also be beneficial to future breeding strategies. Evidence for selection has been documented in domesticated species including maize and rice, but few studies have to date detected signals of artificial selection in the Sorghum bicolor genome. Based on evidence that domesticated S. bicolor and its wild relatives show significant differences in endosperm structure and quality, we sequenced three candidate seed storage protein (kafirin) loci and three candidate starch biosynthesis loci to test whether these genes show non-neutral evolution resulting from the domestication process. We found strong evidence of non-neutral selection at the starch synthase IIa gene, while both starch branching enzyme I and the beta kafirin gene showed weaker evidence of non-neutral selection. We argue that the power to detect consistent signals of non-neutral selection in our dataset is confounded by the absence of low frequency variants at four of the six candidate genes. A future challenge in the detection of positive selection associated with domestication in sorghum is to develop models that can accommodate for skewed frequency spectrums.     

Rapid evolution through gene duplication and subfunctionalization of the testes-specific alpha4 proteasome subunits in Drosophila

Gene duplication is an important mechanism for acquiring new genes and creating genetic novelty in organisms. Evidence suggests that duplicated genes are retained at a much higher rate than originally thought and that functional divergence of gene copies is a major factor promoting their retention in the genome. We find that two Drosophila testes-specific alpha4 proteasome subunit genes (alpha4-t1 and alpha4-t2) have a higher polymorphism within species and are significantly more diverged between species than the somatic alpha4 gene. Our data suggest that following gene duplication, the alpha4-t1 gene experienced relaxed selective constraints, whereas the alpha4-t2 gene experienced positive selection acting on several codons. We report significant heterogeneity in evolutionary rates among all three paralogs at homologous codons, indicating that functional divergence has coincided with genic divergence. Reproductive subfunctionalization may allow for a more rapid evolution of reproductive traits and a greater specialization of testes function. Our data add to the increasing evidence that duplicated genes experience lower selective constraints and in some cases positive selection following duplication. Newly duplicated genes that are freer from selective constraints may provide a mechanism for developing new interactions and a pathway for the evolution of new genes.     

Extensive genome-wide variability of human cytomegalovirus in congenitally infected infants

Research has shown that RNA virus populations are highly variable, most likely due to low fidelity replication of RNA genomes. It is generally assumed that populations of DNA viruses will be less complex and show reduced variability when compared to RNA viruses. Here, we describe the use of high throughput sequencing for a genome wide study of viral populations from urine samples of neonates with congenital human cytomegalovirus (HCMV) infections. We show that HCMV intrahost genomic variability, both at the nucleotide and amino acid level, is comparable to many RNA viruses, including HIV. Within intrahost populations, we find evidence of selective sweeps that may have resulted from immune-mediated mechanisms. Similarly, genome wide, population genetic analyses suggest that positive selection has contributed to the divergence of the HCMV species from its most recent ancestor. These data provide evidence that HCMV, a virus with a large dsDNA genome, exists as a complex mixture of genome types in humans and offer insights into the evolution of the virus.     

Evidence of amino acid diversity-enhancing selection within humans and among primates at the candidate sperm-receptor gene PKDREJ

Sperm-egg interaction is a crucial step in fertilization, yet the identity of most interacting sperm-egg proteins that mediate this process remains elusive. Rapid evolution of some fertilization proteins has been observed in a number of species, including evidence of positive selection in the evolution of components of the mammalian egg coat. The rapid evolution of the egg-coat proteins could strongly select for changes on the sperm receptor, to maintain the interaction. Here, we present evidence that positive selection has driven the evolution of PKDREJ, a candidate sperm receptor of mammalian egg-coat proteins. We sequenced PKDREJ from a panel of 14 primates, including humans, and conducted a comparative maximum-likelihood analysis of nucleotide changes and found evidence of positive selection. An additional panel of 48 humans was surveyed for nucleotide polymorphisms at the PKDREJ locus. The regions predicted to have been subject to adaptive evolution among primates show several amino acid polymorphisms within humans. The distribution of polymorphisms suggests that balancing selection may maintain diverse PKDREJ alleles in some populations. It remains unknown whether there are functional differences associated with these diverse alleles, but their existence could have consequences for human fertility.     

Rates of protein evolution are positively correlated with developmental timing of expression during mouse spermatogenesis

Male reproductive genes often evolve very rapidly, and sexual selection is thought to be a primary force driving this divergence. We investigated the molecular evolution of 987 genes expressed at different times during mouse spermatogenesis to determine if the rate of evolution and the intensity of positive selection vary across stages of male gamete development. Using mouse-rat orthologs, we found that rates of protein evolution were positively correlated with the developmental timing of expression. Genes expressed early in spermatogenesis had rates of divergence similar to the genome median, while genes expressed after the onset of meiosis were found to evolve much more quickly. Rates of protein evolution were fastest for genes expressed during the dramatic morphogenesis of round spermatids into spermatozoa. Late-expressed genes were also more likely to be specific to the male germline. To test for evidence of positive selection, we analyzed the ratio of nonsynonymous to synonymous changes using a maximum likelihood framework in comparisons among mouse, rat, and human. Many genes showed evidence of positive selection, and most of these genes were expressed late in spermatogenesis and were testis specific. Overall, these data suggest that the intensity of positive selection associated with the evolution of male gametes varies considerably across development and acts primarily on phenotypes that develop late in spermatogenesis.     

Detecting strong positive selection in the genome

New statistical tests have been developed in the past decade that enable us to infer evidence of recent strong positive selection from genome-wide data on single-nucleotide polymorphism and to localize the targets of selection in the genome. Based on these tests, past demographic events that led to distortions of the site-frequency spectrum of variation can be distinguished from selection, in particular if linkage disequilibrium is taken into account. These methods have been successfully applied to species from which complete sequence information and polymorphism data are available, including Drosophila melanogaster, humans, and several plant species. To make full use of the available data, however, the tests that were primarily designed for panmictic populations need to be extended to spatially structured populations.     

Parasitism drives host genome evolution: Insights from the Pasteuria ramosa–Daphnia magna system

Because parasitism is thought to play a major role in shaping host genomes, it has been predicted that genomic regions associated with resistance to parasites should stand out in genome scans, revealing signals of selection above the genomic background. To test whether parasitism is indeed such a major factor in host evolution and to better understand host–parasite interaction at the molecular level, we studied genome‐wide polymorphisms in 97 genotypes of the planktonic crustacean Daphnia magna originating from three localities across Europe. Daphnia magna is known to coevolve with the bacterial pathogen Pasteuria ramosa for which host genotypes (clonal lines) are either resistant or susceptible. Using association mapping, we identified two genomic regions involved in resistance to P. ramosa, one of which was already known from a previous QTL analysis. We then performed a naïve genome scan to test for signatures of positive selection and found that the two regions identified with the association mapping further stood out as outliers. Several other regions with evidence for selection were also found, but no link between these regions and phenotypic variation could be established. Our results are consistent with the hypothesis that parasitism is driving host genome evolution.     

Evolution of man in the light of molecular genetics: a review. Part II. Regulation of gene function, evolution of speech and of brains

In the first part of this review the evolutionary history and genomics of the human species were considered in the light of molecular genetic evidence. In this second part the emphasis will be put on the regulation of the function of the genes and evolution of the human-specific traits such as enormously large brains and the capacity to communicate with a spoken language. The age-old question of what specifically makes us humans is also dealt with in its new lightning of molecular genetics of the genome era. It is concluded that, in addition to the structural differences of the genomes, it is most likely that it is different pattern of the regulation of the function of the genes, which evolved for most part through positive natural and sexual selection where the growth and the structure of the human population played a significant role, that differentiates us from our closest living relatives. In this process of the evolution of the most human-specific characteristics, like the size of brains, specifically that or the neocortex, and ability to speak, interbreeding with other forms of the Homo-genus may have played a role. In addition to the role of positive selection in general in the evolution of different human-specific traits, it is evident that this progressive selection has been quite effective, thus leading to accelerated evolution of these traits. Finally it can also be concluded that genetic and cultural evolution have gone hand in hand during the recent, and still continuing, evolution of the mankind interacting with each others in a bidirectional fashion.