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PubMed2005

Natural selection on protein-coding genes in the human genome.

Comparisons of DNA polymorphism within species to divergence between species enables the discovery of molecular adaptation in evolutionarily constrained genes as well as the differentiation of weak from strong purifying selection. The extent to which weak negative and positive darwinian selection have driven the molecular evolution of different species varies greatly, with some species, such as Drosophila melanogaster, showing strong evidence of pervasive positive selection, and others, such as the selfing weed Arabidopsis thaliana, showing an excess of deleterious variation within local populations. Here we contrast patterns of coding sequence polymorphism identified by direct sequencing of 39 humans for over 11,000 genes to divergence between humans and chimpanzees, and find strong evidence that natural selection has shaped the recent molecular evolution of our species. Our analysis discovered 304 (9.0%) out of 3,377 potentially informative loci showing evidence of rapid amino acid evolution. Furthermore, 813 (13.5%) out of 6,033 potentially informative loci show a paucity of amino acid differences between humans and chimpanzees, indicating weak negative selection and/or balancing selection operating on mutations at these loci. We find that the distribution of negatively and positively selected genes varies greatly among biological processes and molecular functions, and that some classes, such as transcription factors, show an excess of rapidly evolving genes, whereas others, such as cytoskeletal proteins, show an excess of genes with extensive amino acid polymorphism within humans and yet little amino acid divergence between humans and chimpanzees.

Amino Acid Substitution↗

PubMed2001

Evidence for positive selection in foot-and-mouth disease virus capsid genes from field isolates.

The nature of selection on capsid genes of foot-and-mouth disease virus (FMDV) was characterized by examining the ratio of nonsynonymous to synonymous substitutions in 11 data sets of sequences obtained from six different serotypes of FMDV. Using a method of analysis that assigns each codon position to one of a number of estimated values of nonsynonymous to synonymous ratio, significant evidence of positive selection was identified in 5 data sets, operating at 1-7% of codon positions. Evidence of positive selection was identified in complete capsid sequences of serotypes A and C and in VP1 sequences of serotypes SAT 1 and 2. Sequences of serotype SAT-2 recovered from a persistently infected African buffalo also revealed evidence for positive selection. Locations of codons under positive selection coincide closely with those of antigenic sites previously identified with the use of monoclonal antibody escape mutants. The vast majority of codons are under mild to strong purifying selection. However, these results suggest that arising antigenic variants benefit from a selective advantage in their interaction with the immune system, either during the course of an infection or in transmission to individuals with previous exposure to antigen. Analysis of amino acid usage at sites under positive selection indicates that this selective advantage can be conferred by amino acid substitutions that share physicochemically similar properties.

Amino Acid Sequence↗

PubMed2006

Tempo and mode of early gene loss in endosymbiotic bacteria from insects.

BACKGROUND: Understanding evolutionary processes that drive genome reduction requires determining the tempo (rate) and the mode (size and types of deletions) of gene losses. In this study, we analysed five endosymbiotic genome sequences of the gamma-proteobacteria (three different Buchnera aphidicola strains, Wigglesworthia glossinidia, Blochmannia floridanus) to test if gene loss could be driven by the selective importance of genes. We used a parsimony method to reconstruct a minimal ancestral genome of insect endosymbionts and quantified gene loss along the branches of the phylogenetic tree. To evaluate the selective or functional importance of genes, we used a parameter that measures the level of adaptive codon bias in E. coli (i.e. codon adaptive index, or CAI), and also estimates of evolutionary rates (Ka) between pairs of orthologs either in free-living bacteria or in pairs of symbionts. RESULTS: Our results demonstrate that genes lost in the early stages of symbiosis were on average less selectively constrained than genes conserved in any of the extant symbiotic strains studied. These results also extend to more recent events of gene losses (i.e. among Buchnera strains) that still tend to concentrate on genes with low adaptive bias in E. coli and high evolutionary rates both in free-living and in symbiotic lineages. In addition, we analyzed the physical organization of gene losses for early steps of symbiosis acquisition under the hypothesis of a common origin of different symbioses. In contrast with previous findings we show that gene losses mostly occurred through loss of rather small blocks and mostly in syntenic regions between at least one of the symbionts and present-day E. coli. CONCLUSION: At both ancient and recent stages of symbiosis evolution, gene loss was at least partially influenced by selection, highly conserved genes being retained more readily than lowly conserved genes: although losses might result from drift due to the bottlenecking of endosymbiontic populations, we demonstrated that purifying selection also acted by retaining genes of greater selective importance.

Animals↗

PubMed2006

Adaptive evolution of the spike gene of SARS coronavirus: changes in positively selected sites in different epidemic groups.

BACKGROUND: It is believed that animal-to-human transmission of severe acute respiratory syndrome (SARS) coronavirus (CoV) is the cause of the SARS outbreak worldwide. The spike (S) protein is one of the best characterized proteins of SARS-CoV, which plays a key role in SARS-CoV overcoming species barrier and accomplishing interspecies transmission from animals to humans, suggesting that it may be the major target of selective pressure. However, the process of adaptive evolution of S protein and the exact positively selected sites associated with this process remain unknown. RESULTS: By investigating the adaptive evolution of S protein, we identified twelve amino acid sites (75, 239, 244, 311, 479, 609, 613, 743, 765, 778, 1148, and 1163) in the S protein under positive selective pressure. Based on phylogenetic tree and epidemiological investigation, SARS outbreak was divided into three epidemic groups: 02-04 interspecies, 03-early-mid, and 03-late epidemic groups in the present study. Positive selection was detected in the first two groups, which represent the course of SARS-CoV interspecies transmission and of viral adaptation to human host, respectively. In contrast, purifying selection was detected in 03-late group. These indicate that S protein experiences variable positive selective pressures before reaching stabilization. A total of 25 sites in 02-04 interspecies epidemic group and 16 sites in 03-early-mid epidemic group were identified under positive selection. The identified sites were different between these two groups except for site 239, which suggests that positively selected sites are changeable between groups. Moreover, it was showed that a larger proportion (24%) of positively selected sites was located in receptor-binding domain (RBD) than in heptad repeat (HR)1-HR2 region in 02-04 interspecies epidemic group (p = 0.0208), and a greater percentage (25%) of these sites occurred in HR1-HR2 region than in RBD in 03-early-mid epidemic group (p = 0.0721). These suggest that functionally different domains of S protein may not experience same positive selection in each epidemic group. In addition, three specific replacements (F360S, T487S and L665S) were only found between 03-human SARS-CoVs and strains from 02-04 interspecies epidemic group, which reveals that selective sweep may also force the evolution of S genes before the jump of SARS-CoVs into human hosts. Since certain residues at these positively selected sites are associated with receptor recognition and/or membrane fusion, they are likely to be the crucial residues for animal-to-human transmission of SARS-CoVs, and subsequent adaptation to human hosts. CONCLUSION: The variation of positive selective pressures and positively selected sites are likely to contribute to the adaptive evolution of S protein from animals to humans.

Amino Acid Sequence↗

PubMed2004

The origin and evolution of geminivirus-related DNA sequences in Nicotiana.

A horizontal transmission of a geminiviral DNA sequence, into the germ line of an ancestral Nicotiana, gave rise to multiple repeats of geminivirus-related DNA, GRD, in the genome. We follow GRD evolution in Nicotiana tabacum (tobacco), an allotetraploid, and its diploid relatives, and show GRDs are derived from begomoviruses. GRDs occur in two families: the GRD5 family's ancestor integrated into the common ancestor of three diploid species, Nicotiana kawakamii, Nicotiana tomentosa and Nicotiana tomentosiformis, on homeologous group 4 chromosomes. The GRD3 family was acquired more recently on chromosome 2 in a lineage of N. tomentosiformis, the paternal ancestor of tobacco. Both GRD families include individual members that are methylated and diverged. Using relative rates of synonymous and nonsynonymous nucleotide substitutions, we tested for evidence of selection on GRD units and found none within the GRD3 and GRD5 families. However, the substitutions between GRD3 and GRD5 do show a significant excess of synonymous changes, suggesting purifying selection and hence a period of autonomous evolution between GRD3 and GRD5 integration. We observe in the GRD3 family, features of Helitrons, a major new class of putative rolling-circle replicating eukaryotic transposon, not found in the GRD5 family or geminiviruses. We speculate that the second integration event, resulting in the GRD3 family, involved a free-living geminivirus, a Helitron and perhaps also GRD5. Thus our data point towards recurrent dynamic interplay between geminivirus and plant DNA in evolution.

Base Sequence↗

PubMed1998

Molecular evolution of a duplication: the sex-peptide (Acp70A) gene region of Drosophila subobscura and Drosophila madeirensis.

In Drosophila melanogaster, the Acp70A gene, which is involved in the postmating reactions of the female, is a single-copy gene. However, in Drosophila subobscura, the gene is duplicated and both copies are transcribed. To study the molecular evolution of the duplication, a 2.1-kb fragment encompassing both copies of the duplication was sequenced for 10 lines of D. subobscura and one line of Drosophila madeirensis. Estimates of the divergence between the two copies of the duplicated region and between the two species studied, D. subobscura and D. madeirensis, revealed that both copies of the Acp70a gene had evolved independently since their duplication. The ratio of nonsynonymous to silent divergence between copies was generally higher than one. The McDonald and Kreitman test revealed an excess of nonsynonymous changes fixed since the duplication and before the split of the D. subobscura and D. madeirensis lineages. These results point to natural selection driving protein evolution after the duplication. Specifically, adaptive evolution appears to have caused the initial differentiation between copies of the N-terminal parts of the proteins, while purifying selection could be responsible for the high conservation of the C-terminal parts.

Amino Acid Sequence↗

PubMed2002

Selection and gene duplication: a view from the genome.

Immediately after a gene duplication event, the duplicate genes have redundant functions. Is natural selection therefore completely relaxed after duplication? Does one gene evolve more rapidly than the other? Several recent genome-wide studies have suggested that duplicate genes are always under purifying selection and do not always evolve at the same rate.

Animals↗

PubMed2002

Phylogenetic evidence for frequent positive selection and recombination in the meningococcal surface antigen PorB.

Previous estimates of rates of synonymous (d(S)) and nonsynonymous (d(N)) substitution among Neisseria meningitidis gene sequences suggested that the surface loops of the variable outer membrane protein PorB were under only weak selection pressure from the host immune response. These findings were consistent with studies indicating that PorB variants were not always protective in immunological and microbiological assays and questioned the suitability of this protein as a vaccine component. PorB, which is expressed at high levels on the surface of the meningococcus, has been implicated in mechanisms of pathogenesis and has also been used as a typing target in epidemiological investigations. In this work, using more precise estimates of selection pressures and recombination rates, we have shown that some residues in the surface loops of PorB are under very strong positive selection, as great as that observed in human immunodeficiency virus-1 surface glycoproteins, whereas amino acids within the loops and the membrane-spanning regions of the protein are under purifying selection, presumably because of structural constraints. Congruence tests showed that recombination occurred at a rate that was not sufficient to erase all phylogenetic similarity and did not greatly bias selection analysis. Homology models of PorB structure indicated that many strongly selected sites encoded residues that were predicted to be exposed to host immune responses, implying that this protein is under strong immune selection and requires further examination as a potential vaccine candidate. These data show that phylogenetic inference can be used to complement immunological and biochemical data in the choice of vaccine candidates.

Amino Acid Sequence↗

PubMed2005

Convergent loss of an anciently duplicated, functionally divergent RH2 opsin gene in the fugu and Tetraodon pufferfish lineages.

We describe the complete opsin gene families from the sequenced fugu and Tetraodon pufferfish genomes. We report the convergent loss of function of an anciently duplicated, functionally divergent RH2 or "green-sensitive" opsin gene in both pufferfish lineages, designated RH2-2. In fugu, RH2-2 apparently ceased to function very recently following a transposon-induced deletion that truncated the N-terminal 115 amino acids from the translated protein. Although a lack of frameshift or nonsense mutations in the fugu RH2-2 pseudogene suggests that the gene was lost very recently in this lineage, we were unable to detect any evidence of a selective sweep associated with the fixation of the truncated allele from population data. Interspecific comparison of the remaining fugu RH2-2 coding sequence paradoxically indicates that the gene was under strong purifying selection until the truncation occurred.

Amino Acid Sequence↗

PubMed2005

Bayes empirical bayes inference of amino acid sites under positive selection.

Codon-based substitution models have been widely used to identify amino acid sites under positive selection in comparative analysis of protein-coding DNA sequences. The nonsynonymous-synonymous substitution rate ratio (d(N)/d(S), denoted omega) is used as a measure of selective pressure at the protein level, with omega > 1 indicating positive selection. Statistical distributions are used to model the variation in omega among sites, allowing a subset of sites to have omega > 1 while the rest of the sequence may be under purifying selection with omega < 1. An empirical Bayes (EB) approach is then used to calculate posterior probabilities that a site comes from the site class with omega > 1. Current implementations, however, use the naive EB (NEB) approach and fail to account for sampling errors in maximum likelihood estimates of model parameters, such as the proportions and omega ratios for the site classes. In small data sets lacking information, this approach may lead to unreliable posterior probability calculations. In this paper, we develop a Bayes empirical Bayes (BEB) approach to the problem, which assigns a prior to the model parameters and integrates over their uncertainties. We compare the new and old methods on real and simulated data sets. The results suggest that in small data sets the new BEB method does not generate false positives as did the old NEB approach, while in large data sets it retains the good power of the NEB approach for inferring positively selected sites.

Alleles↗

PubMed2004

Impact of founder population, drift and selection on the genetic diversity of a recently translocated tree population.

Recently established, temperate tree populations combine a high level of differentiation for adaptive traits, suggesting rapid genetic evolution, with a high level of genetic diversity within population, suggesting a limited impact of genetic drift and purifying selection. To study experimentally the evolutionary forces in a recently established population, we assessed the spatial and temporal patterns of genetic diversity within a disjunct population of Cedrus atlantica established 140 years ago in south-eastern France from a North African source. The population is expanding through natural regeneration. Three generations were sampled, including founder trees. We analysed 12 isozyme loci, three of which were previously found in tight association with selected genes, and quantitative traits. No bottleneck effect was detected in the founder generation, but a simple test of allelic association revealed an initial disequilibrium which disappeared in the following generations. The impact of genetic drift during secondary evolution was limited, as suggested by the weak temporal differentiation. The genetic load was not reduced after 3 generations, and the quantitative variation for adaptive traits did not change either. Thus, initial genetic changes first proceed from a rapid re-organisation of the diversity through mating and recombination, whereas genetic erosion through drift and selection is delayed due to temporal and spatial stochasticity. Two life-history traits of trees contribute to slowing down the processes of genetic erosion: perenniality and large spatial scale. Thus, one would expect recently established tree populations to have a higher diversity than older ones, which seems in accordance with experimental surveys.

Biological Evolution↗

PubMed1990

Production and characterization of a human monoclonal antibody, reactive with a conserved epitope on gp41 of human immunodeficiency virus type I.

A human Epstein-Barr virus-transformed lymphoblastoid B-cell line was generated from peripheral blood mononuclear cells (PBMC) of an asymptomatic human immunodeficiency virus type I (HIV-1) seropositive donor, which produces a human monoclonal antibody K14 (IgG1), reactive with an epitope on the transmembrane part (gp41) of the envelope glycoprotein of HIV-1. This monoclonal antibody reacts with a lysate of HIV-1-infected H9 cells, gradient purified HIV-1, and a vaccinia recombinant HIV-1 gp160 protein, but not with HIV-2 antigens in an enzyme-linked immunosorbent assay (ELISA). When used as an immobilized ligand in an immune affinity column, K14 selectively purifies gp41 from a HIV-1-infected H9 cell lysate. Although no reactivity was observed in ELISA with a panel of partially overlapping synthetic nonapeptides spanning the whole length of HIV-1 gp41, it was shown to react with recombinant envelope proteins, provided that they did contain amino acids 643-692: deletion of this part resulted in the disappearance of the reactivity. Testing of an extensive panel of the sera from HIV-1 seropositive or seronegative donors from Europe and Africa, including a selected group of donors before and after HIV-1 seroconversion, in a competition ELISA with horseradish peroxidase-conjugated K14, showed that the epitope recognized on gp41 is immunodominant and conserved. K14 does not neutralize HIV-1 infectivity or virus-mediated cell fusion, and does not mediate antibody-dependent cellular cytotoxicity.

Antibodies, Monoclonal↗

PubMed2006

Relaxed selection among duplicate floral regulatory genes in Lamiales.

Polyploidization is a prevalent mode of genome diversification within plants. Most gene duplicates arising from polyploidization (paralogs) are typically lost, although a subset may be maintained under selection due to dosage, partitioning of gene function, or acquisition of novel functions. Because they experience selection in the presence of other duplicate loci across the genome, interactions among genes may also play a significant role in the maintenance of paralogs resulting from polyploidization. Previously, we identified duplicates of the genes LFY/FLO and AP3/DEF that directly interact in a floral regulatory pathway and are thought to be the result of ancient polyploidization in the Lamiales (> 50 mya). Although duplicates of MADS box genes including AP3/DEF are common throughout the angiosperm lineage, LFY/FLO duplicates in Lamiales are the first reported outside of tetraploid taxa. In order to explore hypotheses for the joint preservation of these interacting floral regulatory genes including novel LFY/FLO paralogs, here we clone FLO and DEF duplicates from additional Lamiales taxa and apply codon substitution models to test how selection acts on both genes following duplication. We find acceleration in the ratio of nonsynonymous-to-synonymous nucleotide substitutions for one (FLO) or both (DEF) paralogs that appears to be due to relaxed purifying selection as opposed to positive selection and shows a different pattern among functional domains of these genes. Several mechanisms are discussed that might be responsible for preservation of co-orthologs of FLO and DEF in Lamiales, including interactions among the genes of this regulatory pathway.

Arabidopsis Proteins↗

PubMed1997

Complete sequence of two tick-borne flaviviruses isolated from Siberia and the UK: analysis and significance of the 5' and 3'-UTRs.

The complete nucleotide sequence of two tick-transmitted flaviviruses, Vasilchenko (Vs) from Siberia and louping ill (LI) from the UK, have been determined. The genomes were respectively, 10928 and 10871 nucleotides (nt) in length. The coding strategy and functional protein sequence motifs of tick-borne flaviviruses are presented in both Vs and LI viruses. The phylogenies based on maximum likelihood, maximum parsimony and distance analysis of the polyproteins, identified Vs virus as a member of the tick-borne encephalitis virus subgroup within the tick-borne serocomplex, genus Flavivirus, family Flaviviridae. Comparative alignment of the 3'-untranslated regions revealed deletions of different lengths essentially at the same position downstream of the stop codon for all tick-borne viruses. Two direct 27 nucleotide repeats at the 3'-end were found only for Vs and LI virus. Immediately following the deletions a region of 332-334 nt with relatively conserved primary structure (67-94% identity) was observed at the 3'-non-coding end of the virus genome. Pairwise comparisons of the nucleotide sequence data revealed similar levels of variation between the coding region, and the 5' and 3'-termini of the genome, implying an equivalent strong selective control for translated and untranslated regions. Indeed the predicted folding of the 5' and 3'-untranslated regions revealed patterns of stem and loop structures conserved for all tick-borne flaviviruses suggesting a purifying selection for preservation of essential RNA secondary structures which could be involved in translational control and replication. The possible implications of these findings are discussed.

Animals↗

PubMed2006

Testing the neutral theory of molecular evolution using genomic data: a comparison of the human and bovine transcriptome.

Despite growing evidence of rapid evolution in protein coding genes, the contribution of positive selection to intra- and interspecific differences in protein coding regions of the genome is unclear. We attempted to see if genes coding for secreted proteins and genes with narrow expression, specifically those preferentially expressed in the mammary gland, have diverged at a faster rate between domestic cattle (Bos taurus) and humans (Homo sapiens) than other genes and whether positive selection is responsible. Using a large data set, we identified groups of genes based on secretion and expression patterns and compared them for the rate of nonsynonymous (dN) and synonymous (dS) substitutions per site and the number of radical (Dr) and conservative (Dc) amino acid substitutions. We found evidence of rapid evolution in genes with narrow expression, especially for those expressed in the liver and mammary gland and for genes coding for secreted proteins. We compared common human polymorphism data with human-cattle divergence and found that genes with high evolutionary rates in human-cattle divergence also had a large number of common human polymorphisms. This argues against positive selection causing rapid divergence in these groups of genes. In most cases dN/dS ratios were lower in human-cattle divergence than in common human polymorphism presumably due to differences in the effectiveness of purifying selection between long-term divergence and short-term polymorphism.

Animals↗

PubMed2005

Evidence for selection on synonymous mutations affecting stability of mRNA secondary structure in mammals.

BACKGROUND: In mammals, contrary to what is usually assumed, recent evidence suggests that synonymous mutations may not be selectively neutral. This position has proven contentious, not least because of the absence of a viable mechanism. Here we test whether synonymous mutations might be under selection owing to their effects on the thermodynamic stability of mRNA, mediated by changes in secondary structure. RESULTS: We provide numerous lines of evidence that are all consistent with the above hypothesis. Most notably, by simulating evolution and reallocating the substitutions observed in the mouse lineage, we show that the location of synonymous mutations is non-random with respect to stability. Importantly, the preference for cytosine at 4-fold degenerate sites, diagnostic of selection, can be explained by its effect on mRNA stability. Likewise, by interchanging synonymous codons, we find naturally occurring mRNAs to be more stable than simulant transcripts. Housekeeping genes, whose proteins are under strong purifying selection, are also under the greatest pressure to maintain stability. CONCLUSION: Taken together, our results provide evidence that, in mammals, synonymous sites do not evolve neutrally, at least in part owing to selection on mRNA stability. This has implications for the application of synonymous divergence in estimating the mutation rate.

Amino Acid Substitution↗

PubMed1996

Stem-loop potential in MHC genes: a new way of evaluating positive Darwinian selection?

The domains of polymorphic major histocompatibility complex (MHC) proteins which interact with peptides and T-cell receptors are considered to have been under positive evolutionary selection pressure. Evidence for this is a high ratio of non-synonymous to synonymous mutations in the corresponding genomic domains. By this criterion snake venom phospholipase A2 genes have also been under positive selection pressure. Recent studies of the latter genes indicate that positive selection has overridden an evolutionary pressure on base order which normally promotes the potential to extrude single-strand stem-loops from supercoiled duplex DNA ( fold pressure ). This has resulted in base order-dependent stem-loop potential being shifted to introns, which are highly conserved between species. It is now shown that, like snake venom phospholipase A2 genes, the domains of polymorphic MHC genes which appear to have responded to positive selection pressure have decreased base order-dependent stem-loop potential. The evolutionary pressure to generate stem-loop potential (believed to be important for recombination) has been overridden less in exons under negative purifying selection than in exons under positive Darwinian selection. Thus, base order-dependent stem-loop potential shows promise as an independent indicator of positive selection.

Animals↗

PubMed2006

Selective regimen shift and demographic growth increase associated with the emergence of high-fitness variants of canine parvovirus.

The natural evolution of Canine parvovirus (CPV) is characterized by a variety of mutations, mainly in the VP1/VP2 gene. Although positive selection has been previously reported in CPV, little is known about its overall contribution to viral adaptation in the canine population. Herein, the influences of the evolutive constraints on CPV during a period of viral adaptation into a previously uninfected population are more clearly investigated. To do this, 31 sequences of VP1/VP2 gene obtained from symptomatic domestic dogs in Brazil were used, sampled from 1980 to 2000. Marked evolutionary changes in CPV associated with a process of fine-tuning adaptation were observed. Specifically, sequences from the 1980s revealed two distinct antigenic types (i.e. 2a and 2b) cocirculating in Brazil. Moreover, analysis of the selective regimen showed that 90% of the VP2 sites were conserved (d(N)/d(S)=0). In contrast, sequences from the 1990s were composed solely of CPV-2a with 96% of VP2 sites under purifying selection (d(N)/d(S)<1) and site 297 under strong positive selection (omega=4.9). Important features regarding the demographic history of CPV in Brazil were also observed. The viral population size passed through a short period of explosive growth that declined and then stabilized into a constant rate of spread. Remarkably, the explosive growth coincided with the appearance of CPV variants that presented a unique repertoire of mutations never before seen in other worldwide strains. The analysis also showed that the estimated nucleotide substitution was similar to those commonly observed in fast evolving RNA viruses. The present results demonstrated the adaptive potential of CPV to acquire, in short interval of 10 years, key mutations in the VP1/VP 2 gene that increased viral fitness and enabled the virus to disseminate even in vaccinated dogs.

Animals↗