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PubMed2005

Comparative and evolutionary analysis of genes encoding small GTPases and their activating proteins in eukaryotic genomes.

Both small GTPase and its activating protein (GAP) superfamilies exist in various eukaryotes. The small GTPases regulate a wide variety of cellular processes by cycling between active GTP- and inactive GAP-bound conformations. The GAPs promote GTPase inactivation by stimulating the GTP hydrolysis. In this study, we identified 111 small GTPases and 85 GAPs in rice, 65 GAPs in Arabidopsis, 90 small GTPases in Drosophila melanogaster, and 35 GAPs in Saccharomyces cerevisiaeby genome-wide analysis. We then analyzed and compared a total of 498 small GTPases and 422 GAPs from these four eukaryotic and human genomes. Both animals and yeast genomes contained five families of small GTPases and their GAPs. However, plants had only four of these five families because of a lack of the Ras and RasGAP genes. Small GTPases were conserved with common motifs, but GAPs exhibited higher and much more rapid divergence. On the basis of phylogenetic analysis of all small GTPases and GAPs in five eukaryotic organisms, we estimated that their ancestors had small sizes of small GTPases and GAPs and their large-scale expansions occurred after the divergence from their ancestors. Further investigation showed that genome duplications represented the major mechanism for such expansions. Nonsynonymous substitutions per site (Ka) and synonymous substitutions per site (Ks) analyses showed that most of the divergence due to a positive selection occurred in common ancestors, suggesting a major functional divergence in an ancient era.

Amino Acid Motifs↗
PubMed2006

Fast rate of evolution in alternatively spliced coding regions of mammalian genes.

BACKGROUND: At least half of mammalian genes are alternatively spliced. Alternative isoforms are often genome-specific and it has been suggested that alternative splicing is one of the major mechanisms for generating protein diversity in the course of evolution. Another way of looking at alternative splicing is to consider sequence evolution of constitutive and alternative regions of protein-coding genes. Indeed, it turns out that constitutive and alternative regions evolve in different ways. RESULTS: A set of 3029 orthologous pairs of human and mouse alternatively spliced genes was considered. The rate of nonsynonymous substitutions (dN), the rate of synonymous substitutions (dS), and their ratio (omega = dN/dS) appear to be significantly higher in alternatively spliced coding regions compared to constitutive regions. When N-terminal, internal and C-terminal alternatives are analysed separately, C-terminal alternatives appear to make the main contribution to the observed difference. The effects become even more pronounced in a subset of fast evolving genes. CONCLUSION: These results provide evidence of weaker purifying selection and/or stronger positive selection in alternative regions and thus one more confirmation of accelerated evolution in alternative regions. This study corroborates the theory that alternative splicing serves as a testing ground for molecular evolution.

Alternative Splicing↗
PubMed2006

Evaluation of whether accelerated protein evolution in chordates has occurred before, after, or simultaneously with gene duplication.

Gene duplication and loss are predicted to be at least of the order of the substitution rate and are key contributors to the development of novel gene function and overall genome evolution. Although it has been established that proteins evolve more rapidly after gene duplication, we were interested in testing to what extent this reflects causation or association. Therefore, we investigated the rate of evolution prior to gene duplication in chordates. Two patterns emerged; firstly, branches, which are both preceded by a duplication and followed by a duplication, display an elevated rate of amino acid replacement. This is reflected in the ratio of nonsynonymous to synonymous substitution (mean nonsynonymous to synonymous nucleotide substitution rate ratio [Ka:Ks]) of 0.44 compared with branches preceded by and followed by a speciation (mean Ka:Ks of 0.23). The observed patterns suggest that there can be simultaneous alteration in the selection pressures on both gene duplication and amino acid replacement, which may be consistent with co-occurring increases in positive selection, or alternatively with concurrent relaxation of purifying selection. The pattern is largely, but perhaps not completely, explained by the existence of certain families that have elevated rates of both gene duplication and amino acid replacement. Secondly, we observed accelerated amino acid replacement prior to duplication (mean Ka:Ks for postspeciation preduplication branches was 0.27). In some cases, this could reflect adaptive changes in protein function precipitating a gene duplication event. In conclusion, the circumstances surrounding the birth of new proteins may frequently involve a simultaneous change in selection pressures on both gene-copy number and amino acid replacement. More precise modeling of the relative importance of preduplication, postduplication, and simultaneous amino acid replacement will require larger and denser genomic data sets from multiple species, allowing simultaneous estimation of lineage-specific fluctuations in mutation rates and adaptive constraints.

Amino Acid Substitution↗
PubMed1999

Evolution of sea urchin retroviral-like (SURL) elements: evidence from 40 echinoid species.

We conducted a phylogenetic survey of sea urchin retroviral-like (SURL) retrotransposable elements in 33 species of the class Echinoidea (sea urchins, sand dollars, and heart urchins). A 263-bp fragment from the coding region of the reverse transcriptase (RT) gene was amplified, cloned, and sequenced. Phylogenetic relationships of the elements isolated from independent clones, along with those from seven additional echinoid species obtained earlier by Springer et al., were compared with host phylogeny. Vertical transmission and the presence of paralogous sequences that diverged prior to host speciation can explain most of the phylogenetic relationships among SURL elements. Rates of evolution were estimated from cases in which SURL and host phylogenies were concordant. In agreement with conclusions reached previously by Springer et al., average rates of synonymous substitution were comparable with those of single-copy sea urchin DNA. High ratios of synonymous to nonsynonymous substitution suggest that the RT of the elements is under strong purifying selection. However, a high proportion (approximately 15%) of elements with deleterious frameshifts and stop codons and an increase of the ratio of synonymous to nonsynonymous substitutions with divergence time show that in the short term this selection is relaxed. Despite the predominance of vertical transmission, sequence similarity of 83%-94% for SURL elements from hosts that have been separated for 200 Myr suggests four cases of apparent horizontal transfer between the ancestors of the extant echinoid species. In three additional cases, elements with identical RT sequences were found in sea urchin species separated for a minimum of 3 Myr. Thus, horizontal transfer plays a role in the evolution of this retrotransposon family.

Animals↗
PubMed2005

Evidence for natural selection in the HAVCR1 gene: high degree of amino-acid variability in the mucin domain of human HAVCR1 protein.

The family of genes encoding T-cell immunoglobulin and mucin-domain containing proteins (Tim), which are cell-surface molecules expressed in CD4(+) T helper cells, has important roles in the immune system. Here, we report three unusual patterns of genetic variation in the human hepatitis A virus cellular receptor 1 gene (HAVCR1) that are similar to patterns observed in major histocompatibility complex loci. First, levels of polymorphism in exon 4 of HAVCR1 were exceptionally high in humans (nucleotide diversity (pi)=45.45 x 10(-4)). Second, nonsynonymous substitutions and insertion/deletion variants were more frequent than synonymous substitutions in that exon (10 out of 12 variants). The rate of the mean number of nucleotide substitutions at nonsynonymous sites to synonymous sites at HAVCR1-exon 4 is >1 (P(A)/P(S)=1.92 and pi(A)/pi(S)=2.23). Third, levels of divergence among human, chimp, and gorilla sequences were unusually high in HAVCR1-exon 4 sequences. These features suggest that patterns of variation in HAVCR1 have been shaped by both positive and balancing natural selection in the course of primate evolution. Evidence that the effects of natural selection are largely restricted to the mucin domain of HAVCR1 suggests that this region may be of particular evolutionary and epidemiological interest.

Base Sequence↗
PubMed1996

Sequence analysis of a polymorphic Mhc class II gene in Pacific salmon.

Polymorphism of the nucleotide sequences encoding 149 amino acids of linked major histocompatibility complex (Mhc) class II B1 and B2 peptides, and of the intervening intron (548-773 base pairs), was examined within and among seven Pacific salmon (Oncorhynchus) species. Levels of nucleotide diversity were higher for the B1 sequence than for B2 or the intron in comparisons both within and between species. For the codons of the peptide binding region of the B1 sequence, the level of nonsynonymous nucleotide substitution (dN) exceeded the level of synonymous substitution (dS) by a factor of ten for within-species comparisons, and by a factor of four for between-species comparisons. The excess of dN indicates that balancing selection maintains diversity at this salmonid Mhc class II locus, as is common for Mhc loci in other vertebrates. Levels of nucleotide diversity for both the exon and intron sequences were greater among than within species, and there were numerous species-specific nucleotides present in both the coding and noncoding regions. Thus, neighbor-joining analysis of both the intron and exon regions provided phylogenies in which the sequences clustered strongly by species. There was little evidence of shared ancestral (trans-species) polymorphism in the exon phylogeny, and the intron phylogeny depicted standard relationships among the Pacific salmon species. The lack of shared allelic B1 lineages in these closely related species may result from severe bottlenecks that occurred during speciation or during the ice ages that glaciated the rim of the north Pacific Ocean approximately every 100000 years in the Pleistocene.

Amino Acid Sequence↗
PubMed2006

Retrotransposon sequence variation in four asexual plant species.

Transposable elements (TEs) can be viewed as genetic parasites that persist in populations due to their capacity for increase in copy number and the inefficacy of selection against them. A corollary of this hypothesis is that TEs are more likely to spread within sexual populations and be eliminated or inactivated within asexual populations. While previous work with animals has shown that asexual taxa may contain less TE diversity than sexual taxa, comparable work with plants has been lacking. Here we report the results of a study of Ty1/copia, Ty3/gypsy, and LINE-like retroelement diversity in four asexual plant species. Retroelement-like sequences, with a high degree of conservation both within and between species, were isolated from all four species. The sequences correspond to several previously annotated retroelement subfamilies. They also exhibit a pattern of nucleotide substitution characterized by an excess of synonymous substitutions, suggestive of a history of purifying selection. These findings were compared with retroelement sequence evolution in sexual plant taxa. One likely explanation for the discovery of conserved TE sequences in the genomes of these asexual taxa is simply that asexuality within these taxa evolved relatively recently, such that the loss and breakdown of TEs is not yet detectable through analysis of sequence diversity. This explanation is examined by conducting stochastic simulation of TE evolution and by using published information to infer rough estimates of the ages of asexual taxa.

Amino Acid Sequence↗
PubMedDate not supplied

High levels of MHC class II allelic diversity in lake trout from Lake Superior.

Sequence variation in a 216 bp portion of the major histocompatibility complex (MHC) II B1 domain was examined in 74 individual lake trout (Salvelinus namaycush) from different locations in Lake Superior. Forty-three alleles were obtained which encoded 71-72 amino acids of the mature protein. These sequences were compared with previous data obtained from five Pacific salmon species and Atlantic salmon using the same primers. Although all of the lake trout alleles clustered together in the neighbor-joining analysis of amino acid sequences, one amino acid allelic lineage was shared with Atlantic salmon (Salmo salar), a species in another genus which probably diverged from Salvelinus more than 10-20 million years ago. As shown previously in other salmonids, the level of nonsynonymous nucleotide substitution (dN) exceeded the level of synonymous substitution (dS). The level of nucleotide diversity at the MHC class II B1 locus was considerably higher in lake trout than in the Pacific salmon (genus Oncorhynchus). These results are consistent with the hypothesis that lake trout colonized Lake Superior from more than one refuge following the Wisconsin glaciation. Recent population bottlenecks may have reduced nucleotide diversity in Pacific salmon populations.

Alleles↗
PubMed1998

Natural selection at major histocompatibility complex loci of vertebrates.

The loci of the vertebrate major histocompatibility complex encode cell-surface glycoproteins that present peptides to T cells. Certain of these loci are highly polymorphic, and the mechanisms responsible for this polymorphism have been intensely debated. Four independent lines of evidence support the hypothesis that MHC polymorphisms are selectively maintained: (a) The distribution of allelic frequencies does not fit the neutral expectation. (b) The rate of nonsynonymous nucleotide substitution significantly exceeds the rate of synonymous substitution in the codons encoding the peptide-binding region of the molecule. (c) Polymorphisms have been maintained for long periods of time ("trans-species polymorphism"). (d) Introns have been homogenized relative to exons over evolutionary time, suggesting that balancing selection acts to maintain diversity in the latter, in contrast to the former.

Animals↗
PubMed1995

Nucleotide substitution type dependence of generation time effect of molecular evolution.

Using DNA sequence data of 18 genes from 14 mammals, we analyzed how the average molecular evolution rate per year per site (Vy) depends on the generation time (g). (I) Assuming the relation Vy varies; is directly proportional to g(-alpha), the index of generation time effect, (alpha) was estimated to be about 0.14 for amino acid replacement substitutions (A), and about 0.32 for synonymous substitutions (S). (II) Assuming the relation Vy = V(m)g g-1 + V(e)y, where V(m)g and V(e)y are constant independent of g, the fraction, r(e) = V(e)y/Vy, of the mutation rate independent part (V(e)y) in the total evolution rate (Vy) was estimated under the assumptions of the star phylogeny and the constancy of the mutation rate per generation. r(e) was smallest for mouse with the shortest generation time among our analyzed species, and it was estimated to be about 0.57 for A and 0.31 for S. Both results do not support the view that Vy is equal to the neutral mutation rate per site both for A and for S. They are in line with the thesis that, at least for A and probably even for S, the molecular evolution rate is influenced by some causes other than the mutation rate, such as changing environment.

Animals↗
PubMed1995

Natural selection on the gag, pol, and env genes of human immunodeficiency virus 1 (HIV-1).

Natural selection on polymorphic protein-coding loci of human immunodeficiency virus-1 (HIV-1), the more geographically widespread of the two viruses causing human acquired immune deficiency syndrome (AIDS), was studied by estimating the rates of nucleotide substitution per site in comparisons among alleles classified in families of related alleles on the basis of a phylogenetic analysis. In the case of gag, pol, and gp41, the rate of synonymous substitution generally exceeded that of nonsynonymous substitution, indicating that these genes are subject to purifying selection. However, in the case of several of the variable (V) regions of the gp120 gene, especially V2 and V3, comparisons within and between families often showed a significantly higher rate of nonsynonymous than of synonymous nucleotide substitution. This pattern of nucleotide substitution indicates that positive Darwinian selection has acted to diversify these regions at the amino acid level. The V regions have been identified as probable epitopes for antibody recognition; therefore, avoidance of such recognition seems likely to be the basis for positive selection on these regions. By contrast, regions of HIV-1 proteins identified as epitopes for T cell recognition show no evidence of positive selection and are often highly conserved at the amino acid level. These results suggest that selection favoring avoidance of T cell recognition has not been a major factor in the history of HIV-1 and thus that avoidance of T cell recognition is not likely to be a major factor in the pathogenesis of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Synonymous and nonsynonymous substitutions in mammalian genes and the nearly neutral theory.

The nearly neutral theory of molecular evolution predicts larger generation-time effects for synonymous than for nonsynonymous substitutions. This prediction is tested using the sequences of 49 single-copy genes by calculating the average and variance of synonymous and nonsynonymous substitutions in mammalian star phylogenies (rodentia, artiodactyla, and primates). The average pattern of the 49 genes supports the prediction of the nearly neutral theory, with some notable exceptions. The nearly neutral theory also predicts that the variance of the evolutionary rate is larger than the value predicted by the completely neutral theory. This prediction is tested by examining the dispersion index (ratio of the variance to the mean), which is positively correlated with the average substitution number. After weighting by the lineage effects, this correlation almost disappears for nonsynonymous substitutions, but not quite so for synonymous substitutions. After weighting, the dispersion indices of both synonymous and nonsynonymous substitutions still exceed values expected under the simple Poisson process. The results indicate that both the systematic bias in evolutionary rate among the lineages and the episodic type of rate variation are contributing to the large variance. The former is more significant to synonymous substitutions than to nonsynonymous substitutions. Isochore evolution may be similar to synonymous substitutions. The rate and pattern found here are consistent with the nearly neutral theory, such that the relative contributions of drift and selection differ between the two types of substitutions. The results are also consistent with Gillespie's episodic selection theory.

Animals↗
PubMed1997

Molecular evolution of the Amy multigenes in the subgenus Sophophora of Drosophila.

Molecular evolution of the Amy multigenes in Drosophila was investigated using PCR amplification. Twenty-five partial Amy sequences from 13 species belonging mainly to the subgenus Sophophora were determine, and a molecular phylogeny of the Amy genes in Drosophila was constructed, together with published Amy sequences. Clustering of species are mostly consistent with the traditional classification and that inferred from other genes. From sequence divergence between PCR products, several species, including D. elegans and D. fuyamai, were suggested to have multiple copies of the Amy genes. The loss of an intron took place at least three times after the Sophophora radiation. In order to investigate the mechanism of sequence evolution, the numbers of amino acid replacement and synonymous substitutions in five lineages were estimated. The heterogeneity in the relative numbers of synonymous and replacement substitutions among the lineages was found. Possible roles of selection in the sequence evolution of the Amy gene are discussed.

Animals↗
PubMed2004

Genomic regionality in rates of evolution is not explained by clustering of genes of comparable expression profile.

In mammalian genomes, linked genes show similar rates of evolution, both at fourfold degenerate synonymous sites (K4) and at nonsynonymous sites (KA). Although it has been suggested that the local similarity in the synonymous substitution rate is an artifact caused by the inclusion of disparately evolving gene pairs, we demonstrate here that this is not the case: after removal of disparately evolving genes, both (1) linked genes and (2) introns from the same gene have more similar silent substitution rates than expected by chance. What causes the local similarity in both synonymous and nonsynonymous substitution rates? One class of hypotheses argues that both may be related to the observed clustering of genes of comparable expression profile. We investigate these hypotheses using substitution rates from both human-mouse and mouse-rat comparisons, and employing three different methods to assay expression parameters. Although we confirm a negative correlation of expression breadth with both K4 and KA, we find no evidence that clustering of similarly expressed genes explains the clustering of genes of comparable substitution rates. If gene expression is not responsible, what about other causes? At least in the human-mouse comparison, the local similarity in KA can be explained by the covariation of KA and K4. As regards K4, our results appear consistent with the notion that local similarity is due to processes associated with meiotic recombination.

Animals↗
PubMed2004

Apparent selection intensity for the cytochrome oxidase subunit I gene varies with mode of reproduction in echinoderms.

When most amino acid substitutions in protein-coding genes are slightly deleterious rather than selectively neutral, life history differences can potentially modify the effective population size or the selective regime, resulting in altered ratios of non-synonymous to synonymous substitutions among taxa. We studied substitution patterns for the mitochondrial cytochrome oxidase subunit I (COI) gene in a sea star genus (Leptasterias spp.) with an obligate brood-protecting mode of reproduction and small-scale population genetic subdivision, and compared the results to available COI sequences in nine other genera of echinoderms with pelagic larvae: three sea stars, five sea urchins and one brittle star. We predicted that this life history difference would be associated with differences in the ratio of non-synonymous (dN) to synonymous (dS) substitution rates. Leptasterias had a significantly greater dN/dS ratio (both between species and within species), a significantly smaller transition/transversion rate ratio, and a significantly lower average nucleotide diversity within species, than did the non-brooding genera. Other explanations for the results, such as altered mutation rates or selective sweeps, were not supported by the data analysis. These findings highlight the potential influence of reproductive traits and other life history factors on patterns of nucleotide substitution within and between species.

Animals↗
PubMed1987

Nucleotide sequence and molecular evolution of mouse retrovirus-like IAP elements.

We determined the nucleotide (nt) sequences of cDNA and genomic clones for murine intracisternal type A particle (IAP) elements, which are retrovirus-like repetitive sequences in rodent genomes. The nucleotide sequence of the cDNA resembled that of retrovirus RNA genomes in its lack of the U5 sequence within the 3' long terminal repeat. By sequence comparison of our clones with reported rodent IAP elements, we located the probable gag, pol and env gene regions. The sequences for the pol, env and the 3' two-thirds of the gag region were conserved among the IAP elements. In the regions, synonymous substitutions occurred more frequently than non-synonymous ones, which suggested that the regions in question were functionally constrained until fairly recently. The rate of nucleotide substitutions in the regions was estimated to be 6-10 X 10(-9) nt per site per year, and significantly higher than that of the cellular genes. These rates may exemplify a characteristic of the nucleotide substitutions for an endogenous retrovirus. The sequence homology between the IAP element and IgE-binding factor gene is discussed.

Animals↗
PubMed1995

Recent African origin of modern humans revealed by complete sequences of hominoid mitochondrial DNAs.

We analyzed the complete mitochondrial DNA (mtDNA) sequences of three humans (African, European, and Japanese), three African apes (common and pygmy chimpanzees, and gorilla), and one orangutan in an attempt to estimate most accurately the substitution rates and divergence times of hominoid mtDNAs. Nonsynonymous substitutions and substitutions in RNA genes have accumulated with an approximately clock-like regularity. From these substitutions and under the assumption that the orangutan and African apes diverged 13 million years ago, we obtained a divergence time for humans and chimpanzees of 4.9 million years. This divergence time permitted calibration of the synonymous substitution rate (3.89 x 10(-8)/site per year). To obtain the substitution rate in the displacement (D)-loop region, we compared the three human mtDNAs and measured the relative abundance of substitutions in the D-loop region and at synonymous sites. The estimated substitution rate in the D-loop region was 7.00 x 10(-8)/site per year. Using both synonymous and D-loop substitutions, we inferred the age of the last common ancestor of the human mtDNAs as 143,000 +/- 18,000 years. The shallow ancestry of human mtDNAs, together with the observation that the African sequence is the most diverged among humans, strongly supports the recent African origin of modern humans, Homo sapiens sapiens.

Africa↗
PubMed2004

Extreme difference in rate of mitochondrial and nuclear DNA evolution in a large ectotherm, Galápagos tortoises.

We sequenced approximately 4.5 kb of mtDNA from 161 individuals representing 11 named taxa of giant Galápagos tortoises (Geochelone nigra) and about 4 kb of non-coding nuclear DNA from fewer individuals of these same 11 taxa. In comparing mtDNA and nucDNA divergences, only silent substitutions (introns, ITS, mtDNA control region, and synonymous substitutions in coding sequences) were considered. mtDNA divergence was about 30 times greater than that for nucDNA. This rate discrepancy for mtDNA and nucDNA is the greatest yet documented and is particularly surprising for large ectothermic animals that are thought to have relatively low rates of mtDNA evolution. This observation may be due to the somewhat unusual reproductive biology and biogeographic history of these organisms. The implication is that the ratio of effective population size of nucDNA/mtDNA is much greater than the usually assumed four. The nearly neutral theory of molecular evolution predicts this would lead to a greater difference between rates of evolution.

Animals↗