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PubMed2006

Degeneracy in the genetic code and its symmetries by base substitutions.

Degeneracy in the genetic code is known to minimise the deleterious effects of the most frequent base substitutions: transitions at the third base of codons are generally synonymous substitutions. Transversions that alter degeneracy were reported by Rumer. Here the other transversions are shown to leave invariant degeneracy when applied to the first base of codons. As a summary, degeneracy is considered with respect to all three types of base substitutions, the transitions and the two types of transversions. The symmetries of degeneracy by base substitutions are independent of the representation of the genetic code and discussed with respect to the quasi-universality of the genetic code.

Amino Acids↗
PubMed2006

Homologous recombination and the pattern of nucleotide substitution in Ehrlichia ruminantium.

Patterns of nucleotide substitution at orthologous loci were examined between three genomes of Ehrlichia ruminantium, the causative agent of heartwater disease of ruminants. The most recent common ancestor of two genomes (Erwe and Erwo) belonging to the Welgevonden strain was estimated to have occurred 26,500-57,000 years ago, while the most recent common ancestor of these two genomes and the Erga genome (Gardel strain) was estimated to have occurred 2.1-4.7 million years ago. The search for genes showing extremely high values of the number of synonymous substitutions per site was used to identify genes involved in past homologous recombination. The most striking case involved the map1 gene, encoding major antigenic protein-1; evidence for homologous recombination is consistent with previous phylogenetic analysis of map1 alleles. At this and certain other loci, homologous recombination may have contributed to the evolution of host-pathogen interactions. In addition, comparison of the patterns of synonymous and nonsynonymous substitution provided evidence for positive selection favoring a high level of amino acid change between the Welgevonden and Gardel strains at a locus of unknown function (designated Erum4340 in the Erwo genome).

Computational Biology↗
PubMed2003

Molecular evolution of the dotA gene in Legionella pneumophila.

The molecular evolution of dotA, which is related to the virulence of Legionella pneumophila, was investigated by comparing the sequences of 15 reference strains (serogroups 1 to 15). It was found that dotA has a complex mosaic structure. The whole dotA gene of Legionella pneumophila subsp. pneumophila serogroups 2, 6, and 12 has been transferred from Legionella pneumophila subsp. fraseri. A discrepancy was found between the trees inferred from the nucleotide and deduced amino acid sequences of dotA, which suggests that multiple hits, resulting in synonymous substitutions, have occurred. Gene phylogenies inferred from three different segments (the 5'-end region, the central, large periplasmic domain, and the 3'-end region) showed impressively dissimilar topologies. This was concordant with the sequence polymorphisms, indicating that each region has experienced an independent evolutionary history, and was evident even within the same domain of each strain. For example, the PP2 domain was found to have a heterogeneous structure, which led us hypothesize that the dotA gene of L. pneumophila may have originated from two or more different sources. Comparisons of synonymous and nonsynonymous substitutions demonstrated that the PP2 domain has been under strong selective pressure with respect to amino acid change. Split decomposition analysis also supported the intragenic recombination of dotA. Multiple recombinational exchange within the dotA gene, encoding an integral cytoplasmic membrane protein that is secreted, probably provided increased fitness in certain environmental niches, such as within a particular biofilm community or species of amoebae.

Bacterial Proteins↗
PubMed2005

Evidence for purifying selection against synonymous mutations in mammalian exonic splicing enhancers.

Silent sites in mammals have classically been assumed to be free from selective pressures. Consequently, the synonymous substitution rate (Ks) is often used as a proxy for the mutation rate. Although accumulating evidence demonstrates that the assumption is not valid, the mechanism by which selection acts remain unclear. Recent work has revealed that the presence of exonic splicing enhancers (ESEs) in coding sequence might influence synonymous evolution. ESEs are predominantly located near intron-exon junctions, which may explain the reduced single-nucleotide polymorphism (SNP) density in these regions. Here we show that synonymous sites in putative ESEs evolve more slowly than the remaining exonic sequence. Differential mutabilities of ESEs do not appear to explain this difference. We observe that substitution frequency at fourfold synonymous sites decreases as one approaches the ends of exons, consistent with the existing SNP data. This gradient is at least in part explained by ESEs being more abundant near junctions. Between-gene variation in Ks is hence partly explained by the proportion of the gene that acts as an ESE. Given the relative abundance of ESEs and the reduced rates of synonymous divergence within them, we estimate that constraints on synonymous evolution within ESEs causes the true mutation rate to be underestimated by not more than approximately 8%. We also find that Ks outside of ESEs is much lower in alternatively spliced exons than in constitutive exons, implying that other causes of selection on synonymous mutations exist. Additionally, selection on ESEs appears to affect nonsynonymous sites and may explain why amino acid usage near intron-exon junctions is nonrandom.

Alternative Splicing↗
PubMed1993

Remarkably high rate of molecular evolution of ruminant placental lactogens.

The sequences of ovine and bovine placental lactogens (based on published cDNA sequences) are remarkably different, indicating a very rapid rate of evolution. Analysis of the cDNA sequences indicates that the rate of nonsynonymous substitution in these proteins is considerably greater than the rate of synonymous substitution. This is an unusual situation, which suggests that the observed rapid rate of evolution is due to incorporation of adaptive rather than neutral mutations.

Animals↗
PubMed2006

Molecular evolution at the cytochrome oxidase subunit 2 gene among divergent populations of the intertidal copepod, Tigriopus californicus.

The cytochrome c oxidase subunit 2 gene (COII) encodes a highly conserved protein that is directly responsible for the initial transfer of electrons from cytochrome c to cytochrome c oxidase (COX) crucial to the production of ATP during cellular respiration. Despite its integral role in electron transport, we have observed extensive intraspecific nucleotide and amino acid variation among 26 full-length COII sequences sampled from seven populations of the marine copepod, Tigriopus californicus. Although intrapopulation divergence was virtually nonexistent, interpopulation divergence at the COII locus was nearly 20% at the nucleotide level, including 38 nonsynonymous substitutions. Given the high degree of interaction between the cytochrome c oxidase subunit 2 protein (COX2) and the nuclear-encoded subunits of COX and cytochrome c (CYC), we hypothesized that some codons in the COII gene are likely to be under positive selection in order to compensate for amino acid substitutions in other subunits. Estimates of the ratio of nonsynonymous to synonymous substitution (omega), obtained using a series of maximum likelihood models of codon substitution, indicated that the majority of codons in T. californicus COII are under strong purifying selection (omega << 1), while approximately 4% of the sites in this gene appear to evolve under relaxed selective constraint (omega = 1). A branch-site maximum likelihood model identified three sites that may have experienced positive selection within the central California sequence clade in our COII phylogeny; these results are consistent with previous studies showing functional and fitness consequences among interpopulation hybrids between central and northern California populations.

Amino Acid Sequence↗
PubMed1991

Role of diversifying selection and gene conversion in evolution of major histocompatibility complex loci.

Genes at the major histocompatibility complex (MHC) in mammals are known to have exceptionally high polymorphism and linkage disequilibrium. In addition, these genes form highly complicated gene families that have evolved through gene conversion and unequal crossing-over. It has been shown recently that amino acid substitution at the antigen recognition site (ARS) is more rapid than synonymous substitution, suggesting some kind of positive natural selection working at the ARS. It is highly desirable to know the interactive effect of gene conversion and natural selection on the evolution and variation of MHC gene families. A population genetic model is constructed that incorporates both selection and gene conversion. Diversifying selection is assumed in which sequence diversity is enhanced not only between alleles at the same locus but also between duplicated genes. Expressed and nonexpressed loci are assumed as in the class I gene family of MHC, with gene conversion occurring among all loci. Extensive simulation studies reveal that very weak selection at individual amino acid sites in combination with gene conversion can explain the unusual pattern of evolution and polymorphisms. Here both gene conversion and natural selection contribute to enhancing polymorphism.

Alleles↗
PubMed2005

Molecular evolution of the primate developmental genes MSX1 and PAX9.

In primates, the craniofacial skeleton and the dentition are marked by high levels of interspecific variation. Despite this, there are few comparative species studies conducted at the molecular level to investigate this functional diversity. We have determined nucleotide sequences of MSX1 and PAX9, two developmental genes, in a sample of 27 diverse primate species in order to identify coding or regulatory variation that may be associated with phenotypic diversity. Our analyses have identified four highly conserved noncoding sequences, including one that is conserved across primates and with dogs but not with mice. Although we find that substitution rates vary significantly across MSX1 exons, comparisons of nonsynonymous and synonymous substitution rates (dN/dS) suggest that, as a whole, MSX1 and PAX9 amino acid sequences have been under functional constraint throughout primate evolution. Compared to all other primates in our sample, our analysis of exon 1 in MSX1 finds an unusual pattern of amino acid substitution for Tarsius syrichta, a member of a lineage (tarsiers) that has many unique features among primates. For example, tarsiers are the only extant primates without deciduous incisors, and MSX1 is expressed exclusively in the incisor regions during the earliest stages of dental development. Our overall results provide insight into the utility of comparative species analyses of highly conserved developmental genes and their roles in the evolution of complex phenotypes.

Amino Acid Sequence↗
PubMed2006

Identification of physicochemical selective pressure on protein encoding nucleotide sequences.

BACKGROUND: Statistical methods for identifying positively selected sites in protein coding regions are one of the most commonly used tools in evolutionary bioinformatics. However, they have been limited by not taking the physiochemical properties of amino acids into account. RESULTS: We develop a new codon-based likelihood model for detecting site-specific selection pressures acting on specific physicochemical properties. Nonsynonymous substitutions are divided into substitutions that differ with respect to the physicochemical properties of interest, and those that do not. The substitution rates of these two types of changes, relative to the synonymous substitution rate, are then described by two parameters, gamma and omega respectively. The new model allows us to perform likelihood ratio tests for positive selection acting on specific physicochemical properties of interest. The new method is first used to analyze simulated data and is shown to have good power and accuracy in detecting physicochemical selective pressure. We then re-analyze data from the class-I alleles of the human Major Histocompatibility Complex (MHC) and from the abalone sperm lysine. CONCLUSION: Our new method allows a more flexible framework to identify selection pressure on particular physicochemical properties.

Algorithms↗
PubMed2001

Inference and prediction of courses of the diseases caused by pathologic viruses by estimating molecular evolution of within-host virus.

A new approach for inferring the evolutionary process of within-host virus is presented in this study. This approach includes a sequential-linking algorithm developed by us that can deal with the sequential viral samples that are obtained at different time points from the same host, and reconstruct a longitudinal phylogenetic tree in which the evolutionary relations between viral variants can be shown. A codon-based model, which uses a Markov process to describe substitutions between codons, is also employed in this approach to calculate synonymous and non-synonymous substitution rates and to distinguish positive selection and neutral evolution. The approach is applied to a data set of the V3 region of the HIV-1 envelope genes sequenced in different years after infection of a single patient. The results suggest that this approach may provide a more realistic description of viral evolution than the traditional evolution models because it accounts for both neutral and adaptive evolution. Most important of all, since this approach make it possible to follow up the evolutionary process of within-host virus by analyzing the sequential viral samples, it could be used in inference and prediction of the course of the diseases caused by pathologic viruses and evaluation of the treatment.

Algorithms↗
PubMed1996

Novel alleles HLA-B*7802 and B*51022: evidence for convergency in the HLA-B5 family.

We have characterized two novel HLA-B alleles, B*7802 and B*51022. The Caucasian-derived variant B*7802 most resembles the African-derived variant B*7801, from which B*7802 differs by two nucleotides. Only one of these modifications, however, is translated: a tyrosine for aspartate substitution occurs at residue 74 in B*7802, while the second nucleotide difference reflects a proximal synonymous substitution in codon 23. A second variant, B*51022, differs synonymously only at codon 23 from B*51021. Comparative analysis of the B5 CREG demonstrates that other pairs of B5 alleles differ synonymously only at codon 23 or synonymously at codon 23 and non-synonymously at a second more distal location. Contrary to the genesis of like pairs of B5 alleles via introduction of coordinate yet distant mutagenic events onto a single B5 progenitor, we postulate that synonymously different B5 progenitor molecules, B5ATT and B5ATC, are evolving in convergence to generate homologous B5 allele pairs differing silently at codon 23. Our finding that B*7802 is a single amino acid away from complete convergence with B*7801 and that B*51022 and B*51021 are in complete convergence is exemplary of such evolution.

Alleles↗
PubMed2002

Patterns of polymorphism in the MHC class II of a non-passerine bird, the great snipe (Gallinago media).

The genomic organisation of the major histocompatibility complex (MHC) seems to vary considerably between different bird species. In order to understand this variation it is important to gather information from different species. We have, for the first time, investigated MHC class II polymorphism in a wader species, the great snipe (Gallinago media). Eleven alleles were found in five sequenced individuals; these come from at least three different loci, but RFLP data suggest that a larger number of genes may be present. For MHC genes, amino acid substitutions followed the, for MHC genes, general pattern of high non-synonymous substitution rates in peptide-binding regions, suggesting that the sequenced alleles may be expressed. The number of genes, lengths of introns and exon sequences of the great snipe MHC seem to be intermediate between those of chicken and passerine birds.

Amino Acid Sequence↗
PubMed1991

Analysis of genetic mutations in human lactate dehydrogenase-A(M) deficiency using DNA conformation polymorphism in combination with polyacrylamide gradient gel and silver staining.

Human lactate dehydrogenase (LDH)-A mutant gene was analyzed by polymerase chain reaction - DNA conformation polymorphism (DCP). We used polyacrylamide gradient gel and silver staining procedures for DCP analysis and observed abnormal migration patterns in individuals heterozygous for LDH-A deficiency. Further sequence determination of the mutant alleles consistently resulted in detection of base substitutions, a G to T transversion at codon 328 (GAG----TAG), and synonymous substitutions at codon 115, 160 and 172. Such mutations were easily detectable using the DCP technique. The DCP technique using the polyacrylamide gradient gel and silver staining method seems likely to be useful for the rapid screening of mutations and for further genotype detection.

Amino Acid Sequence↗
PubMed2006

Bursts of nonsynonymous substitutions in HIV-1 evolution reveal instances of positive selection at conservative protein sites.

The fixation of a new allele can be driven by Darwinian positive selection or can be due to random genetic drift. Identifying instances of positive selection is a difficult task, because its impact is routinely obscured by the action of negative selection. The nature of the genetic code dictates that positive selection in favor of an amino acid replacement should often cause a burst of two or three nucleotide substitutions at a single codon site, because a large fraction of amino acid replacements cannot be achieved after just one nucleotide substitution. Here, we study pairs of successive nonsynonymous substitutions at one codon in the course of evolution of HIV-1 genes within HIV-1 populations inhabiting infected individuals. Such pairs are more numerous and more clumped than expected if different substitutions were independent and than what is observed for pairs of successive synonymous substitutions. Bursts of nonsynonymous substitutions in HIV-1 evolution cannot be explained by mutational biases and must, therefore, be due to positive selection. Both reversals, exact or imprecise, of fixed deleterious mutations and acquisitions of amino acids with new properties are responsible for the bursts. Temporal clumping is strongest at codon sites with a low overall rate of nonsynonymous evolution, implying that a substantial fraction of replacements of conservative amino acids are driven by positive selection. We identified many conservative sites of HIV-1 proteins that occasionally experience positive selection.

Amino Acid Substitution↗
PubMed2005

Hepatitis C virus F protein sequence reveals a lack of functional constraints and a variable pattern of amino acid substitution.

Hepatitis C virus (HCV) is an important human pathogen that affects 170 million people worldwide. The HCV genome is an RNA molecule that is approximately 9.6 kb in length and encodes a polyprotein that is cleaved proteolytically to generate at least 10 mature viral proteins. Recently, a new HCV protein named F has been described, which is synthesized as a result of a ribosomal frameshift. Little is known about the biological properties of this protein, but the possibility that the F protein may participate in HCV morphology or replication has been raised. In this work, the presence of functional constraints in the F protein was investigated. It was found that the rate of amino acid substitutions along the F protein was significantly higher than the rate of synonymous substitutions, and comparisons involving genes that represented independent phylogenetic lineages yielded very different divergence/conservation patterns. The distribution of stop codons in the F protein across all HCV genotypes was also investigated; genotypes 2 and 3 were found to have more stop codons than genotype 1. The results of this work suggest strongly that the pattern of divergence in the F protein is not affected by functional constraints.

Amino Acid Substitution↗
PubMed2004

Diversity of human immunodeficiency virus type 1 subtype A and CRF03_AB protease in Eastern Europe: selection of the V77I variant and its rapid spread in injecting drug user populations.

To characterize polymorphisms of the subtype A protease in the former Soviet Union, proviral DNA samples were obtained, with informed consent, from 119 human immunodeficiency virus type 1 (HIV-1)-positive untreated injecting drug users (IDUs) from 16 regions. All individuals studied have never been treated with antiretroviral drugs. The isolates were defined as IDU-A (n = 115) and CRF03_AB (n = 4) by using gag/env HMA/sequencing. The pro region was analyzed by using sequencing and original HIV-ProteaseChip hybridization technology. The mean of pairwise nucleotide distance between 27 pro sequences (23 IDU-A and 4 CRF03_AB) was low (1.38 +/- 0.79; range, 0.00 to 3.23). All sequences contained no primary resistance mutations. However, 13 of 23 (56.5%) subtype A isolates bore the V77I substitution known as the secondary protease mutation. V77I was associated with two synonymous substitutions in triplets 31 and 78, suggesting that all V77I-bearing viruses evolved from a single source in 1997. Hybridization analysis showed that 55 of 115 (47.8%) HIV-1 isolates contained V77I, but this variant was not found in any of 31 DNA samples taken from regions, where the HIV-1 epidemic among IDUs started earlier 1997, as well as in any of four CRF03_AB isolates. The results of analysis of 12 additional samples derived from epidemiologically linked subjects showed that in all four epidemiological clusters the genotype of the donor and the recipients was the same irrespective of the route of transmission. This finding demonstrates the transmission of the V77I mutant variant, which is spreading rapidly within the circulating viral pool in Russia and Kazakhstan. The continued molecular epidemiological and virological monitoring of HIV-1 worldwide thus remains of great importance.

Adolescent↗
PubMed2004

Decreased diversity but increased substitution rate in host mtDNA as a consequence of Wolbachia endosymbiont infection.

A substantial fraction of insects and other terrestrial arthropods are infected with parasitic, maternally transmitted endosymbiotic bacteria that manipulate host reproduction. In addition to imposing direct selection on the host to resist these effects, endosymbionts may also have indirect effects on the evolution of the mtDNA with which they are cotransmitted. Patterns of mtDNA diversity and evolution were examined in Drosophila recens, which is infected with the endosymbiont Wolbachia, and its uninfected sister species D. subquinaria. The level of mitochondrial, but not nuclear, DNA diversity is much lower in D. recens than in D. subquinaria, consistent with the hypothesized diversity-purging effects of an evolutionarily recent Wolbachia sweep. The d(N)/d(S) ratio in mtDNA is significantly greater in D. recens, suggesting that Muller's ratchet has brought about an increased rate of substitution of slightly deleterious mutations. The data also reveal elevated rates of synonymous substitutions in D. recens, suggesting that these sites may experience weak selection. These findings show that maternally transmitted endosymbionts can severely depress levels of mtDNA diversity within an infected host species, while accelerating the rate of divergence among mtDNA lineages in different species.

Animals↗
PubMed2004

Rapid evolution of primate antiviral enzyme APOBEC3G.

Human cytidine deaminase APOBEC3G and the virion infectivity factor (vif) of the human immunodeficiency virus (HIV) are a pair of antagonistic molecules. In the absence of vif, APOBEC3G induces a high rate of dC to dU mutations in the nascent reverse transcripts of HIV that leads to the degradation of the HIV genome. HIV vif, on the other hand, can suppress the translation and trigger the degradation of human APOBEC3G. Here, we studied the rate of APOBEC3G gene evolution from five hominoids and two Old World monkeys. Averaged across the entire coding region, the rate of non-synonymous nucleotide substitutions is approximately 1.4 times the rate of synonymous substitutions, strongly suggesting that APOBEC3G has been under positive Darwinian selection. A comparison between the nucleotide polymorphisms within humans and the substitutions among the seven primates reveals a significant excess of non-synonymous substitutions. Furthermore, the rate of charge-altering non-synonymous substitution is approximately 1.8 times that of charge-conserving substitution, indicating that the selection is promoting the diversity of the protein charge profile. However, no difference in selective pressure on APOBEC3G is detected between hosts and non-hosts of HIV or simian immunodeficiency virus (SIV). These results, together with recent findings that the antiviral activity of APOBEC3G is not limited to HIV/SIV, suggest that the selective pressure on APOBEC3G is not solely from HIV/SIV and that APOBEC3G is a broad antiviral enzyme. The identification of pervasive positive selection for charge-altering amino acid substitutions supports the hypothesis of electrostatic interactions between APOBEC3G and vif or its functional equivalents.

APOBEC-3G Deaminase↗