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At least 217 records · Page 12Linked to original sources
PubMed2006

Evolutionary simulations to detect functional lineage-specific genes.

MOTIVATION: Supporting the functionality of recent duplicate gene copies is usually difficult, owing to high sequence similarity between duplicate counterparts and shallow phylogenies, which hamper both the statistical and experimental inference. RESULTS: We developed an integrated evolutionary approach to identify functional duplicate gene copies and other lineage-specific genes. By repeatedly simulating neutral evolution, our method estimates the probability that an ORF was selectively conserved and is therefore likely to represent a bona fide coding region. In parallel, our method tests whether the accumulation of non-synonymous substitutions reveals signatures of selective constraint. We show that our approach has high power to identify functional lineage-specific genes using simulated and real data. For example, a coding region of average length (approximately 1400 bp), restricted to hominoids, can be predicted to be functional in approximately 94-100% of cases. Notably, the method may support functionality for instances where classical selection tests based on the ratio of non-synonymous to synonymous substitutions fail to reveal signatures of selection. Our method is available as an automated tool, ReEVOLVER, which will also be useful to systematically detect functional lineage-specific genes of closely related species on a large scale. AVAILABILITY: ReEVOLVER is available at http://www.unil.ch/cig/page7858.html.

Animals↗
PubMed2002

Dihydrofolate reductase gene polymorphisms in Pneumocystis carinii f. sp. hominis in Japan.

This study examined polymorphisms in the dihydrofolate reductase (DHFR) gene of Pneumocystis carinii isolates from 27 patients with P. carinii pneumonia (PCP) in Japan. Four substitution sites with two synonymous and two non-synonymous changes were found. Two synonymous substitutions at nucleotide positions 540 and 312 were identified in one and 13 patients, respectively. Two amino acid substitutions (Ala67Val, Cysl66Tyr) were found in two different patients. No linkage of amino acid substitutions in DHFR to those in dihydropteroate synthase was observed. The two patients whose isolates showed non-synonymous DHFR mutations were not exposed to DHFR inhibitors before they developed PCP and were treated successfully with co-trimoxazole.

Amino Acid Sequence↗
PubMed1997

Evidence for a selectively favourable reduction in the mutation rate of the X chromosome.

The equilibrium per-genome mutation rate in sexual species is thought to result from a trade-off between the benefits of reducing the deleterious mutation rate and the costs of increasing fidelity. We propose that selection will often favour a lower mutation rate on the X chromosome than on autosomes, owing to the exposure of deleterious recessive mutations on hemizygous chromosomes. We tested this hypothesis by examining 33 X-linked genes that have been sequenced in both mouse and rat, and compared their rate of evolution against 238 autosomal genes. The X-linked genes were found to have a significantly lower rate of synonymous substitution than the autosomal genes. Neither the supposed higher mutation rate in males nor stronger purifying selection against slightly deleterious mutations on the X chromosome can account for the low value. The most parsimonious explanation is that rodents have a lower mutation rate on the X chromosome than on autosomes. It is therefore likely that previous indirect estimates of the excess male mutation rate are inaccurate. Indeed, after correction we find no evidence for a male-biased mutation rate in rodents. Furthermore, the rate of synonymous substitution in Y-linked genes is not significantly different from that in autosomal ones. The extent to which enhanced male mutation rates are problematic for the mutational deterministic model of the evolution of sex must, in turn, be questioned.

Animals↗
PubMed2002

Comparative molecular evolution of primary (Buchnera) and secondary symbionts of aphids based on two protein-coding genes.

A+T content, phylogenetic relationships, codon usage, evolutionary rates, and ratio of synonymous versus non-synonymous substitutions have been studied in partial sequences of the atpD and aroQ/pheA genes of primary ( Buchnera) and secondary symbionts of aphids and a set of selected non-symbiotic bacteria, belonging to the five subdivisions of the Proteobacteria. Compared to the homologous genes of the last group, both genes belonging to Buchnera behave in a similar way, showing a higher A+T content, forming a monophyletic group, a loss in codon bias, especially in third base position, an evolutionary acceleration and an increase in the number of non-synonymous substitutions, confirming previous results reported elsewhere for other genes. When available, these properties have been partly observed with the secondary symbionts, but with values that are intermediate between Buchnera and free living Proteobacteria. They show high A+T content, but not as high as Buchnera, a non-solved phylogenetic position between Buchnera, and the other gamma-Proteobacteria, a loss in codon bias, again not as high as in Buchnera and a significant evolutionary acceleration in the case of the three atpD genes, but not when considering aroQ/pheA genes. These results give support to the hypothesis that they are symbionts at different stages of the symbiotic accommodation to the host.

AT Rich Sequence↗
PubMedDate not supplied

Evolution of human immunodeficiency virus type 1 in relation to disease progression in children.

OBJECTIVE: To compare patterns of nonsynonymous and synonymous substitutions over time in the V1V2 and C2V3 regions of human immunodeficiency virus type 1 (HIV-1) env and in a conserved segment of pol in HIV-1-infected children with varying rates of CD4+ T-cell decline. STUDY DESIGN/METHODS: Longitudinal study of HIV-1 genetic variants sampled from peripheral blood of 3 children affected with acquired immunodeficiency syndrome (AIDS) and 4 children with slow disease progression. Nested polymerase chain reaction (PCR) was used to detect HIV-1 genetic material in plasma-derived virions and cellular DNA. Sequence variants were enumerated by screening cloned PCR products using heteroduplex mobility assay (HMA) or single-strand conformation polymorphism analysis (SSCP) and nucleotide sequencing. Frequencies of nonsynonymous and synonymous substitutions within sampling points and the accumulation rate of nucleotide substitutions over the period of observation were calculated. RESULTS: In the C2V3 region, higher rates of accumulation of nonsynonymous substitutions were associated with more precipitous declines in CD4+ cell numbers. In the V1V2 region, rates of accumulation of nonsynonymous substitutions were comparable with those in the C2V3 region, but similar rates were observed in AIDS-affected children and children with slow disease progression. The rate of accumulation of nonsynonymous substitutions in the pol region was lower than that in the C2V3 and V1V2 regions. CONCLUSIONS: Rates of accumulation of nucleotide substitutions vary across the HIV-1 genome and differ in relation to disease progression in children. The finding of greater rates of nonsynonymous substitution in the immunodominant C2V3 region in children whose disease progressed rapidly is consistent with a vigorous but inadequate immune response in children who are unable to control HIV-1 infection.

CD4 Lymphocyte Count↗
PubMed2006

Detecting natural selection at the molecular level: a reexamination of some "classic" examples of adaptive evolution.

An important criterion used to detect adaptive evolution in DNA sequence data is omega(i) > 1, where omega(i) is the ratio of nonsynonymous to synonymous substitution rates in lineage i. However, the evaluation of multiple omega(i) within a phylogenetic tree can easily inflate the statistical type I error rate. We developed two rigorous methods of analysis that avoid this and other potential pitfalls. We applied these methods to four published examples of adaptive evolution. One case was strongly supported by our reanalysis (abalone sperm lysin), and one was weakly supported (baboon alpha-globin), but two examples (primate lysozyme and Antarctic fish beta-globin) did not show significant evidence of adaptive evolution. Our first method is a "bottom-up" hierarchical maximum likelihood approach, which (1) tests for significant heterogeneity in omega across the phylogeny, (2) locates its source using a sequence of planned comparisons, and (3) tests homogeneous groups of omega for omega > 1, using a modified level of significance that incorporates the pretesting. The second method is a "top-down" log-linear analysis based on estimates of nonsynonymous and synonymous substitutions in pairs of lineages. The log-linear test is applied to pairs of lineages joined at progressively deeper nodes. For each pair, the analysis simultaneously tests for adaptive evolution (omega > 1), a shift in natural selection (omega1 does not = omega2), and unequal evolution rate (the relative rate test). In both tests, we emphasized that the criterion omega1 not equal omega2 is an important additional indicator of a phylogenetic shift in the balance between natural selection and genetic drift between two related lineages.

Adaptation, Biological↗
PubMed1999

Evolutionary diversification of the mammalian defensins.

Defensins are cysteine-rich cationic peptides that function in antimicrobial defense in both invertebrates and vertebrates. Three main groups of animal defensins are known: insect defensins; mammalian alpha-defensins and vertebrate beta-defensins. It has been difficult to determine whether these molecules are homologous or have independently evolved similar features, but overall the evidence favors a distant relationship. The best evidence of this relationship is structural, particularly from their overall three-dimensional structure and from the spacing of half-cystine residues involved in intra-chain disulfide bonds. Some evidence favors a closer relationship between vertebrate beta-defensins and insect defensins than between the two groups of vertebrate defensins. Examination of nucleotide substitutions between recently duplicated mammalian defensin genes shows that the rate of nonsynonymous (amino-acid-altering) substitution exceeds that of synonymous substitution in the region of the gene encoding the mature defensin. This highly unusual pattern of nucleotide substitution is evidence that natural selection has acted to diversify defensins at the amino acid level. The resulting rapid evolution explains why it is difficult to reconstruct the evolutionary history of these molecules.

Amino Acid Sequence↗
PubMed2006

Isolation and characterization of a MHC class II DRB locus in the European water vole (Arvicola terrestris).

In so-called model species, such as human and mouse, genes of the major histocompatibility complex (MHC) are characterized by extremely high levels of polymorphism, and it is considered that such diversity is maintained by balancing selection. ;There is now a recognized need to expand studies into nonmodel species to examine whether high MHC diversity is mirrored in natural populations, and to determine the ecological, ethological, and evolutionary processes that underpin balancing selection. To address such issues, a necessary prerequisite is the ability to characterize diversity at a single, expressed, polymorphic MHC locus on which selection may be acting. Here, we provide the first description of allelic diversity at exon 2 of an MHC class II DRB locus in the European water vole (Arvicola terrestris), characterize variation across four natural populations, and test whether the patterns of variation are consistent with the effects of balancing selection. Using single-strand conformation polymorphism analysis and subsequent DNA sequencing of gel excisions, five DRB alleles were resolved, each with a unique amino acid sequence, among 100 individuals from four geographically distinct populations. Reverse transcription polymerase chain reaction confirmed that the alleles were products from an expressed locus. Intra-allelic amino acid differences were high (10.5-33.3%), and the nonsynonymous substitution rate exceeded the synonymous substitution rate for the functional peptide-binding region (d (N):d (S)=3.91 and P<0.005). Phylogenetic comparison of resolved alleles with closely related homologues indicated that each allele represented a unique lineage preserved across speciation events. These results indicate that balancing selection has maintained diversity of DRB allelic lineages and amino acid function over evolutionary time scales, but may be less effective at preserving alleles in contemporary populations where stochastic microevolutionary processes may dominate.

Alleles↗
PubMed2006

Can RNA selection pressure distort the measurement of Ka/Ks?

Recently, an interesting question has emerged in the evolutionary interpretation of sequence substitution data as evidence of amino acid selection pressure. Specifically, the Ka/Ks metric was designed to measure selection pressure on amino acid substitutions, assuming that the synonymous substitution rate Ks reflects the neutral nucleotide substitution rate. However, there is increasing evidence for selection pressure at silent sites due to constraints of RNA splicing. Is Ka/Ks an appropriate metric for selection pressure on amino acid substitutions, in the presence of other selection pressures acting only at the RNA level (such as selection for exonic splicing enhancers)? Or can the resulting decreases in Ks from such selection pressures introduce bias into the Ka/Ks metric, so that it no longer gives an accurate measure of amino acid level selection pressure? In this review, we present both mathematical models and empirical evidence for these divergent points of view.

Amino Acid Substitution↗
PubMed2002

Single synonymous codon substitution eliminates pausing during chloramphenicol acetyl transferase synthesis on Escherichia coli ribosomes in vitro.

The coding sequence for chloramphenicol acetyl transferase (CAT) contains several rare codons; three of them are ATA encoding isoleucine in positions 13, 84 and 119 of the amino acid sequence. Expression of CAT on Escherichia coli ribosomes in vitro results in mostly full-length product but also distinct smaller polypeptides from less than 3 kDa to over 20 kDa. As reported earlier, the smaller polypeptides are the predominant products, if translation is initiated with fluorophore-Met-tRNA(f). All this translational pausing is eliminated when the first ATA codon is mutated to ATC, a frequently used codon for isoleucine in E. coli. Addition of large amounts of E. coli tRNA to the coupled transcription/translation reaction does not reduce the number of pause-site peptides seen in the expression of wild-type CAT. Thus we hypothesize that the mRNA structure may be an important determinant for translational pausing.

Base Sequence↗
PubMed1999

Synonymous codon substitutions affect ribosome traffic and protein folding during in vitro translation.

To investigate the possible influence of the local rates of translation on protein folding, 16 consecutive rare (in Escherichia coli) codons in the chloramphenicol acetyltransferase (CAT) gene have been replaced by frequent ones. Site-directed silent mutagenesis reduced the pauses in translation of CAT in E. coli S30 extract cell-free system and led to the acceleration of the overall rate of CAT protein synthesis. At the same time, the silently mutated protein (with unaltered protein sequence) synthesized in the E. coli S30 extract system was shown to possess 20% lower specific activity. The data suggest that kinetics of protein translation can affect the in vivo protein-folding pathway, leading to increased levels of protein misfolding.

Amino Acid Sequence↗
PubMed2005

MHC class II DRB variability and parasite load in the striped mouse (Rhabdomys pumilio) in the Southern Kalahari.

Major histocompatibility complex (MHC) variability is believed to be maintained by pathogen-driven selection, mediated either through heterozygous advantage or frequency-dependent selection. However, empirical support for these hypotheses under natural conditions is rare. In this study, we investigated the genetic constitution of the functionally important MHC class II gene (DRB exon 2) and the parasite load in a population of the striped mouse (Rhabdomys pumilio) in the Southern Kalahari. Fifty-eight individuals were genetically examined and the endoparasite load was quantified by counting fecal helminth eggs by using a modified McMaster technique. Thirty-four animals (58.6%) were infected. We identified 20 different MHC alleles with high levels of sequence divergence between alleles. Particularly, the antigen-binding sites revealed a significant higher rate of nonsynonymous substitutions (d(N)) than synonymous substitutions (d(S)), giving strong evidence of balancing selection. Heterozygosity did influence the infection status (being infected or not) and the individual fecal egg count (FEC) value with significantly higher values observed in homozygous individuals. Furthermore, a positive relationship was found between specific alleles and parasite load. The allele Rhpu-DRB*1 significantly occurred more frequently in infected individuals and in individuals with high FEC values (high parasite load). Individuals with the allele Rhpu-DRB*1 had a 1.5-fold higher chance of being infected than individuals without this allele (odds ratio test, P < 0.05). Contrarily, the allele Rhpu-DRB*8 significantly occurred more frequent in individuals with low FEC values. Our results support the hypotheses that MHC polymorphism in R. pumilio is maintained through pathogen-driven selection acting by both heterozygosity advantage and frequency-dependent selection.

Animals↗
PubMed2005

Selectionism and neutralism in molecular evolution.

Charles Darwin proposed that evolution occurs primarily by natural selection, but this view has been controversial from the beginning. Two of the major opposing views have been mutationism and neutralism. Early molecular studies suggested that most amino acid substitutions in proteins are neutral or nearly neutral and the functional change of proteins occurs by a few key amino acid substitutions. This suggestion generated an intense controversy over selectionism and neutralism. This controversy is partially caused by Kimura's definition of neutrality, which was too strict (|2Ns|< or =1). If we define neutral mutations as the mutations that do not change the function of gene products appreciably, many controversies disappear because slightly deleterious and slightly advantageous mutations are engulfed by neutral mutations. The ratio of the rate of nonsynonymous nucleotide substitution to that of synonymous substitution is a useful quantity to study positive Darwinian selection operating at highly variable genetic loci, but it does not necessarily detect adaptively important codons. Previously, multigene families were thought to evolve following the model of concerted evolution, but new evidence indicates that most of them evolve by a birth-and-death process of duplicate genes. It is now clear that most phenotypic characters or genetic systems such as the adaptive immune system in vertebrates are controlled by the interaction of a number of multigene families, which are often evolutionarily related and are subject to birth-and-death evolution. Therefore, it is important to study the mechanisms of gene family interaction for understanding phenotypic evolution. Because gene duplication occurs more or less at random, phenotypic evolution contains some fortuitous elements, though the environmental factors also play an important role. The randomness of phenotypic evolution is qualitatively different from allele frequency changes by random genetic drift. However, there is some similarity between phenotypic and molecular evolution with respect to functional or environmental constraints and evolutionary rate. It appears that mutation (including gene duplication and other DNA changes) is the driving force of evolution at both the genic and the phenotypic levels.

Animals↗
PubMed2004

Identification of genes with fast-evolving regions in microbial genomes.

Complete sequences of multiple strains of the same microbial species provide an invaluable source for studying the evolutionary dynamics between orthologous genes over a relatively short time scale. Usually the intensity of the selection pressure is inferred from a comparison between the nonsynonymous substitution rate and the synonymous substitution rate. In this paper, we propose an alternative method for detecting genes with one or more fast-evolving regions from pairwise comparisons of orthologous genes. Our method looks for regions with overrepresented nonsynonymous mutations along the alignment, and requires a higher nonsynonymous evolution rate in those regions than the neutral evolution rate. It identifies gene targets under intensive selection pressure that are not detected from the conventional rate comparison analysis. For those identified genes with known annotations, most of them have a clear role in processes such as bacterial defense and host-pathogen interactions. Gene sets reported from our method provide a measure of the phenotypic divergence between two closely related genomes.

Amino Acid Sequence↗
PubMed2002

Identification of neurotransmitter receptor genes under significantly relaxed selective constraint by orthologous gene comparisons between humans and rodents.

Neurotransmitter receptors (neuroreceptors) are classified into two types, G protein-coupled receptors (GPCRs) and ligand-gated ion channels. The former occupies a small part of the large GPCR superfamily, whereas the latter consists of three superfamilies. In these superfamilies, humans and rodents share almost the same set of neuroreceptor genes. This neuroreceptor gene set is good material to examine the degree of selective constraint exerted on each member gene of a given superfamily. If there are any neuroreceptor genes under the degree of selective constraint that is very different from that of the other member genes, they may have influenced the functional features characteristic of human neural activities. With the aim of identifying such neuroreceptor genes, we collected sequence data of orthologous neuroreceptor genes for humans, mice, and rats by database searches. This data set included ortholog pairs for 141 kinds of neuroreceptor genes, which covered almost the whole set of neuroreceptor genes known to be expressed in the human brain. The degree of selective constraint was estimated by computing the ratio (d(N)/d(S)) of the number of nonsynonymous substitutions to that of synonymous substitutions. We found that the d(N)/d(S) ratio ranged widely and its distribution fitted a gamma distribution. In particular, we found that four neuroreceptor genes are under the significantly relaxed selective constraint. They are an ionotropic glutamate receptor subunit NMDA-2C, two GABA(A) receptor subunits, i.e., GABA(A)-epsilon and GABA(A)-theta, and a dopamine receptor D4. Interestingly, these neuroreceptors have been reported to be associated with cognitive abilities such as memory and learning, and responsiveness to novel stimuli. These cognitive abilities can influence the behavioral features of an individual. Thus, it suggests that the relaxed-constraint neuroreceptor genes have evolved, assuring that the nervous system responds to a variety of stimuli with proper flexibility.

Amino Acid Sequence↗
PubMed1998

Evolution of nicotinic acetylcholine receptor subunits.

A phylogenetic tree of a gene family of nicotinic acetylcholine receptor subunits was constructed using 84 nucleotide sequences of receptor subunits from 18 different species in order to elucidate the evolutionary origin of receptor subunits. The tree constructed showed that the common ancestor of all subunits may have appeared first in the nervous system. Moreover, we suggest that the alpha 1 subunits in the muscle system originated from the common ancestor of alpha 2, alpha 3, alpha 4, alpha 5, alpha 6, and beta 3 in the nervous system, whereas the beta 1, gamma, delta, and epsilon subunits in the muscle system shared a common ancestor with the beta 2 and beta 4 subunits in the nervous system. Using the ratio (f) of the number of nonsynonymous substitutions to that of synonymous substitutions, we predicted the functional importance of subunits. We found that the alpha 1 and alpha 7 subunits had the lowest f values in the muscle and nervous systems, respectively, indicating that very strong functional constraints work on these subunits. This is consistent with the fact that the alpha 1 subunit has sites binding to the ligand, and the alpha 7-containing receptor regulates the release of the transmitter. Moreover, the window analysis of the f values showed that strong functional constraints work on the so-called M2 region in all five types of muscle subunits. Thus, the window analysis of the f values is useful for evaluating the degree of functional constraints in not only the entire gene region, but also the within-gene subregion.

Animals↗
PubMed2002

Intrapatient diversity and its correlation with viral setpoint in human immunodeficiency virus type 1 CRF02_A/G-IbNG infection.

The human immunodeficiency virus type 1 (HIV-1) viral setpoint during the disease-free interval has been strongly associated with future risk of disease progression. An awareness of the correlation between viral setpoint and HIV-1 genetic evolution over time is important in the understanding of viral dynamics and infection. We examined genetic diversity in HIV-1 CRF02_A/G-IbNG-infected seroincident women in Dakar, Senegal; determined whether a viral setpoint kinetic pattern existed for CRF02_A/G-IbNG during the disease-free interval; and correlated viral load level and diversity. Samples were drawn during the disease-free interval from consenting CRF02_A/G-IbNG-infected, antiretroviral therapy-naïve female commercial sex workers in Dakar, Senegal. Based on sequential plasma RNA values, low and high viral setpoint groups were established. Intrapatient diversity and divergence over time was determined from earlier and later time point DNA samples from each person. Most individuals followed the viral setpoint paradigm. For each 1/-/log(10) copy/ml of plasma increase in viral load, intrapatient diversity increased by 1.4% (P = 0.028). A greater diversification rate was observed in the high viral setpoint group than in the low viral setpoint group (P = 0.01). Greater nucleotide (P = 0.015) and amino acid (P = 0.048) divergences and a greater nucleotide divergence rate (P = 0.03) were found in the high viral setpoint group. There was no difference between the groups in the ratio of the number of nonsynonymous substitutions per nonsynonymous site to the number of synonymous substitutions per synonymous site. The greater intrapatient diversity, divergence, and diversification rates observed in the high viral setpoint group supports the notion that diversity is driven by cycles of viral replication resulting in accumulated mutations. Recognizing diversity potential based on viral load levels in individuals may inform the design of vaccines and therapies.

Base Sequence↗