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Results for “Purifying selection”

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PubMed2001

Sequence evolution and copy number of Ty1-copia retrotransposons in diverse plant genomes.

Sequence evolution of the reverse transcriptase (RT) gene in retrotransposons belonging to the Ty1-copia class was studied in 11 plant species. Phylogenetic reconstruction of the evolutionary history of RT sequences indicated a strong pattern of purifying selection, manifested as high ratios of third to first plus second codon position substitutions, and low ratios of nonsynonymous substitutions per nonsynonymous site to synonymous substitutions per synonymous site, especially in internal portions of the element phylogenies. Evidence of purifying selection was most pronounced in plant species with low estimated copy numbers of Ty1-copia elements. This finding is consistent with the hypothesis that high element turnover rates (e.g., caused by high rates of element loss and selection against high element copy number) favors elements capable of transposition. Simulations of RT sequence evolution were conducted to help verify the logical validity of this conclusion. The results argue that it is incorrect to assume that low copy numbers of transposable elements are the product of reduced levels of element activity.

Amino Acid Sequence↗

PubMed2001

A role for selection in regulating the evolutionary emergence of disease-causing and other coding CAG repeats in humans and mice.

The evolutionary expansion of CAG repeats in human triplet expansion disease genes is intriguing because of their deleterious phenotype. In the past, this expansion has been suggested to reflect a broad genomewide expansion of repeats, which would imply that mutational and evolutionary processes acting on repeats differ between species. Here, we tested this hypothesis by analyzing repeat- and flanking-sequence evolution in 28 repeat-containing genes that had been sequenced in humans and mice and by considering overall lengths and distributions of CAG repeats in the two species. We found no evidence that these repeats were longer in humans than in mice. We also found no evidence for preferential accumulation of CAG repeats in the human genome relative to mice from an analysis of the lengths of repeats identified in sequence databases. We then investigated whether sequence properties, such as base and amino acid composition and base substitution rates, showed any relationship to repeat evolution. We found that repeat-containing genes were enriched in certain amino acids, presumably as the result of selection, but that this did not reflect underlying biases in base composition. We also found that regions near repeats showed higher nonsynonymous substitution rates than the remainder of the gene and lower nonsynonymous rates in genes that contained a repeat in both the human and the mouse. Higher rates of nonsynonymous mutation in the neighborhood of repeats presumably reflect weaker purifying selection acting in these regions of the proteins, while the very low rate of nonsynonymous mutation in proteins containing a CAG repeat in both species presumably reflects a high level of purifying selection. Based on these observations, we propose that the mutational processes giving rise to polyglutamine repeats in human and murine proteins do not differ. Instead, we propose that the evolution of polyglutamine repeats in proteins results from an interplay between mutational processes and selection.

Amino Acids↗

PubMed2004

Coalescent processes and relaxation of selective constraints leading to contrasting genetic diversity at paralogs AtHVA22d and AtHVA22e in Arabidopsis thaliana.

Duplicate loci offer a very powerful system for understanding the complicated genome structure and adaptive evolution of a gene family. In this study, the genetic variation at paralogs AtHVA22d and AtHVA22e, members of an ABA- and stress-inducible gene family, is examined in the selfing Arabidopsis thaliana. Population genetic analysis indicates contrasting levels of nucleotide diversity at overall exon sequence and nonsynonymous sites between AtHVA22d (pi = 0.00337, pi(rep) = 0.00158) and AtHVA22e (pi = 0.00054, pi(rep) = 0.00023). The fact of Ka/Ks ratios significantly less than 1 in all sequences indicates that both genes are functional and subjected to purifying selection. In addition, rooted at barley HVA22, accelerated evolution is detected at replacement changes in the AtHVA22d locus, indicating relaxation of purifying selection after gene duplication. However, relative rate tests reveal no deviation from the neutrality at synonymous sites between the two paralogs. Based on clock-like evolution, the rate of synonymous substitution is estimated at 1.83 x 10(-9) substitutions per site per year; and the divergence of the two paralogs is traced to 90 MYA, coinciding with a period of the diversification of angiosperms. Given no codon usage bias in both genes, natural selection alone cannot account for the 6.4-fold differences in the nucleotide variation at synonymous sites between the two paralogs. Random processes resulting in different coalescence times, 3.65 MYA at AtHVA22d vs. 1.20 MYA at AtHVA22e, may have predominantly contributed to the evident differences of the genetic diversity. Partially nonoverlapping modes of expression between the two functional paralogs suggest a subfunctionalization hypothesis for explaining the fates of duplicate loci.

Arabidopsis↗

PubMed2004

Duplicated genes evolve slower than singletons despite the initial rate increase.

BACKGROUND: Gene duplication is an important mechanism that can lead to the emergence of new functions during evolution. The impact of duplication on the mode of gene evolution has been the subject of several theoretical and empirical comparative-genomic studies. It has been shown that, shortly after the duplication, genes seem to experience a considerable relaxation of purifying selection. RESULTS: Here we demonstrate two opposite effects of gene duplication on evolutionary rates. Sequence comparisons between paralogs show that, in accord with previous observations, a substantial acceleration in the evolution of paralogs occurs after duplication, presumably due to relaxation of purifying selection. The effect of gene duplication on evolutionary rate was also assessed by sequence comparison between orthologs that have paralogs (duplicates) and those that do not (singletons). It is shown that, in eukaryotes, duplicates, on average, evolve significantly slower than singletons. Eukaryotic ortholog evolutionary rates for duplicates are also negatively correlated with the number of paralogs per gene and the strength of selection between paralogs. A tally of annotated gene functions shows that duplicates tend to be enriched for proteins with known functions, particularly those involved in signaling and related cellular processes; by contrast, singletons include an over-abundance of poorly characterized proteins. CONCLUSIONS: These results suggest that whether or not a gene duplicate is retained by selection depends critically on the pre-existing functional utility of the protein encoded by the ancestral singleton. Duplicates of genes of a higher biological import, which are subject to strong functional constraints on the sequence, are retained relatively more often. Thus, the evolutionary trajectory of duplicated genes appears to be determined by two opposing trends, namely, the post-duplication rate acceleration and the generally slow evolutionary rate owing to the high level of functional constraints.

Animals↗

PubMed2005

Thromboxane synthase (TBXAS1) polymorphisms in African-American and Caucasian populations: evidence for selective pressure.

Thromboxane synthase (TBXAS1), a cytochrome P450 enzyme, converts prostaglandin H2 into thromboxane A2, a potent vasoconstrictor and inducer of platelet aggregation. Thromboxane A2 has been implicated in modulating cell cytotoxicity and in tumor growth and metastasis. Twelve coding-region variants were identified in the human TBXAS1 gene in 48 African-American and 46 Caucasian individuals, of which eight were amino-acid substitutions. The latter were confirmed in an independent Caucasian population (n=94 unrelated individuals). We performed an evolutionary analysis of patterns of nucleotide diversity and identified patterns of amino acid replacement in human-mouse comparisons consistent with purifying selection on an inter-species time scale using the McDonald-Kreitman test. We also observed patterns of nucleotide diversity within humans consistent with purifying selection acting on existing polymorphism using Tajima's D within coding regions. These evolutionary tests suggest that some of the rare coding variations observed in the human population are deleterious. We used two sequence-homology-based software programs and molecular modeling to predict the potential impact of these polymorphisms on TBXAS1 function. The c.772C>T (p.Lys258Glu), c.1249C>G (p.Gln417Glu), and c.1348G>A (p.Glu450Lys) substitutions are predicted as most likely to alter protein function; another, c.1352C>A (p.Thr451Asn), may also affect function. Given the evolutionary evidence, these variants may be functional and therefore of relevance for disease endpoints related to inflammation and angiogenesis, as well as for the pharmacogenetics of non-steroidal anti-inflammatory drugs.

Black or African American↗

PubMed1984

Characterization of sarcoplasmic reticulum adenosinetriphosphatase purified by selective column adsorption.

Preparations of sarcoplasmic reticulum ATPase made by conventional procedures, with over 85% of the protein consisting of one band in sodium dodecyl sulfate gel electrophoresis, were solubilized in Triton X-100 and separated on an Affi-Gel blue column. All the ATPase activity was eluted in a single fraction containing about 60% of the applied protein. This purified fraction required combination with about 1 mol of fluoresceinyl 5-isothiocyanate (FITC) for inactivation, whereas the original preparation was inactivated by reaction with about 0.6 mol of FITC/mol. The inactive protein retained on the column had an amino acid composition like that of the active protein. The separation on the Affi-Gel blue column provides a convenient procedure for preparation of more active ATPase. The rate of inactivation of the ATPase solubilized in detergent-containing solutions was measured at different protein concentrations. The t1/2 for inactivation was proportional to the square root of the protein concentration. Results are consistent with inactivation proceeding through a small fraction of monomeric ATPase present.

Adenosine Triphosphatases↗

PubMed2003

Position specific variation in the rate of evolution in transcription factor binding sites.

BACKGROUND: The binding sites of sequence specific transcription factors are an important and relatively well-understood class of functional non-coding DNAs. Although a wide variety of experimental and computational methods have been developed to characterize transcription factor binding sites, they remain difficult to identify. Comparison of non-coding DNA from related species has shown considerable promise in identifying these functional non-coding sequences, even though relatively little is known about their evolution. RESULTS: Here we analyse the genome sequences of the budding yeasts Saccharomyces cerevisiae, S. bayanus, S. paradoxus and S. mikatae to study the evolution of transcription factor binding sites. As expected, we find that both experimentally characterized and computationally predicted binding sites evolve slower than surrounding sequence, consistent with the hypothesis that they are under purifying selection. We also observe position-specific variation in the rate of evolution within binding sites. We find that the position-specific rate of evolution is positively correlated with degeneracy among binding sites within S. cerevisiae. We test theoretical predictions for the rate of evolution at positions where the base frequencies deviate from background due to purifying selection and find reasonable agreement with the observed rates of evolution. Finally, we show how the evolutionary characteristics of real binding motifs can be used to distinguish them from artefacts of computational motif finding algorithms. CONCLUSION: As has been observed for protein sequences, the rate of evolution in transcription factor binding sites varies with position, suggesting that some regions are under stronger functional constraint than others. This variation likely reflects the varying importance of different positions in the formation of the protein-DNA complex. The characterization of the pattern of evolution in known binding sites will likely contribute to the effective use of comparative sequence data in the identification of transcription factor binding sites and is an important step toward understanding the evolution of functional non-coding DNA.

Artifacts↗

PubMed2004

Positive selection at reproductive ADAM genes with potential intercellular binding activity.

Many genes with a role in reproduction, including those implicated in fertilization and spermatogenesis, have been shown to evolve at a faster rate relative to genes associated with other functions and tissues. These survey studies usually group a wide variety of genes with different characteristics and evolutionary histories as reproductive genes based on their site of expression or function. We have examined the molecular evolution of the ADAM (a disintegrin and metalloprotease) gene family, a structurally and functionally diverse group of genes expressed in reproductive and somatic tissue to test whether a variety of protein characteristics such as phylogenetic clusters, tissue of expression, and proteolytic and adhesive function can group fast evolving ADAM genes. We found that all genes were evolving under purifying selection (d(N)/d(S) < 1), although reproductive ADAMs, including those implicated in fertilization and spermatogenesis, evolved at the fastest rate. Genes with a role in binding to cell receptors in endogenous tissue appear to be evolving under purifying selection, regardless of the tissue of expression. In contrast, positive selection of codon sites in the disintegrin/cysteine-rich adhesion domains was detected exclusively in ADAMs 2 and 32, two genes expressed in the testis with a potential role in sperm-egg adhesion. Positive selection was detected in the transmembrane/cytosolic tail region of ADAM genes expressed in a variety of tissues.

ADAM Proteins↗

PubMed2002

Acceleration of genomic evolution caused by enhanced mutation rate in endocellular symbionts.

Endosymbionts, which are widely observed in nature, have undergone reductive genome evolution because of their long-term intracellular lifestyle. Here we compared the complete genome sequences of two different endosymbionts, Buchnera and a protist mitochondrion, with their close relatives to study the evolutionary rates of functional genes in endosymbionts. The results indicate that the rate of amino acid substitution is two times higher in symbionts than in their relatives. This rate increase was observed uniformly among different functional classes of genes, although strong purifying selection may have counterbalanced the rate increase in a few cases. Our data suggest that, contrary to current views, neither the Muller's ratchet effect nor the slightly deleterious mutation theory sufficiently accounts for the elevated evolutionary rate. Rather, the elevated evolutionary rate appears to be mainly due to enhanced mutation rate, although the possibility of relaxation of purifying selection cannot be ruled out.

Buchnera↗

PubMed1997

Immunomagnetic selection of purified monocyte and lymphocyte populations from peripheral blood mononuclear cells following cryopreservation.

Cryopreservation is a method commonly used to store human blood samples. We sought to determine if cryopreserved peripheral blood mononuclear cells (PBMC) could be separated effectively into distinct populations by using monoclonal antibodies and immunomagnetic microspheres. PBMC obtained from healthy blood donors and from human immunodeficiency virus-infected subjects were cryopreserved for as long as 18 months. Recovered cells were separated into CD14+ monocytes and CD4+ T-cell subsets by immunomagnetic selection. Flow cytometry analysis indicated >95% depletion of monocytes from PBMC following immunomagnetic selection with anti-CD14. A highly enriched population of CD4+ T cells was obtained from the CD14-depleted cell fraction by using an anti-CD4 monoclonal antibody and detachable immunomagnetic beads. The CD4+ T cells were subsequently separated into CD4+ CD45RO and CD4+ CD45RA fractions. Each fraction contained >90% enrichment for the respective subpopulation and <5% of the reciprocal subpopulation. No significant differences in cell surface expression of leukocyte markers, in efficiency of selection of PBMC subpopulations, or in mitogen-induced proliferation were detected in freshly isolated or cryopreserved cells. Efficient recovery of cryopreserved specimens means that targeted assays can be performed on selected, prospectively stored samples once clinical endpoints have been achieved.

Antibodies, Monoclonal↗

PubMed2004

Molecular evolutionary characterization of the mussel Mytilus histone multigene family: first record of a tandemly repeated unit of five histone genes containing an H1 subtype with "orphon" features.

The present work represents the first characterization of a clustered histone repetitive unit containing an H1 gene in a bivalve mollusk. To complete the knowledge on the evolutionary history of the histone multigene family in invertebrates, we undertake its characterization in five mussel Mytilus species, as an extension of our previous work on the H1 gene family. We report the quintet H4-H2B-H2A-H3-H1 as the major organization unit in the genome of Mytilus galloprovincialis with two 5S rRNA genes with interspersed nontranscribed spacer segments linked to the unit, which is not justified by their cotranscription with histone genes. Surprisingly, 3' UTR regions of histone genes show two different mRNA termination signals, a stem-loop and a polyadenylation signal, both related to the evolution of histone gene expression patterns throughout the cell cycle. The clustered H1 histones characterized share essential features with "orphon" H1 genes, suggesting a common evolutionary origin for both histone subtypes which is supported by the reconstructed phylogeny for H1 genes. The characterization of histone genes in four additional Mytilus species revealed the presence of strong purifying selection acting among the members of the family. The chromosomal location of most of the core histone genes studied was identified by FISH close to telomeric regions in M. galloprovincialis. Further analysis on nucleotide variation would be necessary to assess if H1 proteins evolve according to the birth-and-death model of evolution and if the effect of the strong purifying selection maintaining protein homogeneity could account for the homologies detected between clustered and "orphon" variants.

Amino Acid Sequence↗

PubMed2005

Repositioning-dependent fate of duplicate genes.

Gene duplication is the main source of evolutionary novelties. However, the problem with duplicates is that the purifying selection overlooks deleterious mutations in the redundant sequence, which therefore, instead of gaining a new function, often degrades into a functionless pseudogene. This risk of functional loss instead of gain is much higher for small populations of higher organisms with a slow and complex development. We propose that it is the epigenetic tissue/stage-complementary silencing of duplicates that makes them exposable to the purifying selection, thus saving them from pseudogenization and opening the way towards new function(s). Our genome-wide analyses of gene duplicates in several eukaryotic species combined with the phylogenetic comparison of vertebrate alpha- and beta-globin gene clusters strongly support this epigenetic complementation (EC) model. The distinctive condition for a new duplicate to survive by the EC mechanism seems to be its repositioning to an ectopic site, which is accompanied by changes in the rate and direction of mutagenesis. The most distinguished in this respect is the human genome. In this review, we extend and discuss the data on the EC- and repositioning-dependent fate of gene duplicates with the special emphasis on the problem of detecting brief postduplication period of adaptive evolution driven by positive selection. Accordingly, we propose a new CpG-focused measure of selection that is insensitive to translocation-caused biases in mutagenesis.

Animals↗

PubMed2002

Molecular evolution of the nontandemly repeated genes of the histone 3 multigene family.

In some species, histone gene clusters consist of tandem arrays of each type of histone gene, whereas in other species the genes may be clustered but not arranged in tandem. In certain species, however, histone genes are found scattered across several different chromosomes. This study examines the evolution of histone 3 (H3) genes that are not arranged in large clusters of tandem repeats. Although H3 amino acid sequences are highly conserved both within and between species, we found that the nucleotide sequence divergence at synonymous sites is high, indicating that purifying selection is the major force for maintaining H3 amino acid sequence homogeneity over long-term evolution. In cases where synonymous-site divergence was low, recent gene duplication appeared to be a better explanation than gene conversion. These results, and other observations on gene inactivation, organization, and phylogeny, indicated that these H3 genes evolve according to a birth-and-death process under strong purifying selection. Thus, we found little evidence to support previous claims that all H3 proteins, regardless of their genome organization, undergo concerted evolution. Further analyses of the structure of H3 proteins revealed that the histones of higher eukaryotes might have evolved from a replication-independent-like H3 gene.

Amino Acid Sequence↗

PubMed2025

The Demographic History of Populations and Genomic Imprinting have Shaped the Transposon Patterns in Arabidopsis lyrata.

Purifying selection is expected to prevent the accumulation of transposable elements (TEs) within their host, especially when located in and around genes and if affected by epigenetic silencing. However, positive selection may favor the spread of TEs, causing genomic imprinting under parental conflict, as genomic imprinting allows parent-specific influence over resource accumulation to the progeny. Concomitantly, the number and frequency of TE insertions in natural populations are conditioned by demographic events. In this study, we aimed to test how demography and selective forces interact to affect the accumulation of TEs around genes, depending on their epigenetic silencing, with a particular focus on imprinted genes. To this aim, we compared the frequency and distribution of TEs in Arabidopsis lyrata from Europe and North America. Generally, we found that TE insertions showed a lower frequency when they were inserted in or near genes, especially TEs targeted by epigenetic silencing, suggesting purifying selection at work. We also found that many TEs were lost or got fixed in North American populations during the colonization and the postglacial range expansion from refugia of the species in North America, as well as during the transition to selfing, suggesting a potential "TE load." Finally, we found that silenced TEs increased in frequency and even tended to reach fixation when they were linked to imprinted genes. We conclude that in A. lyrata, genomic imprinting has spread in natural populations through demographic events and positive selection acting on silenced TEs, potentially under a parental conflict scenario.

DNA Transposable Elements↗

PubMed2006

Birth and death of genes promoted by transposable elements in Oryza sativa.

Despite a wide distribution of transposable elements (TEs) in the genomes of higher eukaryotes, much of their evolutionary significance remains unclear. Recent studies have indicated that TEs are involved with biological processes such as gene regulation and the generation of new exons in mammals. In addition, the completion of the genome sequencings in Arabidopsis thaliana and Oryza sativa has permitted scientist to describe a genome-wide overview in plants. In this study, we examined the positions of TEs in the genome of O. sativa. Although we found that more than 10% of the structural genes contained TEs, they were underrepresented in exons compared with non-exonic regions. TEs also appeared to be inserted preferentially in 3'-untranslated regions in exons. These results suggested that purifying selection against TE insertion has played a major role during evolution. Moreover, our comparison of the numbers of TEs in the protein-coding regions between single copy genes and duplicate genes showed that TEs were more frequent in duplicate than single copy genes. This observation indicated that gene duplication events created a large number of functionally redundant genes. Subsequently, many of them were destroyed by TEs because the redundant copies were released from purifying selection. Another biological role of TEs was found to be the recruitment of new exons. We found that approximately 2% of protein-coding genes contained TEs in their coding regions. Insertion of TEs in genic regions may have the potential to be an evolutionary driving force for the creation of new biological functions.

DNA Transposable Elements↗

PubMed2002

Molecular population genetics of sequence length diversity in the Adh region of Drosophila pseudoobscura.

Positive and negative selection on indel variation may explain the correlation between intron length and recombination levels in natural populations of Drosophila. A nucleotide sequence analysis of the 3.5 kilobase sequence of the alcohol dehydrogenase (Adh) region from 139 Drosophila pseudoobscura strains and one D. miranda strain was used to determine whether positive or negative selection acts on indel variation in a gene that experiences high levels of recombination. A total of 30 deletion and 36 insertion polymorphisms were segregating within D. pseudoobscura populations and no indels were fixed between D. pseudoobscura and its two sibling species D. miranda and D. persimilis. The ratio of Tajima's D to its theoretical minimum value (D(min)) was proposed as a metric to assess the heterogeneity in D among D. pseudoobscura loci when the number of segregating sites differs among loci. The magnitude of the D/D(min) ratio was found to increase as the rate of population expansion increases, allowing one to assess which loci have an excess of rare variants due to population expansion versus purifying selection. D. pseudoobscura populations appear to have had modest increases in size accounting for some of the observed excess of rare variants. The D/D(min) ratio rejected a neutral model for deletion polymorphisms. Linkage disequilibrium among pairs of indels was greater than between pairs of segregating nucleotides. These results suggest that purifying selection removes deletion variation from intron sequences, but not insertion polymorphisms. Genome rearrangement and size-dependent intron evolution are proposed as mechanisms that limit runaway intron expansion.

Alcohol Dehydrogenase↗

PubMed2001

The generation and persistence of genetic variation in foot-and-mouth disease virus.

Genetic variation in foot-and-mouth disease virus (FMDV) is of interest for at least two reasons. First, changes to the genes encoding capsid proteins results in antigenic variation, and affects vaccine efficiency and effectiveness of vaccination programs; second, genetic changes can lead to important insights into the transport of virus between countries, regions, herds, and even possibly individuals. Current estimates of RNA virus mutation rates suggest that an average of about one base mis-incorporation is likely to occur each time a single FMDV genome replicates. This should result in the introduction of every possible 1-step mutation from the progenitor genotype into the viraemia of a single infected animal many times a day. In the absence of purifying selection, a single infected animal should therefore generate a genetically very diverse population of virus.Viral-capsid sequences obtained from infected animals sampled over long-term FMDV epidemics suggest that these genetic changes accrue in a remarkably linear 'clock-like' fashion and at rates of around 1% change per year. While such a rate is generally regarded as quite high, it is actually somewhat lower than one might expect based on the rate at which viral diversity could be generated within a single animal. The difference might be explained in a variety of possible ways: (1) the mutation rate has been overestimated; (2) purifying selection is stronger than predicted; (3) only a restricted subset of excreted virus is actually infectious; (4) infected animals only excrete virus from a small partitioned subset of amplified virus, and that most of the generated viral diversity is unable to exit the animal; or (5) only a small fraction of all infected animals participate in the actual disease-transmission process.

Animals↗

PubMed1967

A diagonal electrophoretic method for selective purification of methionine peptides.

1. A method is described that selectively purifies methionine peptides from enzymic digests of a protein. The peptides, after paper electrophoresis, are treated on paper with iodoacetamide at acid pH. This specifically converts methionine residues into their sulphonium salts. When the paper is submitted to electrophoresis at right angles to the original direction, the carbamoylmethylmethionine peptides emerge from an undifferentiated diagonal. 2. Heating at neutral pH converts carbamoylmethylmethionine into homoserine and thereby specifically cleaves the peptides. 3. The effect of the modifications on amino acid composition and sequence analyses of the peptides was studied. 4. When the method was applied to a tryptic digest of S-aminoethyl-chymotrypsinogen A, two peptides were selectively purified that had the expected amino acid sequence.

Alkylation↗