SEARCH · PubMed Health

Results for “Purifying selection”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 325 records · Page 18Linked to original sources

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↗

PubMed2006

Evolutionary divergence of exon flanks: a dissection of mutability and selection.

The intronic sequences flanking exon-intron junctions (i.e., exon flanks) are important for splice site recognition and pre-mRNA splicing. Recent studies show a higher degree of sequence conservation at flanks of alternative exons, compared to flanks of constitutive exons. In this article we performed a detailed analysis on the evolutionary divergence of exon flanks between human and chimpanzee, aiming to dissect the impact of mutability and selection on their evolution. Inside exon flanks, sites that might reside in ancestral CpG dinucleotides evolved significantly faster than sites outside of ancestral CpG dinucleotides. This result reflects a systematic variation of mutation rates (mutability) at exon flanks, depending on the local CpG contexts. Remarkably, we observed a significant reduction of the nucleotide substitution rate in flanks of alternatively spliced exons, independent of the site-by-site variation in mutability due to different CpG contexts. Our data provide concrete evidence for increased purifying selection at exon flanks associated with regulation of alternative splicing.

Alternative Splicing↗

PubMed2005

Synonymous SNPs provide evidence for selective constraint on human exonic splicing enhancers.

The human SNP database was used to detect selection on 238 hexamers previously identified as exonic splicing enhancers (ESEs). We compared the distribution of the 238 putative ESEs in biallelic and triallelic SNPs within five different functional categories of the SNP database: synonymous, nonsynonymous, introns, UTRs, and nongenic SNPs. Since true ESEs do not function outside of exons, SNPs that disrupt ESE motifs were expected to be more common in nonexonic portions of the genome. Our results supported this expectation: ESEs were least prevalent within synonymous SNPs and most common in nongenic SNPs. There were approximately 11% fewer ESEs within synonymous biallelic SNPs than expected under no selective constraint. We also compared the frequency of neutral SNPs, those where neither allele was an ESE, with deleterious SNPs, those where one or more alleles was an ESE, across the five different functional classes of SNPs. In comparison with the other functional classes of SNPs, synonymous SNPs contained an excess of neutral variants (+1.64% and +6.04% for biallelic and triallelic SNPs, respectively) and a dearth of deleterious variants (-13.11% and -52.39% for biallelic and triallelic SNPs, respectively). The observed patterns were consistent with purifying selection on the 238 hexamers to maintain their function as ESEs. However, in contrast to previous work, we did not find evidence for selection to maintain ESE function at nonsynonymous SNPs because selection at the protein level probably obscured any difference at the level of ESE function.

Alternative Splicing↗

PubMed1999

Evidence for genetic drift in endosymbionts (Buchnera): analyses of protein-coding genes.

Buchnera, the bacterial endosymbionts of aphids, undergo severe population bottlenecks during maternal transmission through their hosts. Previous studies suggest an increased effect of drift within these strictly asexual, small populations, resulting in an increased fixation of slightly deleterious mutations. This study further explores sequence evolution in Buchnera using three approaches. First, patterns of codon usage were compared across several homologous Escherichia coli and Buchnera loci, in order to test the prediction that selection for the use of optimal codons is less effective in small populations. A chi 2-based measure of codon bias was developed to adjust for the overall A + T richness of silent positions in the endosymbionts. In contrast to E. coli homologues, adaptive codon bias across Buchnera loci is markedly low, and patterns of codon usage lack a strong relationship with gene expression level. These data suggest that codon usage in Buchnera has been shaped largely by mutational pressure and drift rather than by selection for translational efficiency. One exception to the overall lack of bias is groEL, which is known to be constitutively overexpressed in Buchnera and other endosymbionts. Second, relative-rate tests show elevated rates of sequence evolution of numerous protein-coding loci across Buchnera, compared to E. coli. Finally, consistently higher ratios of nonsynonymous to synonymous substitutions in Buchnera loci relative to the enteric bacteria strongly suggest the accumulation of nonsynonymous substitutions in endosymbiont lineages. Combined, these results suggest a decreased effectiveness of purifying selection in purging endosymbiont populations of slightly deleterious mutations, particularly those affecting codon usage and amino acid identity.

Animals↗

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↗

PubMed1998

Interelement selection in the regulatory region of the copia retrotransposon.

We report the results of an analysis of naturally occurring cis-regulatory variation within and between two families of the copia Drosophila long terminal repeat (LTR) retrotransposon. The copia 5' LTR and adjacent untranslated leader region (ULR) consists of a number of well-characterized sequence motifs which play a role in regulating expression of the element. In order to understand the evolutionary forces which may be responsible for generating and maintaining copia regulatory sequence variation, we have quantified levels of naturally occurring copia LTR-ULR nucleotide variation and subjected the data to a series of tests of neutrality. Our analysis indicates that the copia LTR-ULR has been subject to negative purifying selection within families and positive adaptive selection between families. We discuss these findings with respect to the regulatory evolution of retrotransposons and the phenomenon of interelement selection.

5' Untranslated Regions↗

PubMed2004

Identifying signatures of selection at the enhancer of split neurogenic gene complex in Drosophila.

The Enhancer of split gene complex (E(spl)-C) is one of the more highly annotated gene regions in Drosophila, and the 12 genes within the complex help determine the spacing and patterning of adult bristles. Any E(spl)-C coding, transcribed, or cis-regulatory regions experiencing nonneutral evolution are strong candidates to harbor polymorphisms contributing to naturally occurring variation in bristle number. We confirm that the E(spl)-C is strongly conserved and show that 74% of regulatory elements previously identified in D. melanogaster are conserved in D. pseudoobscura. Regulatory elements in enhancer regions show lower nucleotide diversity and more rare polymorphisms compared with adjacent nonregulatory DNA, suggesting they are under purifying selection, and these effects are particularly pronounced when considering only conserved regulatory elements. The ratio of polymorphism to divergence was significantly different between binding sites and nonbinding sites for transcription factors within enhancer regions, suggesting the action of some form of selection. Too few polymorphisms in regions of the 3' UTR harboring regulatory motifs prevents adequate comparison of diversity and the polymorphism frequency spectrum between 3' UTR motif and nonmotif sequence. We identified at least two broad regions of the gene complex showing strong population subdivision among four populations, which is suggestive of local adaptation or background selection. Finally, two regions of the E(spl)-C exhibit low nucleotide diversity, a high level of rare polymorphisms, and an increase in linkage disequilibrium, which together suggest the action of positive selection. Notably, the gene m2 shows a significant deviation from neutrality by the McDonald-Kreitman test and resides in one of the two regions putatively experiencing a selective sweep. All sites in regions apparently visible to various selective forces are candidates for future work to determine their phenotypic effects.

3' Untranslated Regions↗

PubMed2005

Effects of natural selection on interpopulation divergence at polymorphic sites in human protein-coding Loci.

To develop new strategies for searching for genetic associations with complex human diseases, we analyzed 2784 single-nucleotide polymorphisms (SNPs) in 396 protein-coding genes involved in biological processes relevant to cancer and other complex diseases, with respect to gene diversity within samples of individuals representing the three major historic human populations (African, European, and Asian) and with respect to interpopulation genetic distance. Reduced levels of both intrapopulation gene diversity and interpopulation genetic distance were seen in the case of SNPs located within the 5'-UTR and at nonsynonymous SNPs, causing radical changes to protein structure. Reduction of gene diversity at SNP loci in these categories was evidence of purifying selection acting at these sites, which in turn causes a reduction in interpopulation divergence. By contrast, a small number of SNP sites in these categories revealed unusually high genetic distances between the two most diverged populations (African and Asian); these loci may have historically been subject to divergent selection pressures.

Databases, Genetic↗

PubMed2002

Extinction and rapid emergence of strains of dengue 3 virus during an interepidemic period.

Strains of dengue 3 (DEN-3) virus circulating in Thailand prior to 1992 appear to have disappeared from that location and to have been replaced by two new lineages which have evolved locally, rather than being introduced. Similar DEN-3 virus extinctions may have occurred previously in Thailand in 1962 and 1973. Although no causal relationship could be shown, this strain replacement event was accompanied by DEN-3 replacing DEN-2 as the serotype recovered most frequently from patients in Thailand. Although this implies a change in selection pressure, we found no evidence for positive natural selection at the level of either the E protein or the E protein gene. Further, the extinction of the pre-1992 strains and the appearance of the new lineages occurred during an interepidemic period, suggesting that a genetic bottleneck, rather than selection, might have been important in the emergence of these two new strains of virus. The pre-1992 DEN-3 virus lineage could still be found in 1998, to the west, in Myanmar. The ratio of nonsynonymous-to-synonymous nucleotide changes within a DEN-3 virus population from a single patient was less than the ratio among the consensus sequences of DEN-3 viruses from different patients, suggesting that many of the nonsynonymous nucleotide changes which occurred naturally in the E protein were deleterious and removed by purifying selection.

Amino Acid Sequence↗

PubMed2003

Positive selection during the diversification of class I vomeronasal receptor-like (V1RL) genes, putative pheromone receptor genes, in human and primate evolution.

Vomeronasal receptors are the major receptors for pheromones in vertebrates, and five putative type 1 vomeronasal receptors (V1RL) have been identified in humans. The evolution of the V1RL1 gene in non-human primates, and patterns of selection on V1RL genes, were investigated. The presumed ortholog of V1RL1 was sequenced from 13 species of nonhuman primate, and in eight of these species V1RL1 was a pseudogene. Phylogenetic reconstructions reveal that V1RL1 pseudogene formation occurred independently in multiple primate lineages. Using maximum likelihood estimates of dN/dS ratios in PAML, we show that V1RL genes have evolved under neutral evolution in lineages in which they became a pseudogene. In contrast, among lineages in which V1RL genes contain an open reading frame, the majority of sites are under purifying selection and a minority are under significant positive selection. These results provide an interesting case where all three categories of selection can be teased apart in the same data set using maximum likelihood methods. The finding of positive selection on V1RL genes during primate evolution provides indirect support for the hypothesis that V1RL genes have a function in species-specific pheromone detection in primates.

Amino Acid Sequence↗

PubMed2004

Gene expression intensity shapes evolutionary rates of the proteins encoded by the vertebrate genome.

Natural selection leaves its footprints on protein-coding sequences by modulating their silent and replacement evolutionary rates. In highly expressed genes in invertebrates, these footprints are seen in the higher codon usage bias and lower synonymous divergence. In mammals, the highly expressed genes have a shorter gene length in the genome and the breadth of expression is known to constrain the rate of protein evolution. Here we have examined how the rates of evolution of proteins encoded by the vertebrate genomes are modulated by the amount (intensity) of gene expression. To understand how natural selection operates on proteins that appear to have arisen in earlier and later phases of animal evolution, we have contrasted patterns of mouse proteins that have homologs in invertebrate and protist genomes (Precambrian genes) with those that do not have such detectable homologs (vertebrate-specific genes). We find that the intensity of gene expression relates inversely to the rate of protein sequence evolution on a genomic scale. The most highly expressed genes actually show the lowest total number of substitutions per polypeptide, consistent with cumulative effects of purifying selection on individual amino acid replacements. Precambrian genes exhibit a more pronounced difference in protein evolutionary rates (up to three times) between the genes with high and low expression levels as compared to the vertebrate-specific genes, which appears to be due to the narrower breadth of expression of the vertebrate-specific genes. These results provide insights into the differential relationship and effect of the increasing complexity of animal body form on evolutionary rates of proteins.

Animals↗

PubMed2024

Evolutionary consequences of domestication on the selective effects of new amino acid changing mutations in canids.

The domestication of wild canids led to dogs no longer living in the wild but instead residing alongside humans. Extreme changes in behavior and diet associated with domestication may have led to the relaxation of the selective pressure on traits that may be less important in the domesticated context. Thus, here we hypothesize that strongly deleterious mutations may have become less deleterious in domesticated populations. We test this hypothesis by estimating the distribution of fitness effects (DFE) for new amino acid changing mutations using whole-genome sequence data from 24 gray wolves and 61 breed dogs. We find that the DFE is strikingly similar across canids, with 26-28% of new amino acid changing mutations being neutral/nearly neutral (|s| < 1e-5), and 41-48% under strong purifying selection (|s| > 1e-2). Our results are robust to different model assumptions suggesting that the DFE is stable across short evolutionary timescales, even in the face of putative drastic changes in the selective pressure caused by artificial selection during domestication and breed formation. On par with previous works describing DFE evolution, our data indicate that the DFE of amino acid changing mutations depends more strongly on genome structure and organismal characteristics, and less so on shifting selective pressures or environmental factors. Given the constant DFE and previous data showing that genetic variants that differentiate wolf and dog populations are enriched in regulatory elements, we speculate that domestication may have had a larger impact on regulatory variation than on amino acid changing mutations.

Journal Article↗

PubMed2006

Evidence for conservation and selection of upstream open reading frames suggests probable encoding of bioactive peptides.

BACKGROUND: Approximately 40% of mammalian mRNA sequences contain AUG trinucleotides upstream of the main coding sequence, with a quarter of these AUGs demarcating open reading frames of 20 or more codons. In order to investigate whether these open reading frames may encode functional peptides, we have carried out a comparative genomic analysis of human and mouse mRNA 'untranslated regions' using sequences from the RefSeq mRNA sequence database. RESULTS: We have identified over 200 upstream open reading frames which are strongly conserved between the human and mouse genomes. Consensus sequences associated with efficient initiation of translation are overrepresented at the AUG trinucleotides of these upstream open reading frames, while comparative analysis of their DNA and putative peptide sequences shows evidence of purifying selection. CONCLUSION: The occurrence of a large number of conserved upstream open reading frames, in association with features consistent with protein translation, strongly suggests evolutionary maintenance of the coding sequence and indicates probable functional expression of the peptides encoded within these upstream open reading frames.

3' Untranslated Regions↗

PubMedDate not supplied

Biochemical analysis of membrane proteins from an early maturation stage of phagosomes.

We used an improved technique for pulse-chase labeling of phagosomes using custom-made magnetic microparticles. With the help of a permanent magnet we purified both newly formed, nascent and early matured (i.e., 5-min-old) condensed phagosomes in high amounts. The protein patterns of membrane proteins of newly formed phagosomes and 5-min-old condensed ones were compared by two-dimensional (2-D) electrophoresis. The protein patterns allowed the detection of protein spots that changed in abundance between these two stages. Three protein spots abundant in condensed phagosomes only and one spot well-stained in both stages were collected from ten preparative Coomassie brilliant blue-stained 2-D gels. Following microdigestion, selected purified oligopeptides were sequenced by Edman degradation. While the oligopeptide sequences of proteins from two spots showed high homology to an already sequenced 25 kDa calcium binding protein, the other two showed no significant homology to protein sequences available in sequence databases. Presently polymerase chain reaction (PCR) and cloning experiments are set up to reveal the cDNAs of these proteins in order to study their function by knock-out and gene replacement experiments.

Amino Acid Sequence↗

PubMed2006

Functionally important glycosyltransferase gain and loss during catarrhine primate emergence.

A glycosyltransferase, alpha1,3galactosyltransferase, catalyzes the terminal step in biosynthesis of Galalpha1,3Galbeta1-4GlcNAc-R (alphaGal), an oligosaccharide cell surface epitope. This epitope or antigenically similar epitopes are widely distributed among the different forms of life. Although abundant in most mammals, alphaGal is not normally found in catarrhine primates (Old World monkeys and apes, including humans), all of which produce anti-alphaGal antibodies from infancy onward. Natural selection favoring enhanced resistance to alphaGal-positive pathogens has been the primary reason offered to account for the loss of alphaGal in catarrhines. Here, we question the primacy of this immune defense hypothesis with results that elucidate the evolutionary history of GGTA1 gene and pseudogene loci. One such locus, GGTA1P, a processed (intronless) pseudogene (PPG), is present in platyrrhines, i.e., New World monkeys, and catarrhines but not in prosimians. PPG arose in an early ancestor of anthropoids (catarrhines and platyrrhines), and GGTA1 itself became an unprocessed pseudogene in the late catarrhine stem lineage. Strong purifying selection, denoted by low nonsynonymous substitutions per nonsynonymous site/synonymous substitutions per synonymous site values, preserved GGTA1 in noncatarrhine mammals, indicating that the functional gene product is subjected to considerable physiological constraint. Thus, we propose that a pattern of alternative and/or more beneficial glycosyltransferase activity had to first evolve in the stem catarrhines before GGTA1 inactivation could occur. Enhanced defense against alphaGal-positive pathogens could then have accelerated the replacement of alphaGal-positive catarrhines by alphaGal-negative catarrhines. However, we emphasize that positively selected regulatory changes in sugar chain metabolism might well have contributed in a major way to catarrhine origins.

Animals↗

PubMed2026

Selection profiles in RNA viruses reflect the characteristics of viruses more than individual proteins.

Proteins that are exposed on the surface of a virus are frequently subject to strong selection to escape from neutralizing antibodies. To investigate whether surface-exposed (SE) and non-exposed (NE) proteins encoded by RNA viruses exhibit different patterns of evolution under selection, we analyzed 244 protein-coding genes from 28 species of RNA viruses representing 15 taxonomic families. First, we show that gene-wide rates of non-synonymous (dN) and synonymous (dS) substitutions do not differentiate between SE and NE proteins. To incorporate variation in substitution rates among codon sites, we inferred the posterior distribution over a fixed grid of dN and dS rates for each alignment. This 'evolutionary fingerprint' provides a common framework for comparing the selection profiles of non-homologous genes. Next, we computed the Wasserstein distance for every pair of fingerprints, which is analogous to amount of work required to reshape one distribution to another. After compensating for differences in genetic variation among alignments, we found a small but significant difference between the fingerprints of SE and NE proteins (PERMANOVA, P = 0.03). However, we observed larger and more significant effects of whether the virus is enveloped (P < 10-5) and the interaction between these factors (P=6.9×10-4). The latter effects were driven by high levels of purifying selection in capsid proteins of Picornaviruses. Furthermore, greater amounts of variation in fingerprints were explained by significant differences among virus families and modes of transmission (P < 10-5). These results imply the pattern of selection on a virus protein is shaped more by characteristics of the virus than the protein itself.

RNA Viruses↗

PubMed2004

Solid-phase extraction-electrospray ionization mass spectrometry for the quantification of folate in human plasma or serum.

The measurement of 5-methyltetrahydrofolic acid (5 MT) blood levels is one of several factors used to diagnose folate deficiency in humans. 5 can be selectively purified from either human plasma or human serum via solid-phase extraction procedures and specifically detected and quantified in the extracts with liquid chromatography/isotope-dilution electrospray-ionization mass spectrometry. Two different, yet complementary, solid-phase extraction-liquid chromatography/mass spectrometry methods have been developed and applied to the quantification of 5 MT from such extracts. One method utilizes the high-affinity folate-binding protein from cow's milk coupled with multiple-reaction-monitoring-mode tandem mass spectrometry while the other method utilizes reversed-phase C(18) extraction followed by selected-ion-monitoring-mode mass spectrometry. The accuracy of each method is assessed through a comparative determination of 5 MT levels in homogenous plasma and serum pools. Additionally, each method is compared and evaluated against the "total folate" results provided by routine radioassay and microbiological assay determinations. On the basis of the experimental data presented in this report, it is suggested that both methods have the capacity to serve as potential reference methods for the quantification of circulating 5MT in plasma or serum.

Chromatography, Liquid↗

PubMed1998

Immunoaffinity purification and functional characterization of human transcription factor IIH and RNA polymerase II from clonal cell lines that conditionally express epitope-tagged subunits of the multiprotein complexes.

Purification of multiprotein complexes such as transcription factor (TF) IIH and RNA polymerase II (pol II) has been a tedious task by conventional chromatography. To facilitate the purification, we have developed an effective scheme that allows human TFIIH and pol II to be isolated from HeLa-derived cell lines that conditionally express the FLAG-tagged p62 subunit of human TFIIH and the RPB9 subunit of human pol II, respectively. An approximate 2000-fold enrichment of FLAG-tagged TFIIH and a 1000-fold enhancement of total pol II are achieved by a one-step immunoaffinity purification. The purified complexes are functional in mediating basal and activated transcription, regardless of whether TATA-binding protein or TFIID is used as the TATA-binding factor. Interestingly, repression of basal transcription by the positive cofactor PC4 is alleviated by increasing amounts of TFIID, TFIIH, and pol II holoenzyme, suggesting that phosphorylation of PC4 by these proteins may cause a conformational change in the structure of PC4 that allows for preinitiation complex formation and initiation of transcription. Furthermore, pol II complexes with different phosphorylation states on the carboxyl-terminal domain of the largest subunit are selectively purified from the inducible pol II cell line, making it possible to dissect the role of carboxyl-terminal domain phosphorylation in the transcription process in a highly defined in vitro transcription system.

Chromatography, Affinity↗