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Results for “Purifying selection”

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PubMed2001

Selection against deleterious LINE-1-containing loci in the human lineage.

We compared sex chromosomal and autosomal regions of similar GC contents and found that the human Y chromosome contains nine times as many full-length (FL) ancestral LINE-1 (L1) elements per megabase as do autosomes and that the X chromosome contains three times as many. In addition, both sex chromosomes contain a ca. twofold excess of elements that are >500 bp but not long enough to be capable of autonomous replication. In contrast, the autosomes are not deficient in short (<500 bp) L1 elements or SINE elements relative to the sex chromosomes. Since neither the Y nor the X chromosome, when present in males, can be cleared of deleterious genetic loci by recombination, we conclude that most FL L1s were deleterious and thus subject to purifying selection. Comparison between nonrecombining and recombining regions of autosome 21 supported this conclusion. We were able to identify a subset of loci in the human DNA database that once contained active L1 elements, and we found by using the polymerase chain reaction that 72% of them no longer contain L1 elements in a representative of each of eight different ethnic groups. Genetic damage produced by both L1 retrotransposition and ectopic (nonallelic) recombination between L1 elements could provide the basis for their negative selection.

Chromosomes, Human, Pair 21↗

PubMed2006

Deciphering the ancient and complex evolutionary history of human arylamine N-acetyltransferase genes.

The human N-acetyltransferase genes NAT1 and NAT2 encode two phase-II enzymes that metabolize various drugs and carcinogens. Functional variability at these genes has been associated with adverse drug reactions and cancer susceptibility. Mutations in NAT2 leading to the so-called slow-acetylation phenotype reach high frequencies worldwide, which questions the significance of altered acetylation in human adaptation. To investigate the role of population history and natural selection in shaping NATs variation, we characterized genetic diversity through the resequencing and genotyping of NAT1, NAT2, and the pseudogene NATP in a collection of 13 different populations with distinct ethnic backgrounds and demographic pasts. This combined study design allowed us to define a detailed map of linkage disequilibrium of the NATs region as well as to perform a number of sequence-based neutrality tests and the long-range haplotype (LRH) test. Our data revealed distinctive patterns of variability for the two genes: the reduced diversity observed at NAT1 is consistent with the action of purifying selection, whereas NAT2 functional variation contributes to high levels of diversity. In addition, the LRH test identified a particular NAT2 haplotype (NAT2*5B) under recent positive selection in western/central Eurasians. This haplotype harbors the mutation 341T-->C and encodes the "slowest-acetylator" NAT2 enzyme, suggesting a general selective advantage for the slow-acetylator phenotype. Interestingly, the NAT2*5B haplotype, which seems to have conferred a selective advantage during the past approximately 6,500 years, exhibits today the strongest association with susceptibility to bladder cancer and adverse drug reactions. On the whole, the patterns observed for NAT2 well illustrate how geographically and temporally fluctuating xenobiotic environments may have influenced not only our genome variability but also our present-day susceptibility to disease.

Acetylation↗

PubMed2004

Contrasting modes of natural selection acting on pigmentation genes in the Drosophila dunni subgroup.

Genes that encode for divergent adaptive traits may have genealogies that contrast with those from loci that are not functionally involved in differentiation. Here, we examine DNA sequence variation among the species of the eastern Caribbean Drosophila dunni subgroup at two loci, yellow and dopa decaboxylase (Ddc), which both play integral roles in pigmentation patterning of adult Drosophila. Phylogenetic analyses of these loci produce gene genealogies with topologies that mirror those described for other nuclear genes: the six morphologically distinct species within the subgroup are divided into only three lineages, with one lineage containing four species that share extensive ancestral polymorphism. At the Ddc locus these major lineages are delineated only by silent site variation. We observe a significantly higher rate of synonymous site divergence than non-synonymous divergence, consistent with strong purifying selection acting on the locus. In contrast, the yellow locus exhibits patterns of amino acid divergence and nucleotide diversity that are consistent with recent diversifying selection acting in two different lineages. This selection appears to be targeting amino acid variants in the signal sequence of the Yellow protein, a region which is tightly constrained among members of the larger D. cardini radiation. This result highlights not only the potential importance of yellow in the evolution of divergent pigmentation patterns among members of the D. dunni subgroup, but also hints that variation in signal peptide sequences may play a role in phenotypic diversification.

Amino Acid Sequence↗

PubMed2026

Widespread horizontal transfer and strong selection enhance microbial adaptation in Antarctic soils.

Terrestrial Antarctica harbors compositionally diverse and functionally distinct microbial life. Yet the eco-evolutionary processes underlying adaptation to Antarctica's polyextreme conditions remain largely unknown. Here, we address how horizontal gene transfer (HGT) and de novo mutations influence microbial adaptation in 16 Antarctic soils using combined short- and long-read datasets. Phylogenetic reconciliation and mobile genetic element analysis of 676 metagenome-assembled genomes show frequent HGT across communities. While transferred genes span diverse functional categories, those involved in energy metabolism are exchanged at higher frequency. Genes for aerotrophy, i.e. the consumption of atmospheric trace gases to provide energy, carbon, and hydration, are among the most frequently disseminated. Approximately a quarter of carbon monoxide dehydrogenases and [NiFe]-hydrogenases are predicted to be horizontally acquired and are often associated with mobile genetic elements. Analysis of polymorphisms suggests widespread purifying selection, particularly for aerotrophy genes, providing further evidence that aerotrophy is critical for microbial survival in Antarctica. Genetic variation in hydrogenases is tightly associated with predicted protein structures, with intense selection acting on critical sites preserving stability and function. Together, these findings show that previously unrecognized eco-evolutionary dynamics shape the composition and function of Antarctic microbial communities, and confirm aerotrophy is a strongly selected and horizontally disseminated trait.

Antarctic Regions↗

PubMed2003

Selective pressure on the allantoicase gene during vertebrate evolution.

During vertebrate evolution, the uric acid degradation pathway has been modified and several enzymes have been lost. Consequently, the end product of purine catabolism varies from species to species. In the past few years, we have focused our attention on vertebrate allantoicase (an uricolytic pathway enzyme), whose activity is present in certain fish and amphibians only, but whose mRNA we detected also in mammals. As allantoicase activity disappeared in amniotes, we wonder why these sequences not only remain present in the mammalian genome, but are still transcribed. To elucidate this issue, we have cloned and analyzed comparable cDNA sequences of different organisms from ascidians to mammals. The analysis of the nonsynonymous-synonymous substitution rate that we performed on the coding region comprising exons 3 to 8 by means of maximum likelihood suggested that a certain amount of purifying selection is acting on the allantoicase sequences. Some implications of the preservation of an apparently unnecessary gene in higher vertebrates are discussed.

Amino Acid Sequence↗

PubMed2005

Immunodominance of low molecular weight secretory polypeptides of Mycobacterium tuberculosis to induce cytotoxic T-lymphocyte response.

The cytotoxic T-lymphocyte (CTL) responses to culture filtrate antigens of Mycobacterium tuberculosis H(37)Rv (RvCFP) and purified protein derivative (PPD) were investigated in active pulmonary tuberculosis patients, healthy tuberculosis contacts and non-contacts. Healthy tuberculin skin test (Mantoux) positive tuberculosis contacts demonstrated strong CTL response against RvCFP and Mantoux reactivity was found to correlate with CTL response. The specificity of CTL response in healthy Mantoux positive contacts was further assessed using different molecular weight fractions of RvCFP. Peripheral blood mononuclear cells (PBMCs) derived CTLs recognized multiple antigenic targets and demonstrated predominant cytotoxicity against low molecular weight (below 15 kDa) protein fractions as well as those migrated in the region of 30 kDa. Subsequently, evaluation of CTL responses against selected purified prominent T-cell antigens indicated maximum CTL response directed against Ag 85 complex proteins; most notably Ag 85 A. From this study, it is suggested that identification of more mycobacterial antigens activating various CTL subsets could be an important step for the rational designing of future antituberculous vaccine.

Acyltransferases↗

PubMed2005

Variable selection pressures across lineages in Trichodesmium and related cyanobacteria based on the heterocyst differentiation protein gene hetR.

Due to the irreversible inhibition of nitrogenase by O2, N2 fixation is incompatible with the oxygenic photosynthesis of cyanobacteria. These organisms have therefore evolved various strategies for growing diazotrophically. One group of N2-fixing cyanobacteria has specialized cells, heterocysts, which contain the nitrogenase, lack the oxygenic photosystem II, and are virtually anoxic inside as the result of respiratory activity and a thick glycolipid cell wall. The hetR gene encodes a serine protease which is thought to be involved in the regulation of heterocyst development and in DNA binding. Although hetR is also present in many non-heterocystous N2-fixing cyanobacteria, its function in these organisms is unknown. In this study, hetR sequences of the N2-fixing, non-heterocystous cyanobacterium Trichodesmium spp. and related genera were examined for signatures of selection. In parsimony- or distance-based hetR phylogenies, the filamentous non-heterocystous cyanobacteria Symploca sp. and Leptolyngbya sp. were closest to Trichodesmium sp. However, accommodating molecular attributes of hetR such as nucleotide frequencies and rate heterogeneity in phylogenetic analyses suggested that many other genera could not be excluded as sister taxa of Trichodesmium. Maximum likelihood analysis of the dN/dS ratio (omega) showed that-irrespective of the use of Symploca, Leptolyngbya, or more distant taxa as an outgroup-the lineage between an outgroup and Trichodesmium (omega1=0.02-0.05) and a lineage leading to Trichodesmium erythraeum (omega1=0.02) were under much stronger purifying selection than the other lineages in Trichodesmium (omega0=0.13-0.32). Although the results from the maximum likelihood analyses are most trustworthy because of codon usage bias in Trichodesmium, the results from a simpler tree-based McDonald-Kreitman test were in general agreement. Due to their quite different assumptions, the combination of these two methods of analysis circumvents multiple testing which, in general, is problematic when using branch models. Although the causal selective forces underlying the substitution patterns in hetR have not yet been identified, these findings parallel the variety of physiological, molecular, and behavioral differences in cyanobacteria related to N2 fixation. The heterogeneity of selection pressures in Trichodesmium is more surprising, because multiple adaptation mechanisms have not been described in this genus.

Bacterial Proteins↗

PubMed2005

Positive correlation between evolutionary rate and recombination rate in Drosophila genes with male-biased expression.

Previous studies have shown that genes that are expressed predominantly or exclusively in males tend to evolve rapidly in comparison to other genes. In most cases, however, it is unknown whether this rapid evolution is the result of increased positive (or sexual) selection on male-expressed traits or if it is due to a relaxation of selective constraints. To distinguish between these two possibilities, we analyzed the relationship between the nonsynonymous substitution rate (dN) and local recombination rate for 343 Drosophila genes that were classified as male, female, or nonsex biased in their expression. For the male-biased genes, a positive correlation between dN and recombination rate was observed. This can be explained by an increased rate of adaptive evolution in regions of higher recombination due to a reduction of Hill-Robertson interference. In contrast, the correlation between dN and recombination rate was negative for both female- and nonsex-biased genes, suggesting that these genes are primarily subject to purifying selection, which is expected to be less effective in regions of reduced recombination.

Animals↗

PubMed2006

Selection, recombination and demographic history in Drosophila miranda.

Selection, recombination, and the demographic history of a species can all have profound effects on genomewide patterns of variability. To assess the impact of these forces in the genome of Drosophila miranda, we examine polymorphism and divergence patterns at 62 loci scattered across the genome. In accordance with recent findings in D. melanogaster, we find that noncoding DNA generally evolves more slowly than synonymous sites, that the distribution of polymorphism frequencies in noncoding DNA is significantly skewed toward rare variants relative to synonymous sites, and that long introns evolve significantly slower than short introns or synonymous sites. These observations suggest that most noncoding DNA is functionally constrained and evolving under purifying selection. However, in contrast to findings in the D. melanogaster species group, we find little evidence of adaptive evolution acting on either coding or noncoding sequences in D. miranda. Levels of linkage disequilibrium (LD) in D. miranda are comparable to those observed in D. melanogaster, but vary considerably among chromosomes. These patterns suggest a significantly lower rate of recombination on autosomes, possibly due to the presence of polymorphic autosomal inversions and/or differences in chromosome sizes. All chromosomes show significant departures from the standard neutral model, including too much heterogeneity in synonymous site polymorphism relative to divergence among loci and a general excess of rare synonymous polymorphisms. These departures from neutral equilibrium expectations are discussed in the context of nonequilibrium models of demography and selection.

Animals↗

PubMed2006

Feline lentivirus evolution in cross-species infection reveals extensive G-to-A mutation and selection on key residues in the viral polymerase.

Factors that restrict a virus from establishing productive infection in a new host species are important to understand because cross-species transmission events are often associated with emergent viral diseases. To determine the evolutionary pressures on viruses in new host species, we evaluated the molecular evolution of a feline immunodeficiency virus derived from a wild cougar, Puma concolor, during infection of domestic cats. Analyses were based on the coding portion of genome sequences recovered at intervals over 37 weeks of infection of six cats inoculated by either intravenous or oral-nasal routes. All cats inoculated intravenously, but only one inoculated orally-nasally, became persistently viremic. There were notable accumulations of lethal errors and predominance of G-to-A alterations throughout the genome, which were marked in the viral polymerase gene, pol. Viral structural (env and gag) and accessory (vif and orfA) genes evolved neutrally or were under purifying selection. However, sites under positive selection were identified in reverse transcriptase that involved residues in the nucleotide binding pocket or those contacting the RNA-DNA duplex. The findings of extensive G-to-A alterations in this cross-species infection are consistent with the recently described editing of host cytidine deaminase on lentivirus genomes. Additionally, we demonstrate that the primary site of hypermutation is the viral pol gene and the dominant selective force acting on this feline immunodeficiency virus as it replicates in a new host species is on key residues of the virus polymerase.

Animals↗

PubMed2000

The evolution of an alpha-esterase pseudogene inactivated in the Drosophila melanogaster lineage.

Previous analyses of the alpha-esterase cluster of Drosophila melanogaster revealed 10 active genes and the DmalphaE4a-Psi pseudogene. Here, we reconstruct the evolution of the pseudogene from the sequences of 12 alleles from widely scattered D. melanogaster populations and single alleles from Drosophila simulans and Drosophila yakuba. All of the DmalphaE4a-Psi alleles contain numerous inactivating mutations, suggesting that pseudogene alleles are fixed in natural populations. Several lines of evidence also suggest that DmalphaE4a is now evolving without selective constraint in the D. melanogaster lineage. There are three polymorphic indels which result in frameshifts; a key nucleotide of the intron splice acceptor is polymorphic; the neutral mutation parameter is the same for replacement and silent sites; one of the nonsilent polymorphisms results in a stop codon; only 1 of the 13 replacement polymorphisms is biochemically conservative; residues that are conserved among active esterases have different states in DmalphaE4a-Psi; and there are about half as many transitional polymorphisms as transversional ones. In contrast, the D. simulans and D. yakuba orthologs DsalphaE4a and DyalphaE4a do not have the inactivating mutations of DmalphaE4a-Psi and appear to be evolving under the purifying selection typical of protein- encoding genes. For instance, there have been more substitutions in the introns than in the exons, and more in silent sites than in replacement sites. Furthermore, most of the amino acid substitutions that have occurred between DyalphaE4a and DsalphaE4a are located in sites that typically vary among active alpha-esterases rather than those that are usually conserved. We argue that the original alphaE4a gene had a function which it has lost since the divergence of the D. melanogaster and D. simulans lineages.

Amino Acid Sequence↗

PubMed1999

Natural selection of the Pol gene of bovine immunodeficiency virus.

Genetic variability is a salient feature of lentiviruses, contributing to the pathogenesis of these viruses by enabling them to persist in the host and to resist anti-retroviral treatment. Bovine immunodeficiency virus (BIV), a lentivirus of unknown pathology, infects cattle in the United States and worldwide. Genetic diversity of BIV that is associated with naturally infected cattle is not well studied. We examined the genetic diversity and natural selection of a segment of the BIV pol gene amplified from the leukocyte DNA of naturally infected cattle. A portion of the reverse transcriptase domain (183 bp) of the pol region was targeted for amplification by PCR. PCR products were sequenced directly and aligned. When compared to the sequences of BIV R29-127, a molecular clone of the original BIV R29 isolate, all isolates were greater than 91% identical in nucleotide sequences and 77% identical in amino acid sequences. Pol genotypes were polymorphic at 14% of the nucleotide sites. The ratio of nonsynonymous to synonymous nucleotide substitutions (relative to the number of respective sites, Ka/Ks) was 0.16, indicating that this region of the BIV genome, like that of HIV-1, is subject to purifying selection. Based on the McDonald-Kreitman analysis, this region also was under positive Darwinian selection as HIV-1 and BIV diverged from a common progenitor. Phylogenetic analysis revealed that genotypes were geographically distinct, possibly indicating a common source of infection for animals within a herd.

Amino Acid Sequence↗

PubMed2006

Retrotransposon sequence variation in four asexual plant species.

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

Amino Acid Sequence↗

PubMed2004

Genomic background predicts the fate of duplicated genes: evidence from the yeast genome.

Gene duplication with subsequent divergence plays a central role in the acquisition of genes with novel function and complexity during the course of evolution. With reduced functional constraints or through positive selection, these duplicated genes may experience accelerated evolution. Under the model of subfunctionalization, loss of subfunctions leads to complementary acceleration at sites with two copies, and the difference in average rate between the sequences may not be obvious. On the other hand, the classical model of neofunctionalization predicts that the evolutionary rate in one of the two duplicates is accelerated. However, the classical model does not tell which of the duplicates experiences the acceleration in evolutionary rate. Here, we present evidence from the Saccharomyces cerevisiae genome that a duplicate located in a genomic region with a low-recombination rate is likely to evolve faster than a duplicate in an area of high recombination. This observation is consistent with population genetics theory that predicts that purifying selection is less effective in genomic regions of low recombination (Hill-Robertson effect). Together with previous studies, our results suggest the genomic background (e.g., local recombination rate) as a potential force to drive the divergence between nontandemly duplicated genes. This implies the importance of structure and complexity of genomes in the diversification of organisms via gene duplications.

Evolution, Molecular↗

PubMed1979

Calcium-binding modulator protein from the unfertilized egg of the sea urchin Arbacia punctulata.

We have purified and partly characterized a calcium-binding protein from the unfertilized egg of the sea urchin Arbacia punctulata. This protein closely resembles the calcium-binding modulator protein of bovine brain in its molecular weight, electrophoretic mobility, amino acid analysis, and peptide map. It activates bovine brain phosphodiesterase in the presence of calcium but has no effect on the phosphodiesterase of the Arbacia egg. Densitometric scanning of acrylamide gels of arbacia egg homogenates shows the modulator protein to represent 0.1% of the total protein of the egg. At 10(-4) M free calcium, the protein binds four calcium ions per 17,000-dalton molecule. We have used a column of rabbit skeletal muscle troponin-I covalently coupled to Sepharose 4B as an affinity column to selectively purify the Arbacia egg calcium-binding protein. This column has also been used to purify bovine brain modulator protein and may prove of general use in isolating similar proteins from other sources. The technique may be particularly helpful when only small quantities of starting material are available.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2004

Mutation hotspots in the p53 gene in tumors of different origin: correlation with evolutionary conservation and signs of positive selection.

We present a classification analysis of the mutation spectra of the p53 gene and construct maps of hotspots for the germline (Li-Fraumein syndrome), different types of tumors and their derived cell lines. While spectra from solid tumors share common hotspots with the germline spectrum, they also contain unique sets of somatic hotspots that are not observed in the germline. All these hotspots correspond to amino acid replacements in the DNA-binding interface of p53. The mutation spectra of lymphomas and cell lines derived from lymphomas and lung cancers contained few hotspots compared to solid tumors. Thus, the distribution of hotspots in the p53 gene appears to depend on the tumor type and cell growth conditions; this specificity is missed by the bulk hotspot analysis. A negative correlation was detected between the amino acid replacement propensity in tumors and evolutionary variability: the hotspots are located in the positions that are highly conserved in p53 and its paralogs, p63 and p73. In all the mutation spectra, substitutions leading to amino acid replacements strongly dominate over silent substitutions, indicating that functional sites evolving under strong purifying selection are subject to intensive positive selection in p53-dependent tumors. These results are compatible with the gain-of-function concept of the role of p53 in tumorigenesis.

Amino Acid Sequence↗

PubMed2006

Expression and diversity of Echinococcus multilocularis AgB genes in secondarily infected mice: evaluating the influence of T-cell immune selection on antigenic variation.

The T-cell-mediated immune response exhibits a crucial function in the control of the intrahepatic proliferation of Echinococcus multilocularis larvae in mice and humans, both being natural intermediate hosts of the parasite. Antigen B (AgB), a metabolized Echinococcus spp. lipoprotein, contributes to the modulation of the T-cell immune response, and distinct sites of the corresponding AgB1, AgB3 and AgB4 genes were shown to be under positive selection pressure. Since several AgB gene variants are present in a single Echinococcus metacestode, we used secondary E. multilocularis infections in BALB/c and in athymic nude mice (devoid of T-cell responses) to analyze the effect of the cellular immune response on the expression and diversity of EmAgB1-EmAgB4 genes. We demonstrated hereby that EmAgB transcripts were less abundant in nude mice during the early phase of infection (at one month post-infection), and that EmAgB2 is simultaneously down-regulated when compared to the other three genes. A negative relationship exists between the level of transcription and diversity of EmAgB genes. Moreover, no excess of non-synonymous substitutions was found among the distinct EmAgB alleles from a single host. Together, these results pointed to the effect of purifying selection, which seemed to eliminate the detrimental AgB variants generated during the development of the metacestode within the peritoneal cavity of its intermediate host.

Animals↗

PubMed2004

Average allozyme heterozygosity in vertebrates correlates with Ka/Ks measured in the human-mouse lineage.

It is well established that different allozyme proteins vary in heterozygosity in averages made over large numbers of species. For example, the enzyme 6-phosphogluconate dehydrogenase has a much higher average heterozygosity than glutamate dehydrogenase. Allozyme data alone provide insufficient power to determine the evolutionary cause of such a difference. Many studies have now been carried out on the DNA sequences coding for allozymes. These have identified diverse selective and nonselective causes of polymorphisms at individual loci. However the studies are mainly in a small number of model species; thus, it is difficult to identify from these DNA studies specific causes of global average heterozygosity differences among allozyme proteins. Here we demonstrate that estimates of average heterozygosity for 37 allozyme proteins in vertebrates correlate positively with Ka and Ka/Ks but not with Ks, measured in the human-mouse lineage. The values of Ka/Ks are less than 0.25, and Ka/Ks is negatively correlated with subunit number (quaternary structure), a measure of structural constraint. Proteins with lower levels of constraint have higher values of both Ka/Ks and heterozygosity. These results better support the hypothesis that differences in average allozyme diversity between proteins are more closely related to differences in the level of purifying selection than to differences in the underlying mutation rate or level of positive selection.

Animals↗