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Intragenic variation of synonymous substitution rates is caused by nonrandom mutations at methylated CpG.

It has been observed that synonymous substitution rates vary among genes in various organisms, although the cause of the variation is unresolved. At the intragenic level, however, the variation of synonymous substitutions is somewhat controversial. By developing a rigorous statistical test and applying the test to 418 homologous gene pairs between mouse and rat, we found that more than 90% of gene pairs showed a statistical significance in intragenic variation of synonymous substitution rates. Moreover, by examining all conceivable possibilities for the cause of the variation, we successfully found that intragenic variation of synonymous substitutions in mammalian genes is caused mainly by a nonrandom mutation due to the methylation of CpG dinucleotides rather than by functional constraints.

Amino Acid Sequence↗
PubMed1999

Directional substitution and evolution of nucleotide content in the cytochrome oxidase II gene in earwigs (dermapteran insects).

The cytochrome oxidase subunit II (COII) gene was sequenced for six dermapteran species. The nucleotide composition of this gene is biased in most animals. While the CG content of other insect orders is low (mean, 27.6%; range, 19.5%-33.1%), species from the Forficula genus showed unusually high values (mean, 42.4%; range, 37.3%-44.1%), mostly due to high CG frequencies at third codon positions: the mean CG content at these positions was around 45% (range, 43.9%-46.9%) for Forficula, compared with only 13.3% for other insects. This effect was so strong that in one species, Forficula lesnei, there was no significant difference between the frequencies of the four bases. During evolution, this loss of bias has involved a significant increase in the synonymous substitution rate and an increase of transitions over transversions compared with other insects. A strong directionality of substitutions has favored T-->C and A-->G changes. This phenomenon was also observed between two conspecific populations of Forficula auricularia. A species from a closely related genus, Anechura bipunctata, was intermediate between Forficula and other insects for these parameters, while two remotely related dermapteran species, Labidura riparia and Euborellia moesta, were similar to other insects. These results suggest that the evolution of Forficula DNA content has been both rapid and recent.

Animals↗
PubMed1996

On transition bias in mitochondrial genes of pocket gophers.

The relative contribution of mutation and purifying selection to transition bias has not been quantitatively assessed in mitochondrial protein genes. The observed transition/transversion (s/v) ratio is (micros Ps)/(microv Pv), where micros and microv denote mutation rate of transitions and transversions, respectively, and Ps and Pv denote fixation probabilities of transitions and transversions, respectively. Because selection against synonymous transitions can be assumed to be roughly equal to that against synonymous transversions, Ps/Pv approximately 1 at fourfold degenerate sites, so that the s/v ratio at fourfold degenerate sites is approximately micros/microv, which is a measure of mutational contribution to transition bias. Similarly, the s/v ratio at nondegenerate sites is also an estimate of micros/microv if we assume that selection against nonsynonymous transitions is roughly equal to that against nonsynonymous transversions. In two mitochondrial genes, cytochrome oxidase subunit I (COI) and cytochrome b (cyt-b) in pocket gophers, the s/v ratio is about two at nondegenerate and fourfold degenerate sites for both the COI and the cyt-b genes. This implies that mutation contribution to transition bias is relatively small. In contrast, the s/v ratio is much greater at twofold degenerate sites, being 48 for COI and 40 for cyt-b. Given that the micros/microv ratio is about 2, the Ps/Pv ratio at twofold degenerate sites must be on the order of 20 or greater. This suggests a great effect of purifying selection on transition bias in mitochondrial protein genes because transitions are synonymous and transversions are nonsynonymous at twofold degenerate sites in mammalian mitochondrial genes. We also found that nonsynonymous mutations at twofold degenerate sites are more neutral than nonsynonymous mutations at nondegenerate sites, and that the COI gene is subject to stronger purifying selection than is the cyt-b gene. A model is presented to integrate the effect of purifying selection, codon bias, DNA repair and GC content on s/v ratio of protein-coding genes.

Analysis of Variance↗
PubMed2002

Adaptive evolution of variable region genes encoding an unusual type of immunoglobulin in camelids.

A typical immunoglobulin (Ig) molecule is composed of four polypeptide chains: two identical heavy (H) chains and two identical light (L) chains. This tetrameric structure is conserved in almost all jawed vertebrate species. However, it has been discovered that camels and llamas (family: Camelidae) possess a type of dimeric Ig that consists of two H chains only. These H chains do not associate with L chains, and they do not have the first constant region (CH1), which is present in the conventional Ig. In spite of these changes, the dimeric Ig maintains the normal immune function. To understand the evolution of the dimeric Ig, we studied the phylogenetic relationships of the variable region (V(H)H) genes of the dimeric Ig from Camelidae and those (V(H)) of the conventional Ig from mammals. The results showed that the V(H)H genes form a monophyletic cluster within one of the mammalian V(H) groups, group C. We examined the type of selective force in complementarity-determining regions (CDRs) and framework regions (FRs) by comparing the rate of synonymous (dS) and nonsynonymous (dN) substitutions. We found that the results obtained from V(H)H genes were similar to those from V(H) genes in that CDRs showed an excess of dN over dS (indicating positive selection), whereas the reverse was true for FRs (purifying selection). However, when the extent of positive selection or purifying selection was investigated at each codon site, three major differences between V(H)H and V(H) genes were found. That is, very different types of selective force were observed between V(H)H and V(H) genes (1) at the sites that contact the L chain in the conventional Ig, (2) at the sites that interact with the CH1 region in the conventional Ig, and (3) in the H1 loop. Our findings suggest that adaptive evolution has occurred in the functionally important sites of the V(H)H genes to maintain the normal immune function in the dimeric Ig.

Amino Acid Substitution↗
PubMed1999

Major histocompatibility complex variation in the endangered Przewalski's horse.

The major histocompatibility complex (MHC) is a fundamental part of the vertebrate immune system, and the high variability in many MHC genes is thought to play an essential role in recognition of parasites. The Przewalski's horse is extinct in the wild and all the living individuals descend from 13 founders, most of whom were captured around the turn of the century. One of the primary genetic concerns in endangered species is whether they have ample adaptive variation to respond to novel selective factors. In examining 14 Przewalski's horses that are broadly representative of the living animals, we found six different class II DRB major histocompatibility sequences. The sequences showed extensive nonsynonymous variation, concentrated in the putative antigen-binding sites, and little synonymous variation. Individuals had from two to four sequences as determined by single-stranded conformation polymorphism (SSCP) analysis. On the basis of the SSCP data, phylogenetic analysis of the nucleotide sequences, and segregation in a family group, we conclude that four of these sequences are from one gene (although one sequence codes for a nonfunctional allele because it contains a stop codon) and two other sequences are from another gene. The position of the stop codon is at the same amino-acid position as in a closely related sequence from the domestic horse. Because other organisms have extensive variation at homologous loci, the Przewalski's horse may have quite low variation in this important adaptive region.

Animals↗
PubMed2004

DNA variability and divergence at the notch locus in Drosophila melanogaster and D. simulans: a case of accelerated synonymous site divergence.

DNA diversity in two segments of the Notch locus was surveyed in four populations of Drosophila melanogaster and two of D. simulans. In both species we observed evidence of non-steady-state evolution. In D. simulans we observed a significant excess of intermediate frequency variants in a non-African population. In D. melanogaster we observed a disparity between levels of sequence polymorphism and divergence between one of the Notch regions sequenced and other neutral X chromosome loci. The striking feature of the data is the high level of synonymous site divergence at Notch, which is the highest reported to date. To more thoroughly investigate the pattern of synonymous site evolution between these species, we developed a method for calibrating preferred, unpreferred, and equal synonymous substitutions by the effective (potential) number of such changes. In D. simulans, we find that preferred changes per "site" are evolving significantly faster than unpreferred changes at Notch. In contrast we observe a significantly faster per site substitution rate of unpreferred changes in D. melanogaster at this locus. These results suggest that positive selection, and not simply relaxation of constraint on codon bias, has contributed to the higher levels of unpreferred divergence along the D. melanogaster lineage at Notch.

Animals↗
PubMed1994

New species-specific alleles at the primate MHC-G locus.

Six different ape MHC-G DNA sequences (four in humans: HLA-G*01011, HLA-G*II, HLA-G*0103, and HLA-G*IV; one in chimpanzees: Patr-G*I; and one in gorillas: Gogo-G*1) have been obtained. Only synonymous or conservative ("Thr"-to-"Ser") substitutions are allowed between the four human alleles. One allele of MHC-G exon-2 sequences has been found both in gorilla (Gorilla gorilla) and chimpanzee (Pan troglodytes). The Patr-G*I DNA sequence shows two nonsynonymous substitutions when compared with the human HLA-G*01011 sequence: "CGG"-to-"TGG" ("Arg"-to-"Trp") at codon 35 and "ATG"-to-"ATA" ("Met"-to-"Ile") at codon 76. One nonsynonymous "GAG"-to-"GGG" ("Glu"-to-"Gly") substitution is observed in the Gogo-G*I exon-2 DNA sequence, when compared with the human *01011 allele. None of these three different substitutions have been observed in humans and are, thus, considered species specific. Also, evidence is provided that the human HLA-G*II and G*0103 may have been originated after human speciation. Finally, phylogenetic relationships among the six MHC-G alleles, tamarins G-"like" alleles, and other human class I genes (both "classical" and "nonclassic") are discussed.

Alleles↗
PubMed2005

A synonymous mutation in Yersinia enterocolitica yopE affects the function of the YopE type III secretion signal.

Yersinia spp. inject virulence proteins called Yops into the cytosol of target eukaryotic cells in an effort to evade phagocytic killing via a dedicated protein-sorting pathway termed type III secretion. Previous studies have proposed that, unlike other protein translocation mechanisms, Yops are not recognized as substrates for secretion via a solely proteinaceous signal. Rather, at least some of this information may be encoded within yop mRNA. Herein, we report that the first seven codons of yopE, when fused to the reporter protein neomycin phosphotransferase (Npt), are sufficient for the secretion of YopE1-7-Npt when type III secretion is induced in vitro. Systematic mutagenesis of yopE codons 1 to 7 reveals that, like yopQ, codons 2, 3, 5, and 7 are sensitive to mutagenesis, thereby defining the first empirical similarity between the secretion signals of two type III secreted substrates. Like that of yopQ, the secretion signal of yopE exhibits a bipartite nature. This is manifested by the ability of codons 8 to 15 to suppress point mutations in the minimal secretion signal that change the amino acid specificities of particular codons or that induce alterations in the reading frame. Further, we have identified a single nucleotide position in codon 3 that, when mutated, conserves the predicted amino acid sequence of the YopE1-7-Npt but abrogates secretion of the reporter protein. When introduced into the context of the full-length yopE gene, the single-nucleotide mutation reduces the type III injection of YopE into HeLa cells, even though the predicted amino acid sequence remains the same. Thus, yopE mRNA appears to encode a property that mediates the type III injection of YopE.

Bacterial Outer Membrane Proteins↗
PubMed2004

Distinct patterns of natural selection in the reverse transcriptase gene of HIV-1 in the presence and absence of antiretroviral therapy.

The emergence of human immunodeficiency virus (HIV) drug-resistant mutations during antiretroviral therapy is explained by either the preexistence of low-frequency-resistant strains before the start of therapy or by the selection of unsuppressed resistant strains during therapy. We used pairwise and maximum likelihood analyses of the ratio of nonsynonymous to synonymous substitutions per site (d(N)/d(S)) to study the extent of positive selection in the reverse transcriptase (RT) gene of HIV-1 from multiple data sets of drug-treated (117 sequences) and drug-naive patients (270 sequences). In the pairwise analysis, evidence for positive selection (d(N)/d(S) > 1) was only found in drug-treated individuals and in codons conferring drug resistance. By the maximum likelihood method, a positive selection at codons conferring drug resistance was only observed in patients receiving therapy, and although positive selection was detected in drug-naive patients, this was always at codons unrelated to drug resistance. We therefore document a striking difference in the process of allele fixation in drug resistance codons (RC) between populations of HIV-1-infected individuals naive to treatment and those receiving therapy. Furthermore, although mutations associated with drug resistance are sometimes found in drug-naive patients, we suggest that these are fixed because of linkage to sites experiencing immune escape. Finally, we show that compensatory changes are likely to be important in the development of HIV drug resistance by counter-acting the deleterious effects normally associated with drug resistance mutations.

Amino Acid Sequence↗
PubMed1994

Unraveling selection in the mitochondrial genome of Drosophila.

We examine mitochondrial DNA variation at the cytochrome b locus within and between three species of Drosophila to determine whether patterns of variation conform to the predictions of neutral molecular evolution. The entire 1137-bp cytochrome b locus was sequenced in 16 lines of Drosophila melanogaster, 18 lines of Drosophila simulans and 13 lines of Drosophila yakuba. Patterns of variation depart from neutrality by several test criteria. Analysis of the evolutionary clock hypothesis shows unequal rates of change along D. simulans lineages. A comparison within and between species of the ratio of amino acid replacement change to synonymous change reveals a relative excess of amino acid replacement polymorphism compared to the neutral prediction, suggestive of slightly deleterious or diversifying selection. There is evidence for excess homozygosity in our world wide sample of D. melanogaster and D. simulans alleles, as well as a reduction in the number of segregating sites in D. simulans, indicative of selective sweeps. Furthermore, a test of neutrality for codon usage shows the direction of mutations at third positions differs among different topological regions of the gene tree. The analyses indicate that molecular variation and evolution of mtDNA are governed by many of the same selective forces that have been shown to govern nuclear genome evolution and suggest caution be taken in the use of mtDNA as a "neutral" molecular marker.

Animals↗
PubMed2006

Physiological and genetic characteristics of black-boned sheep (Ovis aries).

Here we report for the first time the discovery of sheep that have black bones and black muscles. The spectral pattern of pigment extracted from tissues of these black-boned sheep is similar to that of black-boned Chinese silky fowl. Additionally, black-boned sheep have significantly higher plasma colour, tyrosinase activity and kidney function than normal sheep. Synonymous nucleotide substitutions in the tyrosinase (TYR) and melanocortin 1 receptor (MC1R) genes were detected in black-boned sheep when compared with the corresponding sequences in normal sheep. In addition, a missense mutation (215T>C) in exon 2 of tyrosinase-related protein 1 (TYRP1) was detected in black-boned sheep, and this resulted in a putative valine-to-alanine substitution at codon 68 (Val68Ala).

Animals↗
PubMed2026

Resurgence and molecular epidemiology of dengue virus serotype 4 amid the COVID-19 pandemic in Thailand.

INTRODUCTION: Dengue virus serotype 4 (DENV4) co-circulates with other serotypes in Thailand, a hyperendemic setting characterized by cyclical shifts in serotype predominance. During the COVID-19 pandemic, related public health interventions may have influenced dengue detection, transmission and epidemiological dynamics. MATERIALS AND METHODS: A total of 413 dengue NS1/PCR-positive samples collected from 2018 to 2024 at a tertiary hospital in Bangkok were serotyped using a real-time PCR DENV1-4 subtyping assay. Forty-seven DENV4-positive samples (Ct < 32) underwent whole-genome sequencing using the ATOPlex DENV1-4 panel on the DNBSEQ-G99RS platform. Sequencing reads were processed using CLC Genomics Workbench, followed by phylogenetic, mutation, codon-based selection-pressure, and epitope-mapping analyses. RESULTS: DENV4 was identified in 18.2% (75/413) of samples, with 48% of cases requiring hospitalization. Detection increased markedly from 11.8% (22/186) during 2018-2021-23.3% (53/227) during 2022-2024 (proportion ratio, 1.97; p&#x202f;=&#x202f;0.0025). Among the 47 whole-genome-sequenced samples, most strains clustered within genotype I lineage 4I_A.3 and showed lineage-associated non-synonymous substitutions. NS1-A90T, NS2A-L113F, and NS3-F523Y appeared exclusively during 2022-2024 (p&#x202f;<&#x202f;0.001), whereas NS2A-L113F, NS5-G223S, and NS5-Q631R showed concordant positive-selection signals by FEL and MEME. CONCLUSIONS: This hospital-based study highlights an increase in DENV4 detection in Bangkok during 2022-2024 compared with 2018-2021, accompanied by predominance of lineage 4I_A.3 distinct from Malaysian and Indonesian strains reported during a similar period. These findings support integrated clinical and genomic surveillance to monitor DENV serotype and genotype dynamics and inform public health and vaccine strategies.

COVID-19 pandemic↗
PubMed2005

Comprehensive search for intra- and inter-specific sequence polymorphisms among coding envelope genes of retroviral origin found in the human genome: genes and pseudogenes.

BACKGROUND: The human genome carries a high load of proviral-like sequences, called Human Endogenous Retroviruses (HERVs), which are the genomic traces of ancient infections by active retroviruses. These elements are in most cases defective, but open reading frames can still be found for the retroviral envelope gene, with sixteen such genes identified so far. Several of them are conserved during primate evolution, having possibly been co-opted by their host for a physiological role. RESULTS: To characterize further their status, we presently sequenced 12 of these genes from a panel of 91 Caucasian individuals. Genomic analyses reveal strong sequence conservation (only two non synonymous Single Nucleotide Polymorphisms [SNPs]) for the two HERV-W and HERV-FRD envelope genes, i.e. for the two genes specifically expressed in the placenta and possibly involved in syncytiotrophoblast formation. We further show--using an ex vivo fusion assay for each allelic form--that none of these SNPs impairs the fusogenic function. The other envelope proteins disclose variable polymorphisms, with the occurrence of a stop codon and/or frameshift for most--but not all--of them. Moreover, the sequence conservation analysis of the orthologous genes that can be found in primates shows that three env genes have been maintained in a fully coding state throughout evolution including envW and envFRD. CONCLUSION: Altogether, the present study strongly suggests that some but not all envelope encoding sequences are bona fide genes. It also provides new tools to elucidate the possible role of endogenous envelope proteins as susceptibility factors in a number of pathologies where HERVs have been suspected to be involved.

Alleles↗
PubMed2003

Genetic variation of glycoproteins B and H of human herpesvirus 7 in Hong Kong.

Glycoprotein B (gB) and glycoprotein H (gH) of human herpesvirus 7 (HHV-7) are believed to play an important role in virus entry and as targets for host immune response. This study examined the genetic diversity of these glycoproteins among 90 HHV-7 isolates collected from different individuals in Hong Kong. Overall, both the gB and gH genes were found to be highly conserved. Nucleotide polymorphism was detected only at four positions of the gB-encoding region, and all of these were synonymous substitutions. Most (97.8%) Hong Kong isolates were of gB allele group C. Two isolates collected from a Pakistani family showed a novel sequence pattern that did not match known gB allele groups. This sequence pattern was detected consistently from serial samples collected from the same individual, indicating a stable genetic entity. The gH-encoding region exhibited nucleotide polymorphism at six positions. Three of these were nonsynonymous substitutions (codon 271 Lys --> Gln, codon 308 Gly --> Glu, codon 397 Asn --> Tyr). Most (84.4%) Hong Kong isolates were of the gH allele group B, and all others were of the gH allele group C. These data indicate the possibility of using gB or gH alleles as markers for studying world-wide population movements and genetics.

Adolescent↗
PubMed2006

Analysis of the genome-wide variations among multiple strains of the plant pathogenic bacterium Xylella fastidiosa.

BACKGROUND: The Gram-negative, xylem-limited phytopathogenic bacterium Xylella fastidiosa is responsible for causing economically important diseases in grapevine, citrus and many other plant species. Despite its economic impact, relatively little is known about the genomic variations among strains isolated from different hosts and their influence on the population genetics of this pathogen. With the availability of genome sequence information for four strains, it is now possible to perform genome-wide analyses to identify and categorize such DNA variations and to understand their influence on strain functional divergence. RESULTS: There are 1,579 genes and 194 non-coding homologous sequences present in the genomes of all four strains, representing a 76. 2% conservation of the sequenced genome. About 60% of the X. fastidiosa unique sequences exist as tandem gene clusters of 6 or more genes. Multiple alignments identified 12,754 SNPs and 14,449 INDELs in the 1528 common genes and 20,779 SNPs and 10,075 INDELs in the 194 non-coding sequences. The average SNP frequency was 1.08 x 10(-2) per base pair of DNA and the average INDEL frequency was 2.06 x 10(-2) per base pair of DNA. On an average, 60.33% of the SNPs were synonymous type while 39.67% were non-synonymous type. The mutation frequency, primarily in the form of external INDELs was the main type of sequence variation. The relative similarity between the strains was discussed according to the INDEL and SNP differences. The number of genes unique to each strain were 60 (9a5c), 54 (Dixon), 83 (Ann1) and 9 (Temecula-1). A sub-set of the strain specific genes showed significant differences in terms of their codon usage and GC composition from the native genes suggesting their xenologous origin. Tandem repeat analysis of the genomic sequences of the four strains identified associations of repeat sequences with hypothetical and phage related functions. CONCLUSION: INDELs and strain specific genes have been identified as the main source of variations among strains, with individual strains showing different rates of genome evolution. Based on these genome comparisons, it appears that the Pierce's disease strain Temecula-1 genome represents the ancestral genome of the X. fastidiosa. Results of this analysis are publicly available in the form of a web database.

Analysis of Variance↗
PubMed2006

Mitochondrial genome sequence evolution in Chlamydomonas.

The mitochondrial genomes of the Chlorophyta exhibit significant diversity with respect to gene content and genome compactness; however, quantitative data on the rates of nucleotide substitution in mitochondrial DNA, which might help explain the origin of this diversity, are lacking. To gain insight into the evolutionary forces responsible for mitochondrial genome diversification, we sequenced to near completion the mitochondrial genome of the chlorophyte Chlamydomonas incerta, estimated the evolutionary divergence between Chlamydomonas reinhardtii and C. incerta mitochondrial protein-coding genes and rRNA-coding regions, and compared the relative evolutionary rates in mitochondrial and nuclear genes. Synonymous and nonsynonymous substitution rates do not differ significantly between the mitochondrial and nuclear protein-coding genes. The mitochondrial rRNA-coding regions, however, are evolving much faster than their nuclear counterparts, and this difference might be explained by relaxed functional constraints on the mitochondrial translational apparatus due to the small number of proteins synthesized in Chlamydomonas mitochondria. Substitution rates at synonymous sites in a nonstandard mitochondrial gene (rtl) and at intronic and synonymous sites in nuclear genes expressed at low levels suggest that the mutation rate is similar in these two genetic compartments. Potential evolutionary forces shaping mitochondrial genome evolution in Chlamydomonas are discussed.

Animals↗
PubMed1995

Molecular systematics of the Trilliaceae sensu lato as inferred from rbcL sequence data.

In this paper, we examine the phylogenetic affinities of Trilliaceae sensu lato. DNA sequences of the rbcL gene were analyzed for 8 species from Trilliaceae sensu lato (Trillium kamtschaticum, T. sessile, Daiswa polyphylla, Kinugasa japonica, Paris tetraphylla, Scoliopus bigelovii, S. hallii, and Medeola virginiana) and 10 other species from Liliaceae sensu lato. The analysis indicates that Trilliaceae sensu stricto (Trillium, Daiswa, Kinugasa, and Paris) is monophyletic and that Trilliaceae sensu lato is not monophyletic. Scoliopus and Medeola do not form a clade with Trilliaceae sensu stricto. Instead, they form a clade with Uvulariaceae and Liliaceae sensu stricto, respectively. Relative to the rbcL genes of Trilliaceae sensu stricto, Scoliopus and Medeola displayed approximately 14-24 synonymous substitutions per 100 sites. In similar comparisons with Streptopus and Clintonia (Uvulariaceae), these displayed approximately 1-4 synonymous substitutions per 100 sites. The rbcL gene analysis supports the previous suggestion that Scoliopus and Medeola should be moved from Trilliaceae to Liliaceae sensu stricto. The analysis also indicated that Veratrum (Melanthiaceae) may be related to Trilliaceae sensu stricto. For reconstructing the phylogeny of lower taxonomic level as such, it was found that data on nonsynonymous base substitution as well as weighting in the first and second positions of codons are not useful.

Base Sequence↗