Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “synonymous substitution”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

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

At least 289 records · Page 16Linked to original sources
PubMed2000

Effects of natural selection on patterns of DNA sequence variation at the transferrin, somatolactin, and p53 genes within and among chinook salmon (Oncorhynchus tshawytscha) populations.

This paper describes DNA sequence variation within and among four populations of chinook salmon (Oncorhynchus tshawytscha) at the transferrin, somatolactin and p53 genes. Patterns of variation among salmon species at the transferrin gene have been hypothesized to be shaped by positive natural selection for new alleles because the rate of nonsynonymous substitution is significantly greater than the rate of synonymous substitution. The twin goals of this study were to determine if the history of selection among salmon species at the transferrin gene is also reflected in patterns of intraspecific variation in chinook salmon, and to look for evidence of local adaptation at the transferrin gene by comparing patterns of nonsynonymous and synonymous variation among chinook salmon populations. The analyses presented here show that unlike patterns of variation between species, there is no evidence of greater differentiation among chinook salmon populations at nonsynonymous compared to synonymous sites. There is also no evidence of a reduction of within-species variation due to the hitchhiking effect at the transferrin gene, although in some populations nonsynonymous and synonymous derived mutations are both at higher frequencies than expected under a simple neutral model. Population size weighted selection coefficients (4Ns) that are consistent with both the inter and intraspecific data range from approximately 10 to approximately 235, and imply that between 1 and 40% of new nonsynonymous mutations at the transferrin gene have been beneficial.

Alleles↗
PubMed1998

Large number of polymorphic nucleotides and a termination codon in the env gene of the endogenous human retrovirus ERV3.

The terminal portion of the pol gene and the entire env gene of the human endogenous retrovirus ERV3 was screened for polymorphic nucleotides. For this purpose fragments amplified from the desired regions of ERV3 were subjected to single strand conformational analysis (SSCP analysis). Using this approach, we detected 13 polymorphic nucleotides, namely four in the pol gene and nine in the env gene. Three of the nucleotide substitutions were synonymous (not affecting the amino acid code). One of the non-synonymous nucleotide substitutions changed an arginine codon to a termination codon. The alleles at the different polymorphic sites could be arranged into five ERV3 haplotypes, two of which were new. To evaluate the possible significance of the termination codon, which precludes expression of a putative immunoregulatory factor, we examined samples of DNA from patients with multiple sclerosis, a demyelinating disease of presumed autoimmune etiology. We did not find an association between the ERV3 allele with the termination codon and this disease. Perhaps the presence of a stop codon combined with the high number of non-synonymous nucleotide substitutions in the reading frame of the env gene reflects absence of selective constraints during evolution. Obviously, our findings contradict the assumption that the reading frame of the ERV3 env gene has been conserved throughout evolution.

Codon, Terminator↗
PubMed2003

Human disease genes: patterns and predictions.

We compared genes at which mutations are known to cause human disease (disease genes) with other human genes (nondisease genes) using a large set of human-rodent alignments to infer evolutionary patterns. Such comparisons may be of use both in predicting disease genes and in understanding the general evolution of human genes. Four features were found to differ significantly between disease and nondisease genes, with disease genes (i) evolving with higher nonsynonymous/synonymous substitution rate ratios (Ka/Ks), (ii) evolving at higher synonymous substitution rates, (iii) with longer protein-coding sequences, and (iv) expressed in a narrower range of tissues. Discriminant analysis showed that these differences may help to predict human disease genes. We also investigated other factors affecting the mode of evolution in the disease genes: Ka/Ks is significantly affected by protein function, mode of inheritance, and the reduction of life expectancy caused by disease.

Adolescent↗
PubMed2005

SARS-CoV genome polymorphism: a bioinformatics study.

A dataset of 103 SARS-CoV isolates (101 human patients and 2 palm civets) was investigated on different aspects of genome polymorphism and isolate classification. The number and the distribution of single nucleotide variations (SNVs) and insertions and deletions, with respect to a "profile", were determined and discussed ("profile" being a sequence containing the most represented letter per position). Distribution of substitution categories per codon positions, as well as synonymous and non-synonymous substitutions in coding regions of annotated isolates, was determined, along with amino acid (a.a.) property changes. Similar analysis was performed for the spike (S) protein in all the isolates (55 of them being predicted for the first time). The ratio Ka/Ks confirmed that the S gene was subjected to the Darwinian selection during virus transmission from animals to humans. Isolates from the dataset were classified according to genome polymorphism and genotypes. Genome polymorphism yields to two groups, one with a small number of SNVs and another with a large number of SNVs, with up to four subgroups with respect to insertions and deletions. We identified three basic nine-locus genotypes: TTTT/TTCGG, CGCC/TTCAT, and TGCC/TTCGT, with four subgenotypes. Both classifications proposed are in accordance with the new insights into possible epidemiological spread, both in space and time.

Amino Acid Sequence↗
PubMed1998

Antarctic fish hemoglobins: evidence for adaptive evolution at subzero temperature.

Notothenioids represent a large group of marine teleosts that are mostly endemic to the Antarctic Ocean. In this environment, the low metabolic demand and the high oxygen concentration reduce the need for hemoglobin(s) [Hb(s)]. The extreme condition is represented by the icefish (Channichthyidae, Notothenioidei), the only vertebrates that lack Hb. We obtained the nucleotide sequence coding for the beta-globin chain of the single major Hb form in six red-blooded notothenioids. These included Gymnodraco acuticeps, one of the closest species to the Hb-less icefish, which is also the only known fish having a single Hb without Bohr effect. This species shows a higher rate of nonsynonymous substitutions (KA), in contrast with the homogeneity of synonymous substitution (KS) rates, and KA/KS ratios significantly greater than one in the majority of comparisons. These results are suggestive of positive selection, diversifying the single major Hb toward specialized functions. A single Hb that is free to diversify means that its role in routine oxygen transport can be reduced in the presence of a combination of physiological, ecological, and environmental factors. Although a reduced "routine" function for Hb, as is apparent in G. acuticeps, might, indeed, evoke the lack of Hb in icefish, evidence of diversifying selection reported here is at variance with the hypothesis of a simple trend from a single Hb toward the Hb-less condition.

Adaptation, Physiological↗
PubMed1998

Nonsynonymous substitution in abalone sperm fertilization genes exceeds substitution in introns and mitochondrial DNA.

Strong positive Darwinian selection acts on two sperm fertilization proteins, lysin and 18-kDa protein, from abalone (Haliotis). To understand the phylogenetic context for this dramatic molecular evolution, we obtained sequences of mitochondrial cytochrome c oxidase subunit I (mtCOI), and genomic sequences of lysin, 18-kDa, and a G protein subunit. Based on mtDNA differentiation, four north Pacific abalone species diverged within the past 2 million years (Myr), and remaining north Pacific species diverged over a period of 4-20 Myr. Between-species nonsynonymous differences in lysin and 18-kDa exons exceed nucleotide differences in introns by 3.5- to 24-fold. Remarkably, in some comparisons nonsynonymous substitutions in lysin and 18-kDa genes exceed synonymous substitutions in mtCOI. Lysin and 18-kDa intron/exon segments were sequenced from multiple red abalone individuals collected over a 1,200-km range. Only two nucleotide changes and two sites of slippage variation were detected in a total of >29,000 nucleotides surveyed. However, polymorphism in mtCOI and a G protein intron was found in this species. This finding suggests that positive selection swept one lysin allele and one 18-kDa allele to fixation. Similarities between mtCOI and lysin gene trees indicate that rapid adaptive evolution of lysin has occurred consistently through the history of the group. Comparisons with mtCOI molecular clock calibrations suggest that nonsynonymous substitutions accumulate 2-50 times faster in lysin and 18-kDa genes than in rapidly evolving mammalian genes.

Animals↗
PubMed2005

Sequence variation and gene duplication at MHC DQB loci of baiji (Lipotes vexillifer), a Chinese river dolphin.

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 important role in the recognition of parasites. Baiji (Lipotes vexillifer) is one of the most endangered species in the world. Its wild population has declined to fewer than 100 individuals and has a very high risk of becoming extinct in the near future. In this study we present a first step in the molecular characterization of a DQB-like locus of baiji by nucleotide sequence analysis of the polymorphic exon 2 segments. In the examined 172 bp sequences from a group of 18 incidentally captured or stranded individuals, 48 variable sites were determined and 43 alleles were identified, many of which were represented by only one clone. Three to seven alleles were found in each individual, suggesting gene duplications. No deletion, insertion, or exceptional stop codon was detected, suggesting these alleles function in vivo. Phylogenetic reconstruction using neighbor joining grouped the 43 alleles into two distinct lineages, differing by seven nucleotides and four amino acids. Substitutions of amino acids tend to be clustered around sites postulated to be responsible for selective peptide recognition. In the peptide-binding region (PBR) of the DQB locus, the average number of nonsynonymous substitutions per site is greater than that of synonymous substitutions per site (0.1962 versus 0.0256, respectively). Nucleotide and amino acid sequences both showed a relatively high level of similarity (nucleotides 90.6%; amino acids 80.6%) to those of beluga whale (Delphinapterus leucas) and narwhal (Monodon monoceros). The high level of baiji MHC polymorphism revealed in the present study has not been reported in other cetaceans and could be a consequence of the small baiji population adapting to freshwater with a relatively high level of pathogens.

Amino Acid Sequence↗
PubMed1988

The structure and evolution of the spider monkey delta-globin gene.

We have isolated the delta-globin gene of the New-World spider monkey, Ateles geoffroyi, and compared its nucleotide sequence with those of other primate delta- and beta-globin genes. Among primate delta-globin genes, the rate of nonsynonymous substitutions is much less than the rate of synonymous substitutions. This suggests that primate delta-globin genes may remain under evolutionary conservation, perhaps because hemoglobin A2 has an as yet unknown physiological importance.

Amino Acid Sequence↗
PubMed1996

Evolution of hemopoietic ligands and their receptors. Influence of positive selection on correlated replacements throughout ligand and receptor proteins.

The rates of amino acid replacement in cytokines and their receptors are high and vary considerably. To determine whether this reflects the action of positive selection, rates of nonsynonymous DNA substitution were examined and found to exceed the synonymous substitution rate in certain exons of rodent IL-3, granulocyte-macrophage stimulating factor, and IL-4. To determine the extent to which positive selection could account for correlations between the amino acid replacement rates of hemopoietins and their receptors, rates were examined in various domains: the correlation with ligand rate was not confined to the ligand-binding domain of the receptor, but extended into the transmembrane and cytoplasmic domains and even to leader peptide domains of both ligand and receptor. As the majority of these replacements are unlikely to be strongly advantageous, different levels of both positive and purifying selection contribute to the extensive variation in hemopoietin/receptor evolutionary rates. Changes in a few residues critical for ligand-receptor interaction may be followed by changes of lesser selective importance in both molecules: replacements of growth hormone residues that form hydrogen or salt bridges with the receptor occur in lineages in which there are many concurrent replacements. A ligand/receptor rate correlation is not found between the seven-transmembrane receptors and their ligands, whose mature forms are often short and completely conserved. This study predicts that a minority of concurrent evolutionary changes in hemopoietins and their receptors reflect directly compensatory changes.

Amino Acids↗
PubMed1999

Synonymous and nonsynonymous substitution rates in diatoms: a comparison between chloroplast and nuclear genes.

Rates of synonymous and nonsynonymous nucleotide substitutions and codon usage bias (ENC) were estimated for a number of nuclear and chloroplast genes in a sample of centric and pennate diatoms. The results suggest that DNA evolution has taken place, on an average, at a slower rate in the chloroplast genes than in the nuclear genes: a rate variation pattern similar to that observed in land plants. Synonymous substitution rates in the chloroplast genes show a negative association with the degree of codon usage bias, suggesting that genes with a higher degree of codon usage bias have evolved at a slower rate. While this relationship has been shown in both prokaryotes and multicellular eukaryotes, it has not been demonstrated before in diatoms.

Cell Nucleus↗
PubMed1994

Natural selection at the class II major histocompatibility complex loci of mammals.

The role of natural selection at major histocompatibility complex (MHC) loci was studied by analysis of molecular sequence data from mammalian class II MHC loci. As found previously for the class I MHC molecule and a hypothetical model of the class II molecule, the rate of non-synonymous nucleotide substitution exceeded that of synonymous substitution in the codons encoding the antigen recognition site of polymorphic class II molecules. This pattern is evidence that the polymorphism at these loci is maintained by a form of balancing selection, such as overdominant selection. By contrast, in the case of monomorphic class II loci, no such enhancement of the rate of non-synonymous substitution was observed. Phylogenetic analysis indicates that, in contrast to monomorphic ('non-classical') class I MHC loci, some monomorphic class II loci of mammals are quite ancient. The DMA and DMB loci, for example, diverged before all other known mammalian class II loci, possibly before the divergence of tetrapods from bony fishes. Analysis of the patterns of sharing of polymorphic residues at class II MHC loci by mammals of different species revealed that extensive convergent evolution has occurred at these loci; but no support was found for the hypothesis that MHC polymorphisms have been maintained since before the divergence of orders of eutherian mammals.

Animals↗
PubMed2004

Ancestral loss of short wave-sensitive cone visual pigment in lorisiform prosimians, contrasting with its strict conservation in other prosimians.

Mammals are basically dichromatic in color vision, possessing middle to long wave-sensitive (M/LWS) and the short wave-sensitive (SWS) cone opsins in the retina, whereas some nocturnal mammals lack functional SWS opsins. Prosimians, primitive primates consisting of three extant groups (Lorisiformes, Lemuriformes, and Tarsiiformes), include many nocturnal species. Among nocturnal prosimians, a species of lorisiforms, the greater galago (Otolemur crassicaudatus), is known to lack a functional SWS opsin gene, while lemuriforms and tarsiiforms appear to retain SWS opsins in the retina. It has not been established, however, whether the loss of SWS opsin is a universal phenomenon among lorisiforms and whether the functional SWS opsin genes of lemuriforms and tarsiiforms are under strict or relaxed selective constraint. To gain better insight into an association between nocturnality and loss of SWS function, we isolated and sequenced the SWS opsin genes from two species of lorisiforms, the slow loris (Nycticebus coucang; nocturnal) and the lesser galago (Galago senegalensis; nocturnal), and one species each of lemuriforms and tarsiiforms, the brown lemur (Eulemur fulvus; cathemeral) and the western tarsier ( Tarsius bancanus; nocturnal), respectively. Our sequence analysis revealed that (1) the SWS opsin gene was disrupted in the common ancestor of galagids and lorisids and (2) the rate of nonsynonymous nucleotide substitution has been kept significantly lower than that of synonymous substitution in tarsier and lemur, demonstrating the presence of strict selective constraint on the SWS opsin genes in tarsiiforms and lemuriforms.

Animals↗
PubMed1996

Large-scale search for genes on which positive selection may operate.

We conducted a systematic search for the candidate genes on which positive selection may operate, on the premise that for such genes the number of nonsynonymous substitution is expected to be larger than that of synonymous substitutions when the nucleotide sequences of genes under investigation are compared with each other. By obtaining 3,595 groups of homologous sequences from the DDBJ, EMBL, and GenBank DNA sequence databases, we found that 17 gene groups can be the candidates for the genes on which positive selection may operate. Thus, such genes are found to occupy only about 0.5% of the vast number of gene groups so far available. Interestingly enough 9 out of the 17 gene groups were the surface antigens of parasites or viruses.

Amino Acid Sequence↗
PubMed2000

Rapid evolution of the family of CONSTANS LIKE genes in plants.

A family of CONSTANS LIKE genes (COLs) has recently been identified in Arabidopsis thaliana and other plant species. CONSTANS, the first isolated member, is a putative zinc finger transcription factor that promotes the induction of flowering in A. thaliana in long photoperiods. Phylogenetic analysis of the COL family demonstrated that it is organized into a few distinct groups, some of which evolved before the divergence of gymnosperms and angiosperms. Molecular evolutionary analyses showed that COL genes within the Brassicaceae family evolve rapidly. The number of nonsynonymous substitutions was larger, and the ratio of nonsynonymous to synonymous substitutions was higher. The analysis also indicated that the rate of evolution is heterogeneous between different domains in the COL genes. The results support previous data indicating that plant regulatory genes evolve relatively fast and that the rate of evolution varies significantly between different regions of those genes. The rate of evolution of COL genes seems to have accelerated during later stages of evolution, possibly as an effect of frequent gene duplications.

Amino Acid Sequence↗
PubMed2000

An unusual form of purifying selection in a sperm protein.

Protamines are small, highly basic DNA-binding proteins found in the sperm of animals. Interestingly, the proportion of arginine residues in one type of protamine, protamine P1, is about 50% in mammals. Upon closer examination, it was found that both the total number of amino acids and the positions of arginine residues have changed considerably during the course of mammalian evolution. This evolutionary pattern suggests that protamine P1 is under an unusual form of purifying selection, in which the high proportion of arginine residues is maintained but the positions may vary. In this case, we would expect that the rate of nonsynonymous substitution is not particularly low compared with that of synonymous substitution, despite purifying selection. We would also expect that the selection for a high arginine content results in a high frequency of the nucleotide G in the coding region of this gene, because all six arginine codons contain at least one G. These expectations were confirmed in our study of mammalian protamine genes. Analysis of nonmammalian vertebrate genes also showed essentially the same patterns of evolutionary changes, suggesting that this unusual form of purifying selection has been active since the origin of bony vertebrates. The protamine gene of an insect species shows similar patterns, although its purifying selection is less intense. These observations suggest that arginine-rich selection is a general feature of protamine evolution. The driving force for arginine-rich selection appears to be the DNA-binding function of protamine P1 and an interaction with a protein kinase in the fertilized egg.

Amino Acid Sequence↗
PubMed2004

Detecting selection in noncoding regions of nucleotide sequences.

We present a maximum-likelihood method for examining the selection pressure and detecting positive selection in noncoding regions using multiple aligned DNA sequences. The rate of substitution in noncoding regions relative to the rate of synonymous substitution in coding regions is modeled by a parameter zeta. When a site in a noncoding region is evolving neutrally zeta = 1, while zeta > 1 indicates the action of positive selection, and zeta < 1 suggests negative selection. Using a combined model for the evolution of noncoding and coding regions, we develop two likelihood-ratio tests for the detection of selection in noncoding regions. Data analysis of both simulated and real viral data is presented. Using the new method we show that positive selection in viruses is acting primarily in protein-coding regions and is rare or absent in noncoding regions.

Base Sequence↗
PubMed1987

Sequence analysis of cDNAs for the human and bovine ATP synthase beta subunit: mitochondrial DNA genes sustain seventeen times more mutations.

We have cloned and sequenced human and bovine cDNAs for the beta subunit of the ATP synthase (ATP-syn beta), a nuclear DNA (nDNA) encoded oxidative phosphorylation (OXPHOS) gene. The two cDNAs were found to share 99% amino acid homology and 94% nucleotide homology. The evolutionary rate of ATPsyn beta was then compared with that of two mitochondrial DNA (mtDNA) ATP synthase genes (ATPase 6 and 8), seven other mtDNA OXPHOS genes, and a number of nuclear genes. The synonymous substitution rate for ATPsyn beta proved to be 1.9 x 10(-9) substitutions per site per year (substitutions x site-1 x year-1) (SSY). This is less than 1/2 that of the average nDNA gene, 1/12 the rate of ATPase 6 and 8, and 1/17 the rate of the average mtDNA gene. The synonymous and replacement substitution rates were used to calculate a new parameter, the "selective constraint ratio". This revealed that even the most variable mtDNA protein was more constrained than the average nDNA protein. Thus, the high substitution mutation rate and strong selective constraints of mammalian mtDNA proteins suggest that mtDNA mutations may result in a disproportionately large number of human hereditary diseases of OXPHOS.

Amino Acid Sequence↗
PubMed1997

Comparative evolutionary rates of introns and exons in murine rodents.

Analysis of DNA sequences of 132 introns and 140 exons from 42 pairs of orthologous genes of mouse and rat was used to compare patterns of evolutionary change between introns and exons. The mean of the absolute difference in length (measured in base pairs) between the two species was nearly five times as high in the case of introns as in the case of exons. The average rate of nucleotide substitution in introns was very similar to the rate of synonymous substitution in exons, and both were about three times the rate of substitution at nonsynonymous sites in exons. G+C content of introns and exons of the same gene were correlated; but mean G+C content at the third positions of exons was significantly higher than that of introns or positions 1-2 of exons from the same gene. G+C content was conserved over evolutionary time, as indicated by strong correlations between mouse and rat; but the change in G+C content was greatest at position 3 of exons, intermediate in introns, and lowest at positions 1-2 in introns.

Animals↗