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PubMed2001

Inference and prediction of courses of the diseases caused by pathologic viruses by estimating molecular evolution of within-host virus.

A new approach for inferring the evolutionary process of within-host virus is presented in this study. This approach includes a sequential-linking algorithm developed by us that can deal with the sequential viral samples that are obtained at different time points from the same host, and reconstruct a longitudinal phylogenetic tree in which the evolutionary relations between viral variants can be shown. A codon-based model, which uses a Markov process to describe substitutions between codons, is also employed in this approach to calculate synonymous and non-synonymous substitution rates and to distinguish positive selection and neutral evolution. The approach is applied to a data set of the V3 region of the HIV-1 envelope genes sequenced in different years after infection of a single patient. The results suggest that this approach may provide a more realistic description of viral evolution than the traditional evolution models because it accounts for both neutral and adaptive evolution. Most important of all, since this approach make it possible to follow up the evolutionary process of within-host virus by analyzing the sequential viral samples, it could be used in inference and prediction of the course of the diseases caused by pathologic viruses and evaluation of the treatment.

Algorithms↗
PubMed2025

Translation of the downstream ORF from bicistronic mRNAs by human cells: Impact of codon usage and splicing in the upstream ORF.

Biochemistry textbooks describe eukaryotic mRNAs as monocistronic. However, increasing evidence reveals the widespread presence and translation of upstream open reading frames preceding the "main" ORF. DNA and RNA viruses infecting eukaryotes often produce polycistronic mRNAs and viruses have evolved multiple ways of manipulating the host's translation machinery. Here, we introduce an experimental model to study gene expression regulation from virus-like bicistronic mRNAs in human cells. The model consists of a short upstream ORF and a reporter downstream ORF encoding a fluorescent protein. We have engineered synonymous variants of the upstream ORF to explore large parameter space, including codon usage preferences, mRNA folding features, and splicing propensity. We show that human translation machinery can translate the downstream ORF from bicistronic mRNAs, albeit reporter protein levels are thousand times lower than those from the upstream ORF. Furthermore, synonymous recoding of the upstream ORF exclusively during elongation significantly influences its own translation efficiency, reveals cryptic splice signals, and modulates the probability of downstream ORF translation. Our results are consistent with a leaky scanning mechanism facilitating downstream ORF translation from bicistronic mRNAs in human cells, offering new insights into the role of upstream ORFs in translation regulation.

Humans↗
PubMed1992

Molecular analysis of genetic mutation in electrophoretic variant of human lactate dehydrogenase-A(M) subunit.

An electrophoretic variant of lactate dehydrogenase-A (M) subunit was discovered in a patient with multiple myeloma. DNA analysis of the variant allele revealed a nucleotide substitution (transition) of C to T at codon 314 (CGT-TGT), and this mutation resulted in the replacement of an arginine by a cysteine (R314C). This amino acid replacement affects the net charge of the subunit and makes the LDH-A variant have a faster electrophoretic mobility. The responsible missense mutation created a new restriction site, AGGCCT, which can be simply detected by endonuclease AatI digestion. In addition, four synonymous substitutions with no amino-acid replacements were found at codons 51, 119, 163 and 175 in the LDH-A gene from the patient.

Aged↗
PubMed1996

Synonymous substitutions in the Xdh gene of Drosophila: heterogeneous distribution along the coding region.

The Xdh (rosy) region of Drosophila subobscura has been sequenced and compared to the homologous region of D. pseudoobscura and D. melanogaster. Estimates of the numbers of synonymous substitutions per site (Ks) confirm that Xdh has a high synonymous substitution rate. The distributions of both nonsynonymous and synonymous substitutions along the coding region were found to be heterogeneous. Also, no relationship has been detected between Ks estimates and codon usage bias along the gene, in contrast with the generally observed relationship among genes. This heterogeneous distribution of synonymous substitutions along the Xdh gene, which is expression-level independent, could be explained by a differential selection pressure on synonymous sites along the coding region acting on mRNA secondary structure. The synonymous rate in the Xdh coding region is lower in the D. subobscura than in the D. pseudoobscura lineage, whereas the reverse is true for the Adh gene.

Animals↗
PubMed2006

PrP genotypes of atypical scrapie cases in Great Britain.

Great Britain and elsewhere have detected atypical scrapie infection in sheep with PrP genotypes thought to be genetically resistant to the classical form of scrapie. DNA sequencing of the PrP gene of British atypical scrapie cases (n=69), classical scrapie cases (n=59) and scrapie-free controls (n=138) was undertaken to identify whether PrP variants, other than the three well-characterized polymorphic codons, influenced susceptibility to atypical scrapie infection. Four non-synonymous changes, M112T, M137T, L141F and P241S, were detected that are most probably associated with the A(136)R(154)Q(171) haplotype. Only the PrP variant containing a phenylalanine residue at amino acid position 141 was found to be associated more commonly with the atypical scrapie cases. In addition to the single nucleotide polymorphisms associated with the ARQ allele, two out of nine atypical scrapie cases with the ARR/ARR genotype were found to contain a 24 bp insertion, leading to an additional octapeptide repeat. In terms of PrP genetics, one classification of the GB scrapie cases examined in this study would place animals carrying any homozygous or heterozygous combination of ARR, AHQ or AF(141)RQ alleles, or any one of these alleles when paired with ARQ, as being susceptible to atypical scrapie infection, and animals heterozygous or homozygous for VRQ or homozygous for ARQ as being susceptible to classical scrapie disease. The AHQ PrP allele was associated with the highest incidence of atypical scrapie (263 per 100 000 alleles), whilst VRQ was associated with the lowest incidence (10 per 100 000 alleles).

Alleles↗
PubMed2000

Evolution of circulating wild poliovirus and of vaccine-derived poliovirus in an immunodeficient patient: a unifying model.

We determined nucleotide sequences of the VP1 and 2AB genes and portions of the 2C and 3D genes of two evolving poliovirus lineages: circulating wild viruses of T geotype and Sabin vaccine-derived isolates from an immunodeficient patient. Different regions of the viral RNA were found to evolve nonsynchronously, and the rate of evolution of the 2AB region in the vaccine-derived population was not constant throughout its history. Synonymous replacements occurred not completely randomly, suggesting the need for conservation of certain rare codons (possibly to control translation elongation) and the existence of unidentified constraints in the viral RNA structure. Nevertheless the major contribution to the evolution of the two lineages came from linear accumulation of synonymous substitutions. Therefore, in agreement with current theories of viral evolution, we suggest that the majority of the mutations in both lineages were fixed as a result of successive sampling, from the heterogeneous populations, of random portions containing predominantly neutral and possibly adverse mutations. As a result of such a mode of evolution, the virus fitness may be maintained at a more or less constant level or may decrease unless more-fit variants are stochastically generated. The proposed unifying model of natural poliovirus evolution has important implications for the epidemiology of poliomyelitis.

Adolescent↗
PubMed2005

ERCC1 codon 118 polymorphism is a predictive factor for the tumor response to oxaliplatin/5-fluorouracil combination chemotherapy in patients with advanced colorectal cancer.

PURPOSE: The aim of our study was to assess whether the polymorphism of the nucleotide excision repair enzyme, excision repair cross-complementing rodent repair deficiency, complementation group 1 (ERCC1), had an effect on the tumor response in patients treated with standard chemotherapy regimens for a metastatic colorectal cancer. We have studied the synonymous polymorphism that causes a single nucleotide change C to T at codon 118 converting a codon of common usage (AAC) to a less used codon (AAT), both coding asparagine. This change results in a decreased ERCC1 gene expression, which impairs repair activity. EXPERIMENTAL DESIGN: Ninety-one patients with a median age of 55.1 years treated for a metastatic colorectal cancer were included in our retrospective study. The ERCC1 polymorphism was analyzed in the normal tissue of all patients. RESULTS: Twenty (22%) were homozygous for AAC codon (C/C genotype), 30 were (33%) homozygous for AAT codon (T/T genotype), and 41 (45%) were heterozygous (C/T genotype). The objective response rate to oxaliplatin in combination with 5-fluorouracil (5-FU) was significantly higher in the T/T genotype group compared with the C/T and the C/C genotype groups (61.9%, 42.3%, and 21.4%, respectively; P = 0.018). By contrast, no significant difference was observed when patients were treated with either 5-FU alone (45%, 29.2%, and 33.3%, respectively; P = 0.407) or in combination with irinotecan (46.1%, 25.0%, and 27.3%, respectively; P = 0.305). CONCLUSIONS: Our observations allowed us to define the first useful predictive criterion for oxaliplatin/5-FU response in patients with metastatic colorectal cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Genomic background drives the divergence of duplicated amylase genes at synonymous sites in Drosophila.

In some Drosophila species, there are two types of greatly diverged amylase (Amy) genes (Amy clusters 1 and 2), each encoding active amylase isozymes. Cluster 1 is located at the middle of its chromosomal arm, and the region has a normal local recombination rate. However, cluster 2 is near the centromere, and this region is known to have a reduced recombination rate. Although nonsynonymous substitutions follow a molecular clock, synonymous substitutions were accelerated in cluster 2 after gene duplications. This resulted in a higher GC content at the third codon position (GC3) and codon usage bias in cluster 1, and lower GC3 content and codon usage bias in the cluster 2. However, no systematic difference in GC content was observed in the first and second codon positions or the 3'-flanking regions. Therefore, differences in local recombination rate rather than mutation bias might explain the divergence at synonymous sites between the two Amy clusters within species (Hill-Robertson effect). Alternatively, the different patterns and levels of expression between the two clusters may imply that the reduced expression level in cluster 2 caused by chromatin potentiation decreased the codon bias. Both of these hypotheses imply the importance of the genomic background as a driving force of divergence between non-tandemly duplicated genes.

3' Flanking Region↗
PubMed2002

Codon-substitution models to detect adaptive evolution that account for heterogeneous selective pressures among site classes.

The nonsynonymous to synonymous substitution rate ratio (omega = d(N)/d(S)) provides a sensitive measure of selective pressure at the protein level, with omega values <1, =1, and >1 indicating purifying selection, neutral evolution, and diversifying selection, respectively. Maximum likelihood models of codon substitution developed recently account for variable selective pressures among amino acid sites by employing a statistical distribution for the omega ratio among sites. Those models, called random-sites models, are suitable when we do not know a priori which sites are under what kind of selective pressure. Sometimes prior information (such as the tertiary structure of the protein) might be available to partition sites in the protein into different classes, which are expected to be under different selective pressures. It is then sensible to use such information in the model. In this paper, we implement maximum likelihood models for prepartitioned data sets, which account for the heterogeneity among site partitions by using different omega parameters for the partitions. The models, referred to as fixed-sites models, are also useful for combined analysis of multiple genes from the same set of species. We apply the models to data sets of the major histocompatibility complex (MHC) class I alleles from human populations and of the abalone sperm lysin genes. Structural information is used to partition sites in MHC into two classes: those in the antigen recognition site (ARS) and those outside. Positive selection is detected in the ARS by the fixed-sites models. Similarly, sites in lysin are classified into the buried and solvent-exposed classes according to the tertiary structure, and positive selection was detected at the solvent-exposed sites. The random-sites models identified a number of sites under positive selection in each data set, confirming and elaborating the results of the fixed-sites models. The analysis demonstrates the utility of the fixed-sites models, as well as the power of previous random-sites models, which do not use the prior information to partition sites.

Alleles↗
PubMed2026

Exploring the Mitochondrial Genomes of Phoebe Species (Lauraceae): Structural Dynamics and Functional Conservation.

Plant mitochondrial genomes (mitogenomes) vary markedly in size and architecture despite generally slow rates of sequence evolution. Phoebe is an ecologically and economically valuable genus of Lauraceae, yet its mitogenome diversity remains poorly characterized. In this study, we newly sequenced, assembled, and annotated the mitogenomes of three nationally protected Class II wild plants (P. bournei, P. chekiangensis, P. zhennan) from China and compared their mitogenomic characteristics. The three assemblies were resolved into representative circular configurations ranging from 808 to 864&#x2009;kb, with similar GC contents and conserved protein-coding capacity. Each mitogenome contained distinct 41 protein-coding genes, 27-28 transfer RNAs, and three ribosomal RNAs. Synteny analysis revealed extensive changes in homologous-block order and orientation despite substantial sequence homology among the three species. Abundant repeats occurred predominantly in noncoding regions, while plastid-derived fragments documented historical intracellular DNA transfer. The three species exhibited similar codon usage and predicted RNA-editing patterns, whereas low synonymous divergence limited inference from pairwise ratios. Phylogenetic analysis based on mitochondrial protein-coding genes recovered Phoebe as a well-supported monophyletic lineage. These results reveal substantial structural divergence accompanied by conserved nucleotide composition and coding capacity, providing valuable data for further understanding the evolutionary variation of plant mitogenomes of Phoebe and the Lauraceae.

Phoebe↗
PubMed2001

Parallel acceleration of evolutionary rates in symbiont genes underlying host nutrition.

The overproduction of essential amino acids by Buchnera aphidicola, the primary bacterial mutualist of aphids, is considered an adaptation for increased production of nutrients that are lacking in aphids' diet of plant sap. Given their shared role in host nutrition, amino acid biosynthetic genes of Buchnera are expected to experience parallel changes in selection that depend on host diet quality, growth rate, and population structure. This study evaluates the hypothesis of parallel selection across biosynthetic pathways by testing for correlated changes in evolutionary rates at biosynthetic genes of Buchnera. Previous studies show fast evolutionary rates at tryptophan biosynthetic genes among Buchnera associated with the aphid genus Uroleucon and suggest reduced purifying selection on symbiont nutritional functions in this aphid group. Here, we test for parallel rate acceleration at other amino acid biosynthetic genes of Buchnera-Uroleucon, including those for leucine (leuABC) and isoleucine/valine biosynthesis (ilvC). Ratios of nonsynonymous to synonymous substitutions (d(N)/d(S)) were estimated using codon-based maximum-likelihood methods that account for the extreme AT compositional bias of Buchnera sequences. A significant elevation in d(N)/d(S) at biosynthetic loci but not at two housekeeping genes sampled (dnaN and tuf) suggests reduced host-level selection on biosynthetic capabilities of Buchnera-Uroleucon. In addition, the discovery of trpEG pseudogenes in Buchnera-U. obscurum further supports reduced selection on amino acid biosynthesis.

Alcohol Oxidoreductases↗
PubMed1993

Molecular evolution of the Rh3 gene in Drosophila.

Previous investigations into the evolution of the Drosophila opsin gene family are extended by inter- and intraspecific DNA sequence comparisons of the Rh3 locus in the melanogaster subgroup and D. pseudoobscura. Two separate statistical tests of the neutral-mutation hypothesis suggest that random genetic drift is responsible for virtually all of the observed amino acid replacement substitutions within the melanogaster subgroup. Analyses incorporating the D. pseudoobscura sequences are enigmatic due to the accumulation of multiple substitutions, because the McDonald-Kreitman test is not applicable to species comparisons that approach mutational saturation. However, the data from D. pseudoobscura are not inconsistent with selective neutrality. The ratio of amino acid polymorphisms within species to fixed differences between species imply that there are approximately 31 possible neutral single-step amino-acid-replacement substitutions at this locus. Synonymous substitutions are unevenly distributed among the structural domains of the Rh3 gene. Patterns of synonymous polymorphism are analyzed with respect to GC content and codon bias, and are compared to other loci from the same species.

Amino Acid Sequence↗
PubMed1996

The divergence of major histocompatibility complex class I genes in Sciurus aberti.

Major histocompatibility complex (MHC) class I genes encode cell surface molecules that bind and present immunogenic peptides to cytolytic T lymphocytes. We have developed a model using the MHC (Scab) of tassel-eared squirrels, Sciurus aberti, to investigate the evolution of MHC genes in subspecies that have been effectively isolated in comparable, if not identical, environments. Class I cDNAs from single S. aberti aberti and S. aberti kaibabensis squirrels were cloned and sequenced. These two cDNA transcripts differed by nucleotide substitutions that were predominantly located in codons impacting the peptide binding site, and nonsynonymous substitutions exceeded synonymous substitutions at these sites. These sequences also differed by the insertion of two amino acids in a beta-strand adjacent to position 45 in pocket B of the peptide binding site that may result in a deeper pocket with altered peptide specificity. This indel is present in additional Scab class I sequences, and class I sequences in five subspecies carry identically sized insertions. Phylogenetic analyses of exons 2, 3, and 4 with neighbor-joining and maximum parsimony methods depict that Scab class I sequences diverged at a point intermediate between murid class I sequences and class I sequences of primates, carnivores, and artiodactyls. The relative relatedness of Scab class I sequences to those in the latter group appears to be founded in relative similarities in exons 2 and 3, which encode the peptide binding site. These results bring into question the use of a single model for rodent class I sequences. Moreover, they demonstrate that the inclusion of exons 2 and 3 in phylogenetic analyses of class I may obscure true phylogenetic relationships, perhaps due to convergence through strong selective pressure.

Amino Acid Sequence↗
PubMed1996

Protective immune responses to apical membrane antigen 1 of Plasmodium chabaudi involve recognition of strain-specific epitopes.

Apical membrane antigen 1 (AMA-1), an asexual blood-stage antigen of Plasmodium falciparum, is an important candidate for testing as a component of a malaria vaccine. This study investigates the nature of diversity in the Plasmodium chabaudi adami homolog of AMA-1 and the impact of that diversity on the efficacy of the recombinant antigen as a vaccine against challenge with a heterologous strain of P. chabaudi. The nucleotide sequence of the AMA-1 gene from strain DS differs from the published 556KA sequence at 79 sites. The large number of mutations, the nonrandom distribution of both synonymous and nonsynonymous mutations, and the nature of both the codon changes and the resulting amino acid substitutions suggest that positive selection operates on the AMA-1 gene in regions coding for antigenic sites. Protective immune responses induced by AMA-1 were strain specific. Immunization of mice with the refolded ectodomain of DS AMA-1 provided partial protection against challenge with virulent DS (homologous) parasites but failed to protect against challenge with avirulent 556KA (heterologous) parasites. Passive immunization of mice with rabbit antibodies raised against the same antigen had little effect on heterologous challenge but provided significant protection against the homologous DS parasites.

Amino Acid Sequence↗
PubMed2003

[Study on gene mutations of alpha-thalassemia in the South of China].

There is a high prevalence of thalassemia in the South of China. To explore the genotype of alpha-thalassemia as well as the distribution of alpha globin gene mutation in the South of China, 356 patients with heterozygote alpha(+) thalassemia, heterozygote alpha(0) or homozygote alpha(+) thalassemia and 78 patients with HbH were analyzed. The gene diagnosis methods including Gap-PCR, nested-PCR, PCR-RE, PCR-SSCP, 4P-ASPCR and DNA sequence analysis were used. The results showed that among 356 patients, 295 patients with --SEA/alphaalpha (82.87%), 1 patient with alphaalpha/alpha-alpha(3.7) (0.28%), 3 patients with alphaalpha/alpha-alpha(4.2) (0.84%), 3 patients with alphaalpha/alpha(CS)alpha (0.84%), 1 patient with alphaalpha/alphaalpha(QS) (0.28%) and 2 patients with alphaalpha/alpha(Westmead) alpha (0.56%) were found. The homozygote with -alpha(4.2) or -alpha(3.7) was not found. In 78 patients with HbH, 29 patients with --SEA/alphaalpha(-3.7) (37.2%), 20 patients with --SEA/alphaalpha(-4.2) (25.6%), 19 patients with --SEA/alphaalpha(CS) (24.3%), 2 patients with --SEA/alphaalpha(QS) (2.6%) were detected, and other remaiming 8 patients were needed to be defined. Among the non-defined 8 patients, the synonymous mutation with C-->G transversion (GCC-GCG) at codon 65 in the exon 2 of alpha 2-globin gene was detected in 2 unrelated HbH patients came from Guangxi province. Whether it correlated with the phenotype of HbH disease or it is only a single nucleotide polymorphism site (SNPs), should be confirmed in the future. In addition, a set of gene diagnosis methods based on PCR to screen deletion and non-deletion genotypes of alpha-thalassemia in Chinese was improved. A new method, 4P-ASPCR, to detect Hb CS and Hb QS was also developed. The method was verified to be more accurate, time-saving and economic. In conclusion, the genotypes of alpha-thalassemia in Chinese are very complicated, the genotypes of alpha-thalassemia in Chinese need to be further studied, the results of this research probably have practical significance for the gene diagnosis or antenatal diagnosis of alpha-thalassemia in the South of China.

Base Sequence↗
PubMed2005

Variation in the pattern of synonymous and nonsynonymous difference between two fungal genomes.

The proportion of synonymous nucleotide differences per synonymous site (p(S)) and the proportion of nonsynonymous differences per nonsynonymous site (p(N)) were computed at 1,993,217 individual codons in 4,133 protein-coding genes between the two yeast species Saccharomyces cerevisiae and Saccharomyces paradoxus. When the modified Nei-Gojobori method was used, significantly more codons with p(N) > p(S) were observed than expected, based on random pairing of observed p(S) and p(N) values. However, this finding was most likely explained by the presence of a strong negative correlation between the number of synonymous differences and the number of nonsynonymous differences at codons with at least one difference. As a result of this correlation, codons with p(N) > p(S) were characterized not only by unusually high p(N) but also by unusually low p(S). On the other hand, the number of codons with p(N)>p(S) (where p(S) is the mean p(S) for all codons) was very similar to the random expectation, and the observed number of 30-codon windows with p(N) > p(S) was significantly lower than the random expectation. These results imply that the occurrence of a certain number of codons or codon windows with p(N) > p(S) is expected given the nature of nucleotide substitution and need not imply the action of positive Darwinian selection.

Codon↗
PubMed2006

Selective pressures at a codon-level predict deleterious mutations in human disease genes.

Deleterious mutations affecting biological function of proteins are constantly being rejected by purifying selection from the gene pool. The non-synonymous/synonymous substitution rate ratio (omega) is a measure of selective pressure on amino acid replacement mutations for protein-coding genes. Different methods have been developed in order to predict non-synonymous changes affecting gene function. However, none has considered the estimation of selective constraints acting on protein residues. Here, we have used codon-based maximum likelihood models in order to estimate the selective pressures on the individual amino acid residues of a well-known model protein: p53. We demonstrate that the number of residues under strong purifying selection in p53 is much higher than those that are strictly conserved during the evolution of the species. In agreement with theoretical expectations, residues that have been noted to be of structural relevance, or in direct association with DNA, were among those showing the highest signals of purifying selection. Conversely, those changing according to a neutral, or nearly neutral mode of evolution, were observed to be irrelevant for protein function. Finally, using more than 40 human disease genes, we demonstrate that residues evolving under strong selective pressures (omega<0.1) are significantly associated (p<0.01) with human disease. We hypothesize that non-synonymous change on amino acids showing omega<0.1 will most likely affect protein function. The application of this evolutionary prediction at a genomic scale will provide an a priori hypothesis of the phenotypic effect of non-synonymous coding single nucleotide polymorphisms (SNPs) in the human genome.

Amino Acid Sequence↗
PubMed1986

Simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions.

Two simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions are presented. Although they give no weights to different types of codon substitutions, these methods give essentially the same results as those obtained by Miyata and Yasunaga's and by Li et al.'s methods. Computer simulation indicates that estimates of synonymous substitutions obtained by the two methods are quite accurate unless the number of nucleotide substitutions per site is very large. It is shown that all available methods tend to give an underestimate of the number of nonsynonymous substitutions when the number is large.

Amino Acid Sequence↗