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PubMed2000

[On the phylogenetic relationship of Corvinae birds (Aves, Corvidae) from data of partial sequencing of cytochrome b gene mitochondrial DNA].

To establish phylogenetic relationships within the corvine birds at the interspecific and intergeneric levels, the sequence of the mitochondrial DNA cytochrome b gene was analyzed. The NJ, UPGMA, and MP trees showed similar clustering. Relationships between the jungle crow, on the one hand, and the rook and Australian raven, on the other hand, were closer than between the jungle crow and the hooded and carrion crows. Mitochondrial genome of Australian raven displayed the closest similarity to the ancestral genome of the genus Corvus. Populations inhabiting the eastern part of the carrion crow C. corone orientations area were statistically significantly subdivided into three lineages. These data also confirmed the hypothesis on the location of the carrion crow ancestral lineage in the southeastern part of the area. In general, the transition and transversion substitution levels, their relationships, and distribution over codon positions were similar to that already reported for birds. Synonymous transitions in the third codon position were the prevailing substitution type. Using standard calibration scales, the time of divergence between species and genera within the corvine family was estimated to be 3.1-4 and 3.8-8.8 Myr, respectively. The divergence time between the examined corvine birds and birds of paradise constituted from 8 to 10 Myr.

Cytochrome b Group↗
PubMed2005

An empirical examination of the utility of codon-substitution models in phylogeny reconstruction.

Models of codon substitution have been commonly used to compare protein-coding DNA sequences and are particularly effective in detecting signals of natural selection acting on the protein. Their utility in reconstructing molecular phylogenies and in dating species divergences has not been explored. Codon models naturally accommodate synonymous and nonsynonymous substitutions, which occur at very different rates and may be informative for recent and ancient divergences, respectively. Thus codon models may be expected to make an efficient use of phylogenetic information in protein-coding DNA sequences. Here we applied codon models to 106 protein-coding genes from eight yeast species to reconstruct phylogenies using the maximum likelihood method, in comparison with nucleotide- and amino acid-based analyses. The results appeared to confirm that expectation. Nucleotide-based analysis, under simplistic substitution models, were efficient in recovering recent divergences whereas amino acid-based analysis performed better at recovering deep divergences. Codon models appeared to combine the advantages of amino acid and nucleotide data and had good performance at recovering both recent and deep divergences. Estimation of relative species divergence times using amino acid and codon models suggested that translation of gene sequences into proteins led to information loss of from 30% for deep nodes to 66% for recent nodes. Although computational burden makes codon models unfeasible for tree search in large data sets, we suggest that they may be useful for comparing candidate trees. Nucleotide models that accommodate the differences in evolutionary dynamics at the three codon positions also performed well, at much less computational cost. We discuss the relationship between a model's fit to data and its utility in phylogeny reconstruction and caution against use of overly complex substitution models.

Classification↗
PubMed1991

Molecular considerations in the evolution of bacterial genes.

Synonymous and nonsynonymous substitution rates at the loci encoding glyceraldehyde-3-phosphate dehydrogenase (gap) and outer membrane protein 3A (ompA) were examined in 12 species of enteric bacteria. By examining homologous sequences in species of varying degrees of relatedness and of known phylogenetic relationships, we analyzed the patterns of synonymous and nonsynonymous substitutions within and among these genes. Although both loci accumulate synonymous substitutions at reduced rates due to codon usage bias, portions of the gap and ompA reading frames show significant deviation in synonymous substitution rates not attributable to local codon bias. A paucity of synonymous substitutions in portions of the ompA gene may reflect selection for a novel mRNA secondary structure. In addition, these studies allow comparisons of homologous protein-coding sequences (gap) in plants, animals, and bacteria, revealing differences in evolutionary constraints on this glycolytic enzyme in these lineages.

Amino Acid Sequence↗
PubMed2003

[Mutations of fragile histidine triad gene in Peutz-Jeghers syndrome and canceration].

BACKGROUND & OBJECTIVE: Peutz-Jeghers syndrome (PJS) is an autosomal dominantly inherited disease. Fragile histidine triad (FHIT) gene is an important tumor suppressor gene at the fragile sites region of 3p14. The authors' previous study suggested that PJS patients might have a susceptible gene at the region of 3p14.2. This study was designed to reveal the relationship between the variant of FHIT gene in PJS and its canceration. METHOD: Mutations of FHIT gene in 15 PJS patients and 20 unaffected members in 6 PJS families were determined using denaturing high-performance liquid chromatography (DHPLC), polymerase chain reaction-single strand conformation polymorphism(PCR-SSCP) and DNA sequencing techniques. RESULTS: A non-sense mutation and a frame-shift mutation were identified at codon 54(GAA to TAA) (exon 6) which led to the change of the amino acid from glutamic acid (Glu) to stop codon, and a guanine insertion at codon 62 in exon 6 resulting in a premature stop codon TGA at codon 111 in one PJS patient. A homozygous deletion and a synonymous mutation were detected in exon 8. The homozygous deletion of exon 8 in FHIT gene was found in two polyps tissues and two cancerous tissues. And in 3 sporadic cases, the patients and their mothers have the same bands of SSCP and the same elution profiles of DHPLC when exon 8 was amplified. The DNA sequencing result showed that a synonymous mutation (polymorphism) occurred at codon 98 [CAT (H)-->CAC (H)], this mutation resulted in no change of amino acid. In addition, one base substitute from A to G mutation at 5'end, +42 nucleotide in intron 6 of FHIT gene was detected in seven patients and two unaffected members. CONCLUSION: PJS patients have low frequency point mutation of FHIT gene and their cancerous tissues had homozygous deletions in FHIT gene. This study indicated that the mutations and deletions of FHIT gene in PJS may play a role in the development of PJS and their cancerations.

Acid Anhydride Hydrolases↗
PubMed1996

Selection intensity for codon bias and the effective population size of Escherichia coli.

The selection intensity for codon bias and the synonymous diversity have been used in the recent literature to estimate the effective population size of Escherichia coli. The results have varied between (10)5 and (10)8. It is suggested here that most of this disparity can be explained by a model that accounts for the population structure of the species. Thus it is assumed that weakly selected characters, like synonymous substitutions, are selectively fixed within individual lines or colonies but spread throughout the population in an essentially neutral way when colonies replace one another. In this way, the effective population size that enters expressions for the codon bias will be that of an individual colony, which, if hitchhiking effects are considered, can be a very small number. The effective population size that appears together with the mutation rate in expressions for the synonymous diversity, on the other hand, will be related to the total number of colonies that make up the species and can be a very large number.

Codon↗
PubMed2006

Evolution of MHC class IIB in the genome of wild and ornamental guppies, Poecilia reticulata.

This is the first study to quantify genomic sequence variation of the major histocompatibility complex (MHC) in wild and ornamental guppies, Poecilia reticulata. We sequenced 196-219 bp of exon 2 MHC class IIB (DAB) in 56 wild Trinidadian guppies and 14 ornamental strain guppies. Each of two natural populations possessed high allelic richness (15-16 alleles), whereas only three or fewer DAB alleles were amplified from ornamental guppies. The disparity in allelic richness between wild and ornamental fish cannot be fully explained by fixation of alleles by inbreeding, nor by the presence of non-amplified sequences (ie null alleles). Rather, we suggest that the same allele is fixed at duplicated MHC DAB loci owing to gene conversion. Alternatively, the number of loci in the ornamental strains has contracted during >100 generations in captivity, a hypothesis consistent with the accordion model of MHC evolution. We furthermore analysed the substitution patterns by making pairwise comparisons of sequence variation at the putative peptide binding region (PBR). The rate of non-synonymous substitutions (dN) only marginally exceeded synonymous substitutions (dS) in PBR codons. Highly diverged sequences showed no evidence for diversifying selection, possibly because synonymous substitutions have accumulated since their divergence. Also, the substitution pattern of similar alleles did not show evidence for diversifying selection, plausibly because advantageous non-synonymous substitutions have not yet accumulated. Intermediately diverged sequences showed the highest relative rate of non-synonymous substitutions, with dN/dS>14 in some pairwise comparisons. Consequently, a curvilinear relationship was observed between the dN/dS ratio and the level of sequence divergence.

Alleles↗
PubMed2002

Yersinia enterocolitica type III secretion: mutational analysis of the yopQ secretion signal.

Pathogenic Yersinia spp. secrete Yop proteins via the type III pathway. yopQ codons 1 to 15 were identified as a signal necessary and sufficient for the secretion of a fused reporter protein. Frameshift mutations that alter codons 2 to 15 with little alteration of yopQ mRNA sequence do not abolish type III transport, suggesting a model in which yopQ mRNA may provide a signal for secretion (D. M. Anderson and O. Schneewind, Mol. Microbiol. 31:1139-1148, 2001). In a recent study, the yopE signal was truncated to codons 1 to 12. All frameshift mutations introduced within the first 12 codons of yopE abolished secretion. Also, multiple synonymous mutations that changed the mRNA sequence of yopE codons 1 to 12 without altering the amino acid sequence did not affect secretion. These results favor a model whereby an N-terminal signal peptide initiates YopE into the type III pathway (S. A. Lloyd et al., Mol. Microbiol. 39:520-531, 2001). It is reported here that codons 1 to 10 of yopQ act as a minimal secretion signal. Further truncation of yopQ, either at codon 10 or at codon 2, abolished secretion. Replacement of yopQ AUG with either of two other start codons, UUG or GUG, did not affect secretion. However, replacement of AUG with CUG or AAA and initiating translation at the fusion site with npt did not permit Npt secretion, suggesting that the translation of yopQ codons 1 to 15 is a prerequisite for secretion. Frameshift mutations of yopQ codons 1 to 10, 1 to 11, and 1 to 12 abolished secretion signaling, whereas frameshift mutations of yopQ codons 1 to 13, 1 to 14, and 1 to 15 did not. Codon changes at yopQ positions 2 and 10 affected secretion signaling when placed within the first 10 codons but had no effect when positioned in the larger fusion of yopQ codons 1 to 15. An mRNA mutant of yopQ codons 1 to 10, generated by a combination of nine synonymous mutations, was defective in secretion signaling, suggesting that the YopQ secretion signal is not proteinaceous. A model is discussed whereby the initiation of YopQ polypeptide into the type III pathway is controlled by properties of yopQ mRNA.

3' Untranslated Regions↗
PubMed2002

Complete cDNA sequences of the HLA-DRB1*14011, *1402, *1403 and *1404 alleles.

Sequencing studies of HLA class II molecules have been focused almost exclusively on the highly polymorphic exon 2. In this study the complete cDNA sequence of four alleles of the DR14 lineage (DR52 group) are reported for the first time. The HLA-DRB1*1402 and *1403 sequences were shown to be identical to the previously determined DRB1*13011 sequence, also of the DR52 group, in exons 1, 3, 4, 5 and 6. HLA-DRB1*14011 and *1404 were identical to DRB1*13011 in exons 1, 4, 5 and 6 sequences while they showed specific features within their exon 3 sequence. Both alleles showed a synonymous substitution at the third base of codon 114. However, DRB1*14011 also has a non-synonymous substitution at the first base of codon 112 which results in a histidine to tyrosine substitution. This is a novel substitution as Histidine 112 is conserved in all known HLA class II B genes.

Alleles↗
PubMed2005

Context-dependent codon bias and messenger RNA longevity in the yeast transcriptome.

Context-dependent codon bias and its relationship with messenger RNA (mRNA) longevity was examined in 4,648 mRNA transcripts of the Saccharomyces cerevisiae transcriptome for which mRNA half-lives have been empirically determined. Surprisingly, rare codon usage (codons used <13 times per 1,000 codons in the genome) increased with mRNA half-life. However, it is shown that this pattern was not due to preference for rare codon use within codon families containing both rare and nonrare codons. Rather, the pattern was due to an increase in the frequency of amino acids encoded solely by rare codons, and a decrease in the frequency of amino acids never encoded by rare codons, with mRNA half-life. When standardized by open reading frame length, the use of consecutive rare codons was also positively correlated with mRNA half-life. There was negative correlation between the usage of synonymous A|T dinucleotides spanning codon boundaries and mRNA half-life, despite the fact that the frequency of AT dinucleotide usage overall, and AT dinucleotide usage at other codon position contexts (e.g., 1-2, 2-3, or 3|1 total), was not correlated with mRNA half-life. The use of A|T dinucleotides at synonymous dicodon boundaries could potentially allow for more efficient 3'-5' degradation by endonucleolytic cleavage.

Codon↗
PubMed2004

Variation of the prion gene in chimpanzees and its implication for prion diseases.

In humans, familial prion diseases are linked to mutations in the PRNP gene. We have sequenced part of this gene in a large sample of common chimpanzee, Pan troglodytes (n=130 chromosomes). No variation in codons 129 and 219 has been observed: all chimpanzees were homozygous for the Met allele, which in humans increases susceptibility to Creutzfeldt-Jakob disease. We found two sequence variants: one is a synonymous polymorphism unique to the chimpanzee at codon 226, TAC to TAT (Y), with a TAC allele frequency of 80.6%; the other is a non-synonymous change at codon 148 (R148H) that falls in the target epitope for some common commercial antibodies used for prion diagnostics, and is highly conserved across species. The pathogenicity of this mutation is still unknown.

Amino Acid Sequence↗
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↗
PubMed2001

A survey of the molecular evolutionary dynamics of twenty-five multigene families from four grass taxa.

We surveyed the molecular evolutionary characteristics of 25 plant gene families, with the goal of better understanding general processes in plant gene family evolution. The survey was based on 247 GenBank sequences representing four grass species (maize, rice, wheat, and barley). For each gene family, orthology and paralogy relationships were uncertain. Recognizing this uncertainty, we characterized the molecular evolution of each gene family in four ways. First, we calculated the ratio of nonsynonymous to synonymous substitutions (d(N)/d(S)) both on branches of gene phylogenies and across codons. Our results indicated that the d(N)/d(S) ratio was statistically heterogeneous across branches in 17 of 25 (68%) gene families. The vast majority of d(N)/d(S) estimates were <<1.0, suggestive of selective constraint on amino acid replacements, and no estimates were >1.0, either across phylogenetic lineages or across codons. Second, we tested separately for nonsynonymous and synonymous molecular clocks. Sixty-eight percent of gene families rejected a nonsynonymous molecular clock, and 52% of gene families rejected a synonymous molecular clock. Thus, most gene families in this study deviated from clock-like evolution at either synonymous or nonsynonymous sites. Third, we calculated the effective number of codons and the proportion of G+C synonymous sites for each sequence in each gene family. One or both quantities vary significantly within 18 of 25 gene families. Finally, we tested for gene conversion, and only six gene families provided evidence of gene conversion events. Altogether, evolution for these 25 gene families is marked by selective constraint that varies among gene family members, a lack of molecular clock at both synonymous and nonsynonymous sites, and substantial variation in codon usage.

DNA↗
PubMed2006

A "silent" polymorphism in the MDR1 gene changes substrate specificity.

Synonymous single-nucleotide polymorphisms (SNPs) do not produce altered coding sequences, and therefore they are not expected to change the function of the protein in which they occur. We report that a synonymous SNP in the Multidrug Resistance 1 (MDR1) gene, part of a haplotype previously linked to altered function of the MDR1 gene product P-glycoprotein (P-gp), nonetheless results in P-gp with altered drug and inhibitor interactions. Similar mRNA and protein levels, but altered conformations, were found for wild-type and polymorphic P-gp. We hypothesize that the presence of a rare codon, marked by the synonymous polymorphism, affects the timing of cotranslational folding and insertion of P-gp into the membrane, thereby altering the structure of substrate and inhibitor interaction sites.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Analysis of the mitochondrial genome of cheetahs (Acinonyx jubatus) with neurodegenerative disease.

The complete mitochondrial genome of Acinonyx jubatus was sequenced and mitochondrial DNA (mtDNA) regions were screened for polymorphisms as candidates for the cause of a neurodegenerative demyelinating disease affecting captive cheetahs. The mtDNA reference sequences were established on the basis of the complete sequences of two diseased and two nondiseased animals as well as partial sequences of 26 further individuals. The A. jubatus mitochondrial genome is 17,047-bp long and shows a high sequence similarity (91%) to the domestic cat. Based on single nucleotide polymorphisms (SNPs) in the control region (CR) and pedigree information, the 18 myelopathic and 12 non-myelopathic cheetahs included in this study were classified into haplotypes I, II and III. In view of the phenotypic comparability of the neurodegenerative disease observed in cheetahs and human mtDNA-associated diseases, specific coding regions including the tRNAs leucine UUR, lysine, serine UCN, and partial complex I and V sequences were screened. We identified a heteroplasmic and a homoplasmic SNP at codon 507 in the subunit 5 (MTND5) of complex I. The heteroplasmic haplotype I-specific valine to methionine substitution represents a nonconservative amino acid change and was found in 11 myelopathic and eight non-myelopathic cheetahs with levels ranging from 29% to 79%. The homoplasmic conservative amino acid substitution valine to alanine was identified in two myelopathic animals of haplotype II. In addition, a synonymous SNP in the codon 76 of the MTND4L gene was found in the single haplotype III animal. The amino acid exchanges in the MTND5 gene were not associated with the occurrence of neurodegenerative disease in captive cheetahs.

Acinonyx↗
PubMed1981

Estimation of evolutionary distances between homologous nucleotide sequences.

By using two models of evolutionary base substitutions--"three-substitution-type" and "two-frequency-class" models--some formulae are derived which permit a simple estimation of the evolutionary distances (and also the evolutionary rates when the divergence times are known) through comparative studies of DNA (and RNA) sequences. These formulae are applied to estimate the base substitution rates at the first, second, and third positions of codons in genes for presomatotropins, preproinsulins, and alpha- and beta-globins (using comparisons involving mammals). Also, formulae for estimating the synonymous component (at the third codon position) and the standard errors are obtained. It is pointed out that the rates of synonymous base substitutions not only are very high but also are roughly equal to each other between genes even when amino acid-altering substitution rates are quite different and that this is consistent with the neutral mutation-random drift hypothesis of molecular evolution.

Animals↗
PubMed2000

Viral genetic heterogeneity in HIV-1-infected individuals is associated with increasing use of HAART and higher viremia.

OBJECTIVE: To assess the correlation between the outgrowth of mutant viruses (viral genetic heterogeneity), highly active antiretroviral therapy (HAART), and plasma HIV-1 RNA in a population-based observational cohort study. DESIGN: The study population consisted of 42 HIV-1-infected individuals receiving at least two nucleotide reverse transcriptase (RT) inhibitors and one or more protease inhibitors at study entry. There were no restrictions on antiretroviral therapy after enrollment. METHODS: Plasma samples were obtained from subjects at baseline, at therapy changes, and at quarterly intervals for quantitation of HIV-1 RNA levels and for sequence determination of the entire protease coding region and the first 235 codons of the reverse transcriptase coding region. Data were analyzed using the generalized estimating equation method for longitudinal data and using linear regression analysis. RESULTS: With increased time on HAART there were significant increases in the number of total HIV-1 mutations in the regions sequenced (P = 0.010). There were significant correlations between the increases in the plasma HIV-1 RNA levels and the numbers of total mutations and reverse transcriptase mutations (P = 0.007 and 0.021, respectively). CONCLUSIONS: The number of HIV-1 mutations increased over time. Failure of HAART in this study population was correlated with outgrowth of virus with numerous mutations in the reverse transcriptase and protease coding regions. Phenotypic results correlated with genotypic results, showing decreased susceptibility to antiretrovirals over time in the majority of this population during HAART. Both synonymous and non-synonymous mutations were observed, with a higher incidence of non-synonymous mutations occurring at codons associated with drug resistance.

Adult↗
PubMed2004

Low frequency of deafness-associated GJB2 variants in Kenya and Sudan and novel GJB2 variants.

A large proportion of non-syndromic autosomal recessive deafness (NSARD) in many populations is caused by variants of the GJB2 gene. Here, the frequency of GJB2 variants was studied in 406 and 183 apparently unrelated children from Kenya and Sudan, respectively, with mostly severe to profound non-syndromic deafness. Nine (2.2 %) Kenyan and 12 (6.6 %) of the Sudanese children only were carriers of variants within the coding sequence of the GJB2 gene. Variants in the 5'-adjacent region were detected in further 115 individuals. A total of 10 novel variants was recognized, among them four variants in the adjacent 5'-region of the GJB2 coding exon 2 (g.3318-6T>A, g.3318-15C>T, g.3318-34C>T, g.3318-35T>G), a 6 base-pair deletion (g.3455_3460del [p.Asp46_Gln48delinsGlu]), a variant leading to a stop codon (g.3512C>A [p.Tyr65X]), synonymous variants (g.3395C>T [p.Thr26], g.3503C>T [p.Asn62], g.3627A>C [p.Arg104]), and one non-synonymous variant (g.3816C>A [p.Val167Met]). In addition, the previously described variants g.3352delG (commonly designated 30delG or 35 delG), g.3426G>A [p.Val37Ile], g.3697G>A [p.Arg127His], g.3774G>A [p.Val153Ile], and g.3795G>A [p.Gly160Ser] were identified. With the exception of g.3318-34C>T and g.3352delG, all variants occurred heterozygously. For most of the variants identified in the Kenyan and Sudanese study population, a causative association with NSARD appears to be unlikely. Compared to many other ethnic groups, deafness-associated variants of the coding region of GJB2 are rare in Sudan and Kenya, suggesting a role of other genetic, or epigenetic factors as a cause for deafness in these countries.

Age of Onset↗