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PubMed2004

SWAPSC: sliding window analysis procedure to detect selective constraints.

UNLABELLED: Sliding-window analysis procedure to detect selective constraints (SWAPSC) is a software system to dissect the constraints on the evolution of protein-coding genes. The program estimates rates of nucleotide substitutions at specific codon regions in each branch of a phylogenetic tree. The program uses several sets of simulated sequence alignments to estimate the probability of synonymous and non-synonymous nucleotide substitutions. Thereafter, a statistical analysis is conducted to determine the optimum window size to detect selective constraints. Finally, the optimum window size is slid along the real alignment and a test for significance of the estimated number of synonymous and non-synonymous nucleotide substitutions in each sliding step is conducted. A number of friendly useful output files is generated. AVAILABILITY: SWAPSC is available at http://www.may.ie/academic/biology/staff/mfmolecevolandbioinf.shtml distribution versions for both Linux and Windows operating systems are available, including manual and example files.

Algorithms↗
PubMed2004

[Dysferlinopathy as an extrahepatic cause for the elevation of serum transaminases].

BACKGROUND AND PURPOSE: The aim of the present report is to emphasize that the source of elevated transaminase levels, although usually indicative of hepatocellular damage, can also be of extrahepatic origin. CASE REPORT: A 42-year-old female presented with a moderate persistent elevation of the transaminases glutamic-oxaloacetic transaminase (GOT; synonym: aspartate aminotransferase [AST]) and glutamic-pyruvic transaminase (GPT; synonym: alanine aminotransferase [ALT]) in blood without any apparent clinical symptoms of liver affection. In the course of further diagnostics for clarification of a suspected liver disease, a markedly elevated activity of creatine kinase was found which, in concert with results from myography, magnetic resonance imaging (MRI) and analysis of muscle biopsies, suggested the tentative diagnosis of a distal myopathy type Miyoshi. The diagnosis was confirmed by identification of the underlying mutation in the dysferlin gene. The course of the disease has been slowly but steadily progressive; there is no therapeutic option at present. The relevance of molecular genetic analyses in the diagnostic procedure for distal myopathies, in particular dysferlinopathy, is discussed and the characteristics of this disease are summarized. CONCLUSION: In the case of persistent elevations of the serum transaminases GOT and GPT without liver disorder, a myopathy has to be taken into account as a potential extrahepatic source. In order to avoid needless nondirected expensive investigations and to prevent a delay in diagnostics, activity of serum creatine kinase should be determined which is moderately to strongly elevated in the case of myopathies. If, in particular, a dysferlinopathy is supposed, the underlying mutation should be identified to confirm the diagnosis and as a basis for current and future therapeutic interventions

Adult↗
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↗
PubMedDate not supplied

Genomic divergence between human and chimpanzee estimated from large-scale alignments of genomic sequences.

To study the genomic divergence between human and chimpanzee, large-scale genomic sequence alignments were performed. The genomic sequences of human and chimpanzee were first masked with the RepeatMasker and the repeats were excluded before alignments. The repeats were then reinserted into the alignments of nonrepetitive segments and entire sequences were aligned again. A total of 2.3 million base pairs (Mb) of genomic sequences, including repeats, were aligned and the average nucleotide divergence was estimated to be 1.22%. The Jukes-Cantor (JC) distances (nucleotide divergences) in nonrepetitive (1.44 Mb) and repetitive sequences (0.86 Mb) are 1.14% and 1.34%, respectively, suggesting a slightly higher average rate in repetitive sequences. Annotated coding and noncoding regions of homologous chimpanzee genes were also retrieved from GenBank and compared. The average synonymous and nonsynonymous divergences in 88 coding genes are 1.48% and 0.55%, respectively. The JC distances in intron, 5' flanking, 3' flanking, promoter, and pseudogene regions are 1.47%, 1.41%, 1.68%, 0.75%, and 1.39%, respectively. It is not clear why the genetic distances in most of these regions are somewhat higher than those in genomic sequences. One possible explanation is that some of the genes may be located in regions with higher mutation rates.

Animals↗
PubMedDate not supplied

[Characteristics of the context shift in the frequency of synonymic codons in Escherichia coli].

We have demonstrated, that coding regions of E. coli DNA exhibit the non-random shifts of codon usage frequency depending both on the type of the 3' nucleotide adjacent to the codon and the degree of gene expression. Analysis of primary data--statistics of tetranucleotide occurrences--was performed by the techniques of contingency tables. The results of the investigation allowed us to suggest that the phenomenon observed is connected with the influence of the 3'-adjacent nucleotide on the level of missens-errors and another types of inaccuracy during translation. The specific advantages of such mutations in the third position of the codon are based on the adaptation of the codon to the 3' context in order to increase the efficiency of translation.

Base Sequence↗
PubMed2006

Molecular evolution of hepatitis B virus over 25 years.

Determining the longitudinal molecular evolution of hepatitis B virus (HBV) is difficult due to HBV's genomic complexity and the need to study paired samples collected over long periods of time. In this study, serial samples were collected from eight hepatitis B virus e antigen-negative asymptomatic carriers of HBV genotype B in 1979 and 2004, thus providing a 25-year period to document the long-term molecular evolution of HBV. The rate, nature, and distribution of mutations that emerged over 25 years were determined by phylogenetic and linear regression analysis of full-length HBV genome sequences. Nucleotide hypervariability was observed within the polymerase and pre-S/S overlap region and within the core gene. The calculated mean number of nucleotide substitutions/site/year (7.9 x 10(-5)) was slightly higher than published estimates (1.5 x 10(-5) to 5 x 10(-5)). Nucleotide changes in the quasispecies population did not significantly alter the molecular evolutionary rate, based on linear regression analysis of evolutionary distances among serial clone pre-S region sequences. Therefore, the directly amplified or dominant sequence was sufficient to estimate the putative molecular evolutionary rate for these long-term serial samples. On average, the ratio of synonymous (dS) to nonsynonymous (dN) substitutions was highest for the polymerase-coding region and lowest for the core-coding region. The low dS/dN ratios observed within the core suggest that selection occurs within this gene region, possibly as an immune evasion strategy. The results of this study suggest that HBV sequence divergence may occur more rapidly than previously estimated, in a host immune phase-dependent manner.

Aged↗
PubMed2006

Pattern of nucleotide substitution and divergence of prophenoloxidase in decapods.

Despite the unprecedented development in identification and characterization of prophenoloxidase (proPO) in commercially important decapods, little is known about the evolutionary relationship, rate of amino acid replacement and differential selection pressures operating on proPO of different species of decapods. Here we report the evolutionary relationship among these nine decapod species based on proPO gene and types of selective pressures operating on proPO codon sites. Our analyses revealed that all the nine decapod species shared a common ancestor. The mean percentage sequence divergence at proPO gene was 34.4+/-0.6%. Pairwise estimates of nonsynonymous to synonymous ratio (omega) for Homarus americanus-H. gammarus is greater than one, therefore indicating adaptive evolution (functional diversification) of proPO in these two species. In contrast, strong purifying selection (omega<1) was observed in all other species pairs. However, phylogenetically closely related decapods revealed relatively higher omega value (omega=0.15+/-0.3) than the distantly related species pairs (omega=0.0075+/-0.005). These discrepancies could be due to higher fixation probability of beneficial mutation in closely related species. Maximum likelihood-based codon substitution analyses revealed a strong purifying selection operating on most of the codon sites, therefore suggesting proPO is functionally constrained (purifying selection). Codon substitution analyses have also revealed the evidence of strong purifying selection in haemocyanin subunits of decapods.

Animals↗
PubMed1994

Nonneutral evolution at the mitochondrial NADH dehydrogenase subunit 3 gene in mice.

The neutral theory of molecular evolution asserts that while many mutations are deleterious and rapidly eliminated from populations, those that we observe as polymorphisms within populations are functionally equivalent to each other and thus neutral with respect to fitness. Mitochondrial DNA (mtDNA) is widely used as a genetic marker in evolutionary studies and is generally assumed to evolve according to a strictly neutral model of molecular evolution. One prediction of the neutral theory is that the ratio of replacement (nonsynonymous) to silent (synonymous) nucleotide substitutions will be the same within and between species. We tested this prediction by measuring DNA sequence variation at the mitochondrially encoded NADH dehydrogenase subunit 3 (ND3) gene among 56 individual house mice, Mus domesticus. We also compared ND3 sequence from M. domesticus to ND3 sequence from Mus musculus and Mus spretus. A significantly greater number of replacement polymorphisms were observed within M. domesticus than expected based on comparisons to either M. musculus or M. spretus. This result challenges the conventional view that mtDNA evolves according to a strictly neutral model. However, this result is consistent with a nearly neutral model of molecular evolution and suggests that most amino acid polymorphisms at this gene may be slightly deleterious.

Amino Acid Sequence↗
PubMed1997

pol gene diversity of five human immunodeficiency virus type 1 subtypes: evidence for naturally occurring mutations that contribute to drug resistance, limited recombination patterns, and common ancestry for subtypes B and D.

Naturally occurring mutations in the polymerase gene of human immunodeficiency virus type 1 (HIV-1) have important implications for therapy and the outcome of clinical studies. Using 42 virus isolates obtained from the UNAIDS sample collection, we analyzed the protease (99 amino acids [aa]) and the first 297 aa of reverse transcriptase (RT) coding regions. Based on the V3 sequence analysis, the collection includes subtype A (n = 5), subtype B (n = 12), subtype C (n = 1), subtype D (n = 11), and subtype E (n = 13) viruses. Of the 42 protease genes, 37 contained naturally occurring mutations at positions in the gene that contribute to resistance to protease inhibitors (indinavir, saquinavir, ritonavir, and nelfinavir) in clade B isolates. The phenotypic effect of these substitutions in non-B isolates is unclear. The The 5'half RT coding region of the 42 isolates was found to be less variable, although 19 of the 42 RT sequences contained amino acid substitutions known to contribute to nucleoside and/or nonnucleoside drug resistance. Since the virus isolates were obtained in 1992, it is unlikely that the infected subjects received protease inhibitors, but we found evidence that one subject acquired a zidovudine (AZT)-resistant HIV-1 strain from a contact who had received AZT. Phylogenetic analysis identified five subtype pol clusters: A, B, C, D, and A'. Comparison of env and pol sequences of the same viruses showed no more recombination events than were already identified on the basis of gag/env comparison (M. Cornelissen, G. Kampinga, F. Zorgdrager, J. Goudsmit, and the UNAIDS Network for HIV Isolation and Characterization, J. Virol. 70:8209-8212, 1996). In one of the known recombinants, a crossover site between subtypes A and C could be identified, and in another, a crossover site could not be identified due to lack of a reference subtype F pol sequence. We analyzed the ds/da ratio of gag, pol, and env sequences of 35 isolates, excluding the recombinants. Our analysis showed that gag and pol are subjected to purifying selection with an average ds/da ratio above 1, independent of the subtype and in contrast with V3 (ds/da approximately 1). Based on the low ds/da ratio of the intergroup analysis of A/E and B/D gag and pol sequences, we analyzed the evolutionary relation between subtypes B and D in more detail by constructing separate phylogenetic trees for synonymous and nonsynonymous substitutions. Our analysis suggests a common ancestry for subtypes B and D that is distinct from that of subtypes A and E.

Amino Acid Sequence↗
PubMed1998

Quasispecies nature of three maize streak virus isolates obtained through different modes of selection from a population used to assess response to infection of maize cultivars.

Three maize streak virus (MSV) isolates were derived from an MSV population used to assess the response to infection of maize cultivars. Isolate SP1 was obtained from this population through short acquisition and inoculation periods (1 and 5 min, respectively), using a single Cicadulina mbila vector. Isolate SP2 was derived from SP1 after transmission to a wild perennial host (Coix lacryma-jobi), on which it was maintained for about 4 years without insect transmission. Isolate N2A, the most pathogenic isolate, was obtained from the initial population after serial passages on almost completely resistant inbred maize lines. The complexity of each isolate was analysed by RFLP analysis and sequencing based on 120 SP1 clones, 36 SP2 clones and 40 N2A clones. All three isolates were composed of different but related clones, consistent with a quasispecies structure. The mutations were distributed throughout the genome. Mutation frequencies, based on all available sequences, were 3.8 x 10(-4) for SP1, 10.5 x 10(-4) for SP2 and 6.9 x 10(-4) for N2A. As expected from the bottleneck selection step, the intra-isolate variability of SP1 was relatively low. Comparison between SP1 and SP2 showed that SP1 heterogeneity increased during maintenance on the wild host. Furthermore, the consensus sequences of SP1 and SP2 differed by two non-synonymous substitutions in the complementary sense gene repA. N2A had a relatively low degree of heterogeneity, but was composed of several sub-populations. The results reflect the influence of the mode of selection of MSV isolates on their quasispecies organization, i.e. distribution of variants, and master sequence.

Base Sequence↗
PubMed1995

Denaturing gradient gel electrophoresis analysis for the detection of point mutations in the Chlamydia trachomatis major outer-membrane protein gene.

Fifty clinical strains of Chlamydia trachomatis were studied by denaturing gradient gel electrophoresis (DGGE) of bacterial DNA amplified by the polymerase chain reaction (PCR). The strains belonged to the three most commonly encountered serovars in developed countries--D, E and F. Six reference strains, including the serovar Da strain, were also studied. The DNA sequences explored encompassed the four variable domains (VDs) of omp1, the gene encoding the major outer-membrane protein (MOMP). The corresponding regions in the MOMP contain the species-, subspecies- and serovar-specific epitopes. The four distinct serovars were clearly differentiated by specific migration pattern. No sequence variations were observed among strains of serovar F. However, variant strains within serovars D and E were found, which exhibited migration patterns different from those of the reference strains and these were sequenced directly. According to the observed sequence variations, serovar D strains could be divided into three stable representative groups (D, D1 and D2). Two variants were identified among serovar E strains. No biological differences were observed for the variant strains in terms of growth properties, ecology or pathogenicity. All the nucleotide substitutions detected in the VDs were non-synonymous at the protein level and, for the serovar D strains, could account for differences identified by specific monoclonal antibodies. These substitutions could be involved in antigenic drift, driven by the immune pressure of the host, leading to the emergence of serovariants. The data may explain, in part, chlamydial infection recurrences and could have critical implications for developing rational vaccine strategies.

Algorithms↗
PubMed1995

Variation in synonymous substitution rates among mammalian genes and the correlation between synonymous and nonsynonymous divergences.

Using mammalian gene sequences, the variances in the numbers of synonymous and nonsynonymous substitutions among genes were estimated together with the correlation coefficient between the two. The expected correlation coefficient can be obtained under the neutral theory using these estimated values of the variances. The expected coefficient is found to often be one-half to two-thirds of the observed value. Possible causes for the disagreement were discussed, such as correlated selective constraints on the two types of substitutions and excess doublet mutations. The variance of mutation rate and that of selective constraint were also estimated. The results show that the coefficient of variation of the former is 0.2-0.3, whereas that of the latter is 0.7-0.9.

Animals↗
PubMed2005

[Iron overload and insulin resistance].

There is increasing evidence that moderately elevated body iron stores, below levels commonly found in genetic hemochromatosis, may be associated with adverse health outcomes. Genetic hemochromatosis, characterized by transferrin saturation (TS) greater than 45%, is most often linked to homozygosity of the HFE C282Y allele. The phenotype is also modulated by mutations of more recently discovered genes (including ferroportin, hemojuvelin, hepcidin, and transferrin receptor) and environmental factors (including alcohol, viruses, diet, blood loss). Iron overload without hemochromatosis is characterized by high levels of serum ferritin and normal TS, as seen in dysmetabolic hepatosiderosis. Elevated serum ferritin levels predict incident type 2 diabetes in prospective studies and have been associated with hypertension, dyslipidemia, glucose tolerance disturbances, central adiposity, and metabolic syndrome. High ferritin levels are not synonymous with iron overload and may in some cases be a simple marker of insulin resistance.

Hemochromatosis↗
PubMed2005

Cadherins in maternal-foetal interactions: red queen with a green beard?

Cadherins are homophilic cell surface adhesion proteins, some of which mediate interactions between maternal and foetal tissues during mammalian pregnancy. David Haig suggested that these proteins may exhibit 'green-beard gene' effects, whereby the nature of binding between identical alleles in mother and foetus leads to differential levels of resource transfer. The selfish effects of such self-recognizing alleles should, however, be suppressed over evolutionary time by unlinked genes, which is expected to lead to antagonistic coevolution between placentally expressed cadherins and unlinked modifiers. Such molecular coevolution should leave a signature of positive selection, with high ratios of non-synonymous to synonymous amino acid substitution. We present evidence that three placentally expressed cadherin genes, E-cadherin, P-cadherin and VE-cadherin, have been subject to positive selection. By contrast, a 'control' cadherin that is not expressed in the placenta, H-cadherin, showed no evidence of selection. These results provide support for the hypothesis that the cadherin genes involved in maternal-foetal interactions have been subject to green-beard-effect mutations over the course of evolutionary history, leading to antagonistic coevolution with suppressing elements from the parliament of genes.

Animals↗
PubMed1998

Polymorphism of Mhc-DRB alleles in Cercopithecus aethiops (green monkey): generation and functionality.

DRB genes have been studied for the first time in green monkeys (Cercopithecus aethiops). Eleven new DRB alleles (exon 2, exon 3) have been obtained and sequenced from cDNA. A limited number of lineages have been identified: DRB1*03 (4 alleles), DRB1*07 (3 alleles), DRB5 (1 allele), DRB*w6 (1 allele), and DRB*w7 (2 alleles). The existence of Ceae-DRB1 duplications is supported by the finding of 3 DRB1 alleles in 3 different individuals. Ceae-DRB1*0701 may be non-functional because it bears serine at position 82, which hinders molecule surface expression in mice; the allele is only found in Ceae-DRB duplicated haplotypes. Base changes in cDNA Ceae-DRB alleles are consistent with the generation of polymorphism by point mutations or short segment exchanges between alleles. The eleven green monkey DRB alleles meet the requirements for functionality as antigen-presenting molecules (perhaps, excluding DRB1*0701), since: 1) they have been isolated from cDNA and do not present deletions, insertions or stop codons: 2) structural motifs necessary for a correct folding of the molecule, for the formation of DR/DR dimers and for CD4 interactions are conserved, and 3) the number of non-synonymous substitutions is higher than the number of synonymous substitutions in the peptide binding region (PBR), while the contrary holds true for the non-PBR region.

Alleles↗
PubMed2002

Determination of the genomic structure and mutation screening in schizophrenic individuals for five subunits of the N-methyl-D-aspartate glutamate receptor.

The glutamatergic system is the major excitatory neurotransmitter system in the CNS. Glutamate receptors, and in particular N-methyl-D-aspartate (NMDA) receptors, have been proposed as mediators of many common neuropsychiatric phenotypes including cognition, psychosis, and degeneration. We have reconstructed the genomic structure of all five genes encoding NMDA receptors in silico. We screened each for sequence variation and estimated the allele frequencies of all detected SNPs in pooled samples of 184 UK Caucasian schizophrenics and 184 UK Caucasian blood donor controls. Only a single non-synonymous polymorphism was found indicating extreme selection pressure. The rarity of non-synonymous changes suggests that such variants are unlikely to make a common contribution to common phenotypes. We found a further 26 polymorphisms within exonic or adjacent intronic sequences. The minor alleles of most of these have a relatively high frequency (63% above 0.2). These SNPs will therefore be suitable for studying neuropsychiatric phenotypes that are putatively related to NMDA dysfunction. Pooled analysis provided no support for association between any of the GRIN genes and schizophrenia.

Base Sequence↗
PubMed2007

Novel mutations in the small leucine-rich repeat protein/proteoglycan (SLRP) genes in high myopia.

The importance of the genetic component in high myopia has been well established in population and family studies, but only a few candidate genes have been explored to date. The extracellular matrix small leucine-rich repeat proteins/proteoglycans (SLRPs) regulate collagen fibril diameter and spacing. Given their role in extracellular matrix assembly and expression in the eye, they are likely to regulate its shape and size. Analysis of 85 English and 40 Finnish subjects with high myopia (refractive error of -6 diopters [D] or greater) resulted in 23 sequence variations in four SLRP genes, LUM, FMOD, PRELP, and OPTC. We observed higher number of variations in OPTC in English patients than in controls (p=0.042), and a possibly protective variation in LUM (c.893-105G>A) with p-value of 0.0043. Two intronic variations, six nonsynonymous and one synonymous amino acid changes, were not found in any of the nonmyopic controls. Five changes were detected in opticin, Thr177Arg, Arg229His, Arg325Trp, Gly329Ser, and Arg330His, and all but one (Arg229His) were shown to cosegregate with high myopia in families with incomplete penetrance. A homology model for opticin revealed that Arg229His and Arg325Trp are likely to disrupt the protein structure, and PolyPhen analysis suggested that Thr177Arg, Arg325Trp, and Gly329Ser changes may be damaging. A Leu199Pro change in lumican and Gly147Asp and Arg324Thr variations in fibromodulin are located in the highly conserved leucine-rich repeat (LRR) domains. This study provides new insight into the genetics of high myopia, suggesting that sequence variations in the SLRP genes expressed in the eye may be among the genetic risk factors underlying the pathogenesis of high myopia.

Amino Acid Sequence↗