Frequency Of Nonsynonymous Substitutions Research Articles

Molecular evolution of West Nile virus

Phylogenetic analysis and estimation of the rate of evolution of West Nile virus (WNV) were conducted. Sixty-eight nucleotide sequences of WNV E protein were used for the analysis. The rate of nucleotide substitution accumulation was 2.5 × 10−4 substitutions per site per year. Phylogenetic analysis and estimation of WNV evolution time using molecular-clock methodology demonstrated that the WNV genotypes 1, 2, and 4 with an estimated time of divergence from the common precursor of approximately 2360, 2800, and 5950 years, respectively, circulate on the territory of the European part of Russia. The ratio of frequencies of nonsynonymous substitutions (dN) to synonymous substitutions (dS) can vary within 0.022–0.275 for certain WNV strains grouped according to geographical and/or phylogenetic traits. The highest values of dN/dS ratio were found for modern WNV isolates in Russia and in North America, which appeared in new natural biocenoses of these regions in the last 14 years. dN/dS estimation for WNV species shows that indices of intraspecific dN/dS variability can be used for detecting the presence of accelerated evolution of new WNV isolates. All this confirms the hypothesis that favorable conditions exist for wide distribution and rapid evolution of different WNV genotypes (that arose 2000–6000 years ago) in modern natural and climatic conditions.

Deep sequencing reveals an association between HIV-1 subtype C mutations in gp41 MPER epitopes and mother-to-child transmission

Methods Pyrosequences of HIV-1 subtype-C gp41 heptad repeatregion 2 (HR2), MPER, and membrane-spanning domain (MSD) were generated from 2,000 plasma viral copies/subject from four mothers who transmitted via breast feeding (TM) and four non-transmitting mothers (NTM) in a matched case control study. A bioinformatic pipeline with rigorous quality controls generated ~50,000 quality pyrosequences/subject and provided 25-fold coverage of input virus populations. Population genetic algorithms clustered pyrosequences at 3% genetic distance to study biodiversity using rarefaction/Chao1. Frequency distribution of cluster sizes defined population structure. Consensus sequences constructed from bioclusters for each subject were aligned to an HIV-1 subtype-C consensus sequence to determine number and frequency of nonsynonymous substitutions at each position and to identify mutations by HIV Molecular Immunology Database. Groups were compared using paired t-test.

Single nucleotide polymorphism in the genes of mce1 and mce4 operons of Mycobacterium tuberculosis: analysis of clinical isolates and standard reference strains

BackgroundThe presence of four mammalian cell entry (mce) operons in Mycobacterium tuberculosis suggests the essentiality of the functions of the genes in these operons. The differential expression of the four mce operons in different phases of in vitro growth and in infected animals reported earlier from our laboratory further justifies the apparent redundancy for these genes in the genome.Here we investigate the extent of polymorphism in eight genes in the mce1 and mce4 operons of M. tuberculosis from four standard reference strains (H37Rv, H37Ra, LVS (Low Virulent Strain) and BCG) and 112 clinical isolates varying in their drug susceptibility profile, analysed by direct sequencing and Sequenom MassARRAY platform.ResultsWe discovered 20 single nucleotide polymorphisms (SNPs) in the two operons. The comparative analysis of the genes of mce1 and mce4 operons revealed that yrbE1A [Rv0167] was most polymorphic in mce1 operon while yrbE4A [Rv3501c] and lprN [Rv3495c] had the highest number of SNPs in the mce4 operon. Of 20 SNPs, 12 were found to be nonsynonymous and were further analysed for their pathological relevance to M. tuberculosis using web servers PolyPhen and PMut, which predicted five deleterious nonsynonymous SNPs. A mutation from proline to serine at position 359 of the native Mce1A protein was most deleterious as predicted by both PolyPhen and PMut servers. Energy minimization of the structure of native Mce1A protein and mutated protein was performed using InsightII. The mutated Mce1A protein showed structural changes that could account for the effects of this mutation.ConclusionsOur results show that SNPs in the coding sequences of mce1 and mce4 operons in clinical isolates can be significantly high. Moreover, mce4 operon is significantly more polymorphic than mce1 operon (p < 0.001). However, the frequency of nonsynonymous substitutions is higher in mce1 operon and synonymous substitutions are more in mce4 operon. In silico modeling predict that nonsynonymous SNP at mce1A [Rv0169], a virulence gene could play a pivotal role in causing functional changes in M. tuberculosis that may reflect upon the biology of the bacteria.

Identical Skin Toxins by Convergent Molecular Adaptation in Frogs

The Tree of Life is rife with adaptive convergences at all scales and biological levels of complexity. However, natural selection is not likely to result in the independent evolution of identical gene products. Here we report such a striking example of evolutionary convergence in the toxic skin secretions of two distantly related frog lineages. Caeruleins are important decapeptides in pharmacological and clinical research [1] and are commonly believed to represent a single evolutionary class of peptides [2-4]. Instead, our phylogenetic analyses combining transcriptome and genome data reveal that independently evolved precursor genes encode identical caeruleins in Xenopus and Litoria frogs. The former arose by duplication from the cholecystokinin (cck) gene, whereas the latter was derived from the gastrin gene. These hormone genes that are involved in many physiological processes diverged early in vertebrate evolution, after a segmental duplication during the Cambrian period. Besides implicating convergent mutations of the peptide-encoding sequence, recurrent caerulein origins entail parallel shifts of expression from the gut-brain axis to skin secretory glands. These results highlight extreme structural convergence in anciently diverged genes as an evolutionary mechanism through which recurrent adaptation is attained across large phylogenetic distances.

Molecular evolution of the avian CHD1 genes on the Z and W sex chromosomes.

Genes shared between the nonrecombining parts of the two types of sex chromosomes offer a potential means to study the molecular evolution of the same gene exposed to different genomic environments. We have analyzed the molecular evolution of the coding sequence of the first pair of genes found to be shared by the avian Z (present in both sexes) and W (female-specific) sex chromosomes, CHD1Z and CHD1W. We show here that these two genes evolve independently but are highly conserved at nucleotide as well as amino acid levels, thus not indicating a female-specific role of the CHD1W gene. From comparisons of sequence data from three avian lineages, the frequency of nonsynonymous substitutions (K(a)) was found to be higher for CHD1W (1.55 per 100 sites) than for CHD1Z (0.81), while the opposite was found for synonymous substitutions (K(s), 13.5 vs. 22.7). We argue that the lower effective population size and the absence of recombination on the W chromosome will generally imply that nonsynonymous substitutions accumulate faster on this chromosome than on the Z chromosome. The same should be true for the Y chromosome relative to the X chromosome in XY systems. Our data are compatible with a male-biased mutation rate, manifested by the faster rate of neutral evolution (synonymous substitutions) on the Z chromosome than on the female-specific W chromosome.

Cloning and nucleotide sequence analysis ofpsbD/C operon from chloroplasts ofPopulus deltoides

We report the cloning and nucleotide sequence analysis ofpsbD/C operon from a dicotyledonous tree species,Populus deltoides (poplar). The coding regions ofpsbD andpsbC and deduced amino acid sequences show very high homology with those from other higher plants. In pairwise alignment of the gene sequences,P. deltoides clustered with dicotyledonous annuals rather than withPinus, the only other tree whosepsbD/C nucleotide sequence is available. Comparison of several reported sequences showed that synonymous substitutions were distributed in bothpsbD andpsbC uniformly, throughout the length of the genes. The frequency of nonsynonymous substitutions located in the amino-terminal endof psbD was distinctly higher, suggesting a lower degree of structural constraints in this region of the encoded D2 protein. The arrangement of reading frames and Northern analysis suggest that organization and expression ofpsbD/C operon inP. deltoides is similar to that in other higher plants.

Frequencies of synonymous substitutions in mammals are gene-specific and correlated with frequencies of nonsynonymous substitutions

The frequencies of synonymous substitutions of mammalian genes cover a much wider range than previously thought. We report here that the different frequencies found in homologous genes from a given mammalian pair are correlated with those in the same homologous genes from a different mammalian pair. This indicates that the frequencies of synonymous substitutions are gene-specific (as are the frequencies of nonsynonymous substitutions), or, in other words, that "fast" and "slow" genes in one mammal are fast and slow, respectively, in any other one. Moreover, the frequencies of synonymous substitutions are correlated with the frequencies of nonsynonymous substitution in the same genes.