Tapash Chandra Ghosh

Gene expressivity is the main factor in dictating the codon usage variation among the genes in Pseudomonas aeruginosa

Codon usage biases of all DNA sequences (length greater than or equal to 300 bp) from the complete genome of Pseudomonas aeruginosa have been analyzed. As P. aeruginosa is a GC-rich organism, G and/or C are expected to predominate in their codons. Overall codon usage data analysis indicates that indeed codons ending in G and/or C are predominant in this organism. But multivariate statistical analysis indicates that there is a single major trend in the codon usage variation among the genes in this organism, which has a strong negative correlation with the expressivities of the genes. The majority of the lowly expressed genes are scattered towards the positive end of the major axis whereas the highly expressed genes are clustered towards the negative end. This is the first report where the prokaryotic organism having highly skewed base composition is dictated mainly by translational selection, though some other factors such as the lengths of the genes as well as the hydrophobicity of genes also influence the codon usage variation among the genes in this organism in a minor way.

Studies on codon usage in Entamoeba histolytica.

Codon usage bias of Entamoeba histolytica, a protozoan parasite, was investigated using the available DNA sequence data. Entamoeba histolytica having AT rich genome, is expected to have A and/or T at the third position of codons. Overall codon usage data analysis indicates that A and/or T ending codons are strongly biased in the coding region of this organism. However, multivariate statistical analysis suggests that there is a single major trend in codon usage variation among the genes. The genes which are supposed to be highly expressed are clustered at one end, while the majority of the putatively lowly expressed genes are clustered at the other end. The codon usage pattern is distinctly different in these two sets of genes. C ending codons are significantly higher in the putatively highly expressed genes suggesting that C ending codons are translationally optimal in this organism. In the putatively lowly expressed genes A and/or T ending codons are predominant, which suggests that compositional constraints are playing the major role in shaping codon usage variation among the lowly expressed genes. These results suggest that both mutational bias and translational selection are operational in the codon usage variation in this organism.

Demethylation of (Cytosine-5-C-methyl) DNA and regulation of transcription in the epigenetic pathways of cancer development

Cancer cells and tissues exhibit genome wide hypomethylation and regional hypermethylation. CpG-methylation of DNA (MeCpG-DNA) is defined as the formation of a C–C covalent bond between the 5′-C of cytosine and the –CH3 group of S-adenosylmethionine. Removal of the sole –CH3 group from the methylated cytosine of DNA is one of the many ways of DNA-demethylation, which contributes to activation of transcription. The mechanism of demethylation, the candidate enzyme(s) exhibiting direct demethylase activity and associated cofactors are not firmly established. Genome-wide hypomethylation can be obtained in several ways by inactivation of DNMT enzyme activity, including covalent trapping of DNMT by cytosine base analogues. Removal of methyl layer could also be occurred by excision of the 5-methyl cytosine base by DNA glycosylases. The importance of truly chemically defined direct demethylation of intact DNA in regulation of gene expression, development, cell differentiation and transformation are discussed in this contribution.

Synonymous Codon Usage in Lactococcus lactis: Mutational Bias Versus Translational Selection

Abstract In this study codon usage bias of all experimentally known genes of Lactococcus lactis has been analyzed. Since Lactococcus lactis is an AT rich organism, it is expected to occur A and/or T at the third position of codons and detailed analysis of overall codon usage data indicates that A and/or T ending codons are predominant in this organism. However, multivariate statistical analyses based both on codon count and on relative synonymous codon usage (RSCU) detect a large number of genes, which are supposed to be highly expressed are clustered at one end of the first major axis, while majority of the putatively lowly expressed genes are clustered at the other end of the first major axis. It was observed that in the highly expressed genes C and T ending codons are significantly higher than the lowly expressed genes and also it was observed that C ending codons are predominant in the duets of highly expressed genes, whereas the T endings codons are abundant in the quartets. Abundance of C and T ending codons in the highly expressed genes suggest that, besides, compositional biases, translational selection are also operating in shaping the codon usage variation among the genes in this organism as observed in other compositionally skewed organisms. The second major axis generated by correspondence analysis on simple codon counts differentiates the genes into two distinct groups according to their hydrophobicity values, but the same analysis computed with relative synonymous codon usage values could not discriminate the genes according to the hydropathy values. This suggests that amino acid composition exerts constraints on codon usage in this organism. On the other hand the second major axis produced by correspondence analysis on RSCU values differentiates the genes into two groups according to the synonymous codon usage for cysteine residues (rarest amino acids in this organism), which is nothing but a artifactual effect induced by the RSCU values. Other factors such as length of the genes and the positions of the genes in the leading and lagging strand of replication have practically no influence in the codon usage variation among the genes in this organism.

The base composition of the genes is correlated with the secondary structures of the encoded proteins.

The analysis of a non-redundant set of human proteins, for which both the crystallographic structures and the corresponding gene sequences are available, show that bases at third codon position are non-uniformly distributed along the coding sequences. Significant compositional differences are found by comparing the gene regions corresponding to the different secondary structures of the proteins. Inter-and intra-structure differences were most pronounced in the GC-richest genes. These results are not compatible with any proposed hypotheses based on a neutral process of formation/maintenance of the high GC(3) levels of the genes localized in the GC-richest isochores of the human genome.

Investigation on the causes of codon and amino acid usages variation between thermophilic Aquifex aeolicus and mesophilic Bacillus subtilis.

Abstract Base composition, codon usages and amino acid usages have been analyzed by taking 529 orthologous sequences of Aquifex aeolicus and Bacillus subtilis, having different optimal growth temperatures. These two bacteria do not have significant difference in overall GC composition, but GC(1+2) and GC3 levels were found to vary significantly. Significant increments in purine content and GC3 composition have been observed in the coding sequences of Aquifex aeolicus than its Bacillus subtilis counterparts. Correspondence analyses on codon and amino acid usages reveal that variation in base composition actually influences their codon and amino acid usages. Two selection pressures acting on the nucleotide level (GC3 and purine enrichment), causes variation in the amino acid usage differently in different protein secondary structures. Our results suggest that adaptation of amino acid usages in coil structure of Aquifex aeolicus proteins is under the control of both purine increment and GC3 composition, whereas the adaptation of the amino acids in the helical region of thermophilic bacteria is strongly influenced by the purine content. Evolutionary perspectives concerning the temperature adaptation of DNA and protein molecules of these two bacteria have been discussed on the basis of these results.

Evolutionary Forces in Shaping the Codon and Amino Acid Usages in Blochmannia floridanus

Abstract Endosymbiotic relationship has great effect on ecological system. Codon and amino acid usages bias of endosymbiotic bacteria Blochmannia floridanus (whose host is an ant Camponotus floridanus) was investigated using experimentally known genes of this organism. Correspondence Analysis on RSCU values show that there exists only one single explanatory major axis that is linked to the strand specific mutational biases. Majority of the genes have a tendency to concentrate on the leading strand, which may be related to the adaptive property related to the replication mechanisms. Amino acid usages were markedly different between the highly and lowly expressed genes in this organism and in particular, GC rich amino acids were found to occur significantly higher in highly expressed genes than the lowly expressed genes. Comparative analyses of the orthologous genes of Escherichia coli and Blochmannia floridanus show that highly expressed genes are significantly more conserved than lowly expressed genes. Based on our results we concluded that strand specific mutational bias is strongly operational in selecting the codon usage in this organism. Replicational-transcriptional selection can be invoked from the presence of majority of highly expressed genes in the leading strand. Conservation of GC rich amino acids in the highly expressed genes to its ancestor is the major source of variation in amino acid usages in the organism. Hydrophobicity of the genes is the second major source in differentiating the genes according to their amino acid usages in this organism.

Evolutionary constraints on hub and non-hub proteins in human protein interaction network: Insight from protein connectivity and intrinsic disorder

It has been claimed that proteins with more interacting partners (hubs) are structurally more disordered and have a slow evolutionary rate. Here, in this paper we analyzed the evolutionary rate and structural disorderness of human hub and non-hub proteins present/absent in protein complexes. We observed that both non-hub and hub proteins present in protein complexes, are characterized by high structural disorderness. There exists no significant difference in average evolutionary rate of complex-forming hub and non-hub proteins while we have found a significant difference in the average evolutionary rate between hub and non-hub proteins which are not present in protein complexes. We concluded that higher disorderness in complex forming non-hub proteins facilitates higher number of interactions with a large number of protein subunits. High interaction among protein subunits of complex forming non-hub proteins imposes a selective constraint on their evolutionary rate.

Exploring the Differences in Evolutionary Rates between Monogenic and Polygenic Disease Genes in Human

Comparative analyses on disease and nondisease (ND) genes have greatly facilitated the understanding of human diseases. However, most studies have grouped all the disease genes together and have performed comparative analyses with other ND genes. Thus, the molecular mechanism of disease on which disease genes can be separated into monogenic and polygenic diseases (MDs and PDs) has been ignored in earlier studies. Here, we report a comprehensive study of PD and MD genes with respect to ND genes. Our work shows that MD genes are more conserved than PD genes and that ND genes are themselves more conserved than both classes of disease genes. By separating the ND genes into housekeeping and other genes, it was found that housekeeping genes are the most conserved among all categories of genes, whereas other ND genes show an evolutionary rate intermediate between MD and PD genes. Although PD genes have a higher number of interacting partners than MD and ND genes, the reasons for their higher evolutionary rate require explanation. We provide evidences that the faster evolutionary rate of PD genes is influenced by 1) the predominance of date hubs in protein-protein interaction network, 2) the higher number of disorder residues, 3) the lower expression level, and 4) the involvement with more regulatory processes. Logistic regression analysis suggests that the relative importance of the four individual factors in determining the evolutionary rate variation among the four classes of proteins is in the order of mRNA expression level > presence of party/date hubs > disorder > involvement of proteins in core/regulatory processes.

Multifunctionality dominantly determines the rate of human housekeeping and tissue specific interacting protein evolution

Elucidation of the determinants of the rate of protein sequence evolution is one of the great challenges in evolutionary biology. It has been proposed that housekeeping genes are evolutionarily slower than tissue specific genes. In the present communication, we have examined different determinants that influence the evolutionary rate variation in human housekeeping and tissue specific proteins present in protein-protein interaction network. Studies on yeast proteome, revealed a predominant role of protein connectivity in determining the rate of protein evolution. However, in human, we did not observe any significant influence of protein connectivity on its evolutionary rate. Rather, a significant impact of the proportion of proteins interacting length (amount of protein interface involved in interaction with its partners), expression level and multifunctionality has been observed in determining the rate of protein evolution. We also observed that multi interface proteins are evolutionarily conserved between housekeeping and tissue specific genes and it has been found that the average number of biological processes they associated in these two sets of genes is similar. Moreover, single interface proteins in housekeeping genes evolve more slowly as compared to tissue specific genes owing to their involvement in different number of biological processes. Partial correlation analysis suggests that the relative importance of three individual factors in determining the evolutionary rate variation between housekeeping and tissue specific proteins is in the order of protein multifunctionality>protein expression level>interacting protein length.