The optimization of mRNA expression level by its intrinsic properties-Insights from codon usage pattern and structural stability of mRNA.

Codon usage bias (CUB) and mRNA structural stability are important intrinsic features of mRNA that correlate positively with mRNA expression level. However, it remains unclear whether the mRNA expression level can be regulated by adjusting these two parameters, influencing the mRNAs' structure. Here we explored the influence of CUB and mRNA structural stability on mRNA expression levels in Saccharomyces cerevisiae, using both wild type and computationally mutated mRNAs. Although in wild type, both CUB and mRNA stability positively regulate the mRNA expression level, any deviation from natural situation breaks such equilibrium. The naturally occurring codon composition is responsible for optimizing the mRNA expression, and under such composition, the mRNA structure having highest stability is selected by nature.

Global analysis of human duplicated genes reveals the relative importance of whole-genome duplicates originated in the early vertebrate evolution.

BACKGROUND: Gene duplication is a genetic mutation that creates functionally redundant gene copies that are initially relieved from selective pressures and may adapt themselves to new functions with time. The levels of gene duplication may vary from small-scale duplication (SSD) to whole genome duplication (WGD). Studies with yeast revealed ample differences between these duplicates: Yeast WGD pairs were functionally more similar, less divergent in subcellular localization and contained a lesser proportion of essential genes. In this study, we explored the differences in evolutionary genomic properties of human SSD and WGD genes, with the identifiable human duplicates coming from the two rounds of whole genome duplication occurred early in vertebrate evolution. RESULTS: We observed that these two groups of duplicates were also dissimilar in terms of their evolutionary and genomic properties. But interestingly, this is not like the same observed in yeast. The human WGDs were found to be functionally less similar, diverge more in subcellular level and contain a higher proportion of essential genes than the SSDs, all of which are opposite from yeast. Additionally, we explored that human WGDs were more divergent in their gene expression profile, have higher multifunctionality and are more often associated with disease, and are evolutionarily more conserved than human SSDs. CONCLUSIONS: Our study suggests that human WGD duplicates are more divergent and entails the adaptation of WGDs to novel and important functions that consequently lead to their evolutionary conservation in the course of evolution.

On the quest for selective constraints shaping the expressivity of the genes casting retropseudogenes in human.

BACKGROUND: Pseudogenes, the nonfunctional homologues of functional genes are now coming to light as important resources regarding the study of human protein evolution. Processed pseudogenes arising by reverse transcription and reinsertion can provide molecular record on the dynamics and evolution of genomes. Researches on the progenitors of human processed pseudogenes delved out their highly expressed and evolutionarily conserved characters. They are reported to be short and GC-poor indicating their high efficiency for retrotransposition. In this article we focused on their high expressivity and explored the factors contributing for that and their relevance in the milieu of protein sequence evolution. RESULTS: We here, analyzed the high expressivity of these genes configuring processed or retropseudogenes by their immense connectivity in protein-protein interaction network, an inclination towards alternative splicing mechanism, a lower rate of mRNA disintegration and a slower evolutionary rate. While the unusual trend of the upraised disorder in contrast with the high expressivity of the proteins encoded by processed pseudogene ancestors is accredited by a predominance of hub-protein encoding genes, a high propensity of repeat sequence containing genes, elevated protein stability and the functional constraint to perform the transcription regulatory jobs. Linear regression analysis demonstrates mRNA decay rate and protein intrinsic disorder as the influential factors controlling the expressivity of these retropseudogene ancestors while the latter one is found to have the most significant regulatory power. CONCLUSIONS: Our findings imply that, the affluence of disordered regions elevating the network attachment to be involved in important cellular assignments and the stability in transcriptional level are acting as the prevailing forces behind the high expressivity of the human genes configuring processed pseudogenes.

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.

The combined influence of codon composition and tRNA copy number regulates translational efficiency by influencing synonymous nucleotide substitution.

Codon usage bias is an important genomic phenomenon, where highly expressed genes use optimal codons for smoother translation with high yield, facilitated by the cognate tRNAs. Here, we presented the tRNA co-adaptation index (co-AI) by correlating tRNA gene copy number and codon composition in Saccharomyces cerevisiae. We observed that this co-AI is positively correlated with protein abundance and translation rate. Considering nucleotide substitutions, co-AI influences synonymous substitutions more than gene expression and protein abundance, the most important determinants of evolutionary rate. Co-AI correlates positively with mRNA secondary structure stability and mRNA half-life, which may lead to protein accumulation under high co-AI. However, the highly expressed proteins encoded by high co-AI genes are assisted by molecular chaperones to attain their proper functional conformation and prevent accumulation.

Deciphering the intrinsic properties of fungal proteases in optimizing phytopathogenic interaction.

Phytopathogenic fungi secrete a wide range of enzymes to penetrate and colonize host tissues. Of them protease activity is reported to increase disease aggressiveness in the plant. With the aim to explore the reason of the higher infection potential of proteases, we have compared several genomic and proteomic attributes among different hydrolytic enzymes coded by five pathogenic fungal species which are the potent infectious agents of plant. Categorizing the enzymes into four major groups, namely protease, lipase, amylase and cell-wall degraders, we observed that proteases are evolutionary more conserved, have higher expression levels, contain more hydrophobic buried residues, short linear motifs and post-translational modified (PTM) sites than the other three groups of enzymes. Again, comparing these features of protease between pathogenic and non-pathogenic Aspergillus sps, we have hypothesized that protein structural properties could play significant roles in imposing infection potency to the fungal proteases.

Overlapping Regions in HIV-1 Genome Act as Potential Sites for Host-Virus Interaction.

More than a decade, overlapping genes in RNA viruses became a subject of research which has explored various effect of gene overlapping on the evolution and function of viral genomes like genome size compaction. Additionally, overlapping regions (OVRs) are also reported to encode elevated degree of protein intrinsic disorder (PID) in unspliced RNA viruses. With the aim to explore the roles of OVRs in HIV-1 pathogenesis, we have carried out an in-depth analysis on the association of gene overlapping with PID in 35 HIV1- M subtypes. Our study reveals an over representation of PID in OVR of HIV-1 genomes. These disordered residues endure several vital, structural features like short linear motifs (SLiMs) and protein phosphorylation (PP) sites which are previously shown to be involved in massive host-virus interaction. Moreover, SLiMs in OVRs are noticed to be more functionally potential as compared to that of non-overlapping region. Although, density of experimentally verified SLiMs, resided in 9 HIV-1 genes, involved in host-virus interaction do not show any bias toward clustering into OVR, tat and rev two important proteins mediates host-pathogen interaction by their experimentally verified SLiMs, which are mostly localized in OVR. Finally, our analysis suggests that the acquisition of SLiMs in OVR is mutually exclusive of the occurrence of disordered residues, while the enrichment of PPs in OVR is solely dependent on PID and not on overlapping coding frames. Thus, OVRs of HIV-1 genomes could be demarcated as potential molecular recognition sites during host-virus interaction.

Investigating different duplication pattern of essential genes in mouse and human.

Gene duplication is one of the major driving forces shaping genome and organism evolution and thought to be itself regulated by some intrinsic properties of the gene. Comparing the essential genes among mouse and human, we observed that the essential genes avoid duplication in mouse while prefer to remain duplicated in humans. In this study, we wanted to explore the reasons behind such differences in gene essentiality by cross-species comparison of human and mouse. Moreover, we examined essential genes that are duplicated in humans are functionally more redundant than that in mouse. The proportion of paralog pseudogenization of essential genes is higher in mouse than that of humans. These duplicates of essential genes are under stringent dosage regulation in human than in mouse. We also observed slower evolutionary rate in the paralogs of human essential genes than the mouse counterpart. Together, these results clearly indicate that human essential genes are retained as duplicates to serve as backed up copies that may shield themselves from harmful mutations.

Protein complex forming ability is favored over the features of interacting partners in determining the evolutionary rates of proteins in the yeast protein-protein interaction networks.

BACKGROUND: Evolutionary rates of proteins in a protein-protein interaction network are primarily governed by the protein connectivity and/or expression level. A recent study revealed the importance of the features of the interacting protein partners, viz., the coefficient of functionality and clustering coefficient in controlling the protein evolutionary rates in a protein-protein interaction (PPI) network. RESULTS: By multivariate regression analysis we found that the three parameters: probability of complex formation, expression level and degree of a protein independently guide the evolutionary rates of proteins in the PPI network. The contribution of the complex forming property of a protein and its expression level led to nearly 43% of the total variation as observed from the first principal component. We also found that for complex forming proteins in the network, those which have partners sharing the same functional class evolve faster than those having partners belonging to different functional classes. The proteins in the dense parts of the network evolve faster than their counterparts which are present in the sparse regions of the network. Taking into account the complex forming ability, we found that all the complex forming proteins considered in this study evolve slower than the non-complex forming proteins irrespective of their localization in the network or the affiliation of their partners to same/different functional classes. CONCLUSIONS: We have shown here that the functionality and clustering coefficient correlated with the degree of the protein in the protein-protein interaction network. We have identified the significant relationship of the complex-forming property of proteins and their evolutionary rates even when they are classified according to the features of their interacting partners. Our study implies that the evolutionarily constrained proteins are actually members of a larger number of protein complexes and this justifies why they have enhanced expression levels.