Insights into the molecular correlates modulating functional compensation between monogenic and polygenic disease gene duplicates in human

AbstractFunctional redundancy by gene duplication appears to be a common phenomenon in biological system and hence understanding its underlying mechanism deserves much attention. Here, we investigated the differences between functional compensation of monogenic and polygenic disease genes which are unexplored till date. We found that the competence of functional buffering varies in the order of non-disease genes>monogenic disease genes>polygenic disease genes. This fact has been explained by the sequence identity, expression profile similarity, shared interaction partners and cellular locations between duplicated pairs. Moreover, we observed an inverse relationship between backup capacity and the non-synonymous substitution rate of disease and non-disease genes while the opposite trend is found for their corresponding paralogs. Logistic regression analysis among sequence identity, sharing of expression profile, interaction partners and cellular locations with backup capacity between duplicated pairs demonstrated that the sharing of expression profile is the most dominant regulator of backup capacity

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

<p>Abstract</p> <p>Background</p> <p>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, <it>viz</it>., the coefficient of functionality and clustering coefficient in controlling the protein evolutionary rates in a protein-protein interaction (PPI) network.</p> <p>Results</p> <p>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.</p> <p>Conclusions</p> <p>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.</p

Different functional classes of genes are characterized by different compositional properties

A compositional analysis on a set of human genes classified in several functional classes was performed. We found out that the GC3, i.e. the GC level at the third codon positions, of the genes involved in cellular metabolism was significantly higher than those involved in information storage and processing. Analyses of human/Xenopus ortologous genes showed that: (i) the GC3 increment of the genes involved in cellular metabolism was significantly higher than those involved in information storage and processing; and (ii) a strong correlation between the GC3 and the corresponding GCi, i.e. the GC level of introns, was found in each functional class. The non‐randomness of the GC increments favours the selective hypothesis of gene/genome evolution

Passive Transdermal Systems Whitepaper Incorporating Current Chemistry, Manufacturing and Controls (CMC) Development Principles

In this whitepaper, the Manufacturing Technical Committee (MTC) of the Product Quality Research Institute has updated the 1997 Transdermal Drug Delivery Systems Scale-Up and Post Approval Change workshop report findings to add important new product development and control principles. Important topics reviewed include ICH harmonization, quality by design, process analytical technologies, product and process validation, improvements to control of critical excipients, and discussion of Food and Drug Administration’s Guidance on Residual Drug in Transdermal and Related Drug Delivery Systems as well as current thinking and trends on in vitro–in vivo correlation considerations for transdermal systems

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

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusions</p> <p>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.</p

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