Soumita Podder

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.

Insights into the miRNA regulations in human disease genes

BackgroundMicroRNAs are a class of short non-coding RNAs derived from either cellular or viral transcripts that act post-transcriptionally to regulate mRNA stability and translation. In recent days, increasing numbers of miRNAs have been shown to be involved in the development and progression of a variety of diseases. We, therefore, intend to enumerate miRNA targets in several known disease classes to explore the degree of miRNA regulations on them which is unexplored till date.ResultsHere, we noticed that miRNA hits in cancer genes are remarkably higher than other diseases in human. Our observation suggests that UTRs and the transcript length of cancer related genes have a significant contribution in higher susceptibility to miRNA regulation. Moreover, gene duplication, mRNA stability, AREScores and evolutionary rate were likely to have implications for more miRNA targeting on cancer genes. Consequently, the regression analysis have confirmed that the AREScores plays most important role in detecting miRNA targets on disease genes. Interestingly, we observed that epigenetic modifications like CpG methylation and histone modification are less effective than miRNA regulations in controlling the gene expression of cancer genes.ConclusionsThe intrinsic properties of cancer genes studied here, for higher miRNA targeting will enhance the knowledge on cancer gene regulation.

Insights into the genomic features and evolutionary impact of the genes configuring duplicated pseudogenes in human

Pseudogenes, regarded as ‘genomic fossils’, are DNA sequences resembling functional genes in perspective of sequence homology but completely non‐functional. In this study, we explored the unique characteristic features of human genes, configuring classical duplicated pseudogenes. We found that progenitors of duplicated pseudogenes are characterized by a high expressivity, and ability to encode hub‐proteins in association with a high evolutionary rate. Such unusual features are endorsed by longer protein length, elevated CpG content, and a high recombination rate. The non‐functionalization of their duplicated copies can be attributed to the overabundance of gene paralog number in concert with functional redundancy.

Evolutionary dynamics of human autoimmune disease genes and malfunctioned immunological genes

BackgroundOne of the main issues of molecular evolution is to divulge the principles in dictating the evolutionary rate differences among various gene classes. Immunological genes have received considerable attention in evolutionary biology as candidates for local adaptation and for studying functionally important polymorphisms. The normal structure and function of immunological genes will be distorted when they experience mutations leading to immunological dysfunctions.ResultsHere, we examined the fundamental differences between the genes which on mutation give rise to autoimmune or other immune system related diseases and the immunological genes that do not cause any disease phenotypes. Although the disease genes examined are analogous to non-disease genes in product, expression, function, and pathway affiliation, a statistically significant decrease in evolutionary rate has been found in autoimmune disease genes relative to all other immune related diseases and non-disease genes. Possible ways of accumulation of mutation in the three steps of the central dogma (DNA-mRNA-Protein) have been studied to trace the mutational effects predisposed to disease consequence and acquiring higher selection pressure. Principal Component Analysis and Multivariate Regression Analysis have established the predominant role of single nucleotide polymorphisms in guiding the evolutionary rate of immunological disease and non-disease genes followed by m-RNA abundance, paralogs number, fraction of phosphorylation residue, alternatively spliced exon, protein residue burial and protein disorder.ConclusionsOur study provides an empirical insight into the etiology of autoimmune disease genes and other immunological diseases. The immediate utility of our study is to help in disease gene identification and may also help in medicinal improvement of immune related disease.

Complex-forming proteins escape the robust regulations of miRNA in human.

Most proteins carry out their functions by participating in protein complexes. Recently, miRNAs were identified as promising post‐transcriptional regulators that influence a large proportion of genes in higher eukaryotes. We aim to understand the role of miRNAs in the regulation of human proteins that are present in protein complexes. Here, we show that robust regulation by miRNA is absent in human complex‐forming proteins. Moreover, the numbers of miRNA hits cannot direct the evolutionary fate of complex‐forming proteins independently. However, the duplicated complex‐forming proteins having a severe effect on organismal fitness are profoundly targeted by miRNA, probably to reduce the chances of dosage imbalance.

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

Functional 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.

Overlapping genes: a new strategy of thermophilic stress tolerance in prokaryotes

Overlapping genes (OGs) draw the focus of recent day’s research. However, the significance of OGs in prokaryotic genomes remained unexplored. As an adaptation to high temperature, thermophiles were shown to eliminate their intergenic regions. Therefore, it could be possible that prokaryotes would increase their OG content to adapt to high temperature. To test this hypothesis, we carried out a comparative study on OG frequency of 256 prokaryotic genomes comprising both thermophiles and non-thermophiles. It was found that thermophiles exhibit higher frequency of overlapping genes than non-thermophiles. Moreover, overlap frequency was found to correlate with optimal growth temperature (OGT) in prokaryotes. Long overlap frequency was found to hold a positive correlation with OGT resulting in an abundance of long overlaps in thermophiles compared to non-thermophiles. On the other hand, short overlap (1–4 nucleotides) frequency (SOF) did not yield any direct correlation with OGT. However, the correlation of SOF with CAIavg (extent of variation of codon usage bias measured as the mean of codon adaptation index of all genes in a given genome) and IG% (proportion of intergenic regions) indicate that they might upregulate the aforementioned factors (CAIavg and IG%) which are already known to be vital forces for thermophilic adaptation. From these evidences, we propose that the OG content bears a strong link to thermophily. Long overlaps are important for their genome compaction and short overlaps are important to uphold high CAIavg. Our findings will surely help in better understanding of the significance of overlapping gene content in prokaryotic genomes.

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.

Insights into the dN/dS ratio heterogeneity between brain specific genes and widely expressed genes in species of different complexity.

In mammals, it has long been suggested that brain-specific genes (BSGs) and widely expressed genes (WEGs) have seemingly lower dN/dS ratio than any other gene sets. However, to what extent these genes differ in their dN/dS ratio has still remained controversial. Here, we have revealed lower dN/dS ratio of BSGs than WEGs in human-mouse, human-orangutan, human-chimpanzee and mouse-rat orthologous pair. The significance level of dN/dS ratio difference indicates a trend of decreasing difference as complexity of compared pairs increases. Further studies with the human-mouse pair revealed that, removal of the duplicated genes from both the dataset has nullified this difference which dictates a vital role of duplicated genes in governing the selection pressure. Conclusively, higher paralog number, expression level, and longer regulatory region length of BSGs allow fewer nucleotide substitutions within them. Our results show for the first time to our knowledge lower dN/dS ratio of BSGs than WEGs.