Comparative Genomics and Bioinformatics of Disease Processes

We aim to carry out a bioinformatics analysis of DNA/RNA/protein functional elements, alterations of which lead to diseases. Genetic variations (both acquired and inherited modifications in sequences) and epigenetic variations (in methylation patterns) affect the functional elements leading to aberrations in molecular processes such as DNA replication and pre-mRNA processing. The goal of our team is to carry out research leading to development of computational pipelines that decipher functional elements on disease genes, and that delineate associations with disease-causing genetic/epigenetic variations. It is envisaged that this work leads to developing novel RNA/protein based therapies.

TEAM LEADER: Alphonse Thanaraj Thangavel

TEAM MEMBERS: Matteo Floris, Massimiliano Orsini

Research Focus: Genetic variations and mutations can affect functional DNA/RNA elements leading to aberrations in molecular processes. These processes include DNA replication, transcription, mRNA processing, RNA stability/translation, and protein folding. Functional elements include sites of recombination, of chromosome rearrangements, of methylations, of transcription factor binding, of transcription start, of splicing, of polyadenylation, of UTR elements responsible for stability & translation efficiency of mRNAs, of RNA cis- and trans-regulatory elements, and of critical structural/functional regions on proteins. A major emphasis is to study the association between transcript variants, expression of ncRNA elements/molecules, and genetic variations in the formation of diseases. We conduct research that leads to developing computational pipelines to decipher the functional elements and to decipher the associations with disease-causing genetic variations. Such an effort is expected to lead to a suite of tools and data resources that serve as knowledgebase (to design RNA/protein based therapies) for researchers in disease processes.

Ongoing exemplary project - Splice-Mediated Changes in Isoform Protein Sequences.

Human genome encodes a surprisingly low number of genes; however a large transriptome has been reported for human. Alternative splicing, during the processing of pre-mRNA (transcribed from a gene), of exons is a major contributor to the diversity seen in transcriptome and proteome. Alternatively spliced transcripts from a gene often encode functionally diverse isoform proteins. The synthesis of these isoform proteins is often specific to tissue types, development stages and disease states. At least 15% of human disease-causing mutations occur at splice sites and mediate formation of alterate transcripts and hence isoform proteins. Thus, it is important to characterise functional changes in isoform proteins and to understand the association between the pathological states of the cells and the synthesised protein isoforms; this will help in developing novel peptide-based probes and targets for identifying and treating human diseases. We have now identified a set of disease genes which are alternatively spliced to encode protein isoforms with changes in the organisation/structure of domains and functional signatures.

Database on splice-mediated changes in protein isoform sequences.

The above work has led to a database SpliVaP (Splicing and variant proteins) accessible from here.

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Comparative Genomics and Bioinformatics of Disease Processes

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	Comparative Genomics and Bioinformatics of Disease Processes We aim to carry out a bioinformatics analysis of DNA/RNA/protein functional elements, alterations of which lead to diseases. Genetic variations (both acquired and inherited modifications in sequences) and epigenetic variations (in methylation patterns) affect the functional elements leading to aberrations in molecular processes such as DNA replication and pre-mRNA processing. The goal of our team is to carry out research leading to development of computational pipelines that decipher functional elements on disease genes, and that delineate associations with disease-causing genetic/epigenetic variations. It is envisaged that this work leads to developing novel RNA/protein based therapies. TEAM LEADER: Alphonse Thanaraj Thangavel TEAM MEMBERS: Matteo Floris, Massimiliano Orsini Research Focus: Genetic variations and mutations can affect functional DNA/RNA elements leading to aberrations in molecular processes. These processes include DNA replication, transcription, mRNA processing, RNA stability/translation, and protein folding. Functional elements include sites of recombination, of chromosome rearrangements, of methylations, of transcription factor binding, of transcription start, of splicing, of polyadenylation, of UTR elements responsible for stability & translation efficiency of mRNAs, of RNA cis- and trans-regulatory elements, and of critical structural/functional regions on proteins. A major emphasis is to study the association between transcript variants, expression of ncRNA elements/molecules, and genetic variations in the formation of diseases. We conduct research that leads to developing computational pipelines to decipher the functional elements and to decipher the associations with disease-causing genetic variations. Such an effort is expected to lead to a suite of tools and data resources that serve as knowledgebase (to design RNA/protein based therapies) for researchers in disease processes. Ongoing exemplary project - Splice-Mediated Changes in Isoform Protein Sequences. Human genome encodes a surprisingly low number of genes; however a large transriptome has been reported for human. Alternative splicing, during the processing of pre-mRNA (transcribed from a gene), of exons is a major contributor to the diversity seen in transcriptome and proteome. Alternatively spliced transcripts from a gene often encode functionally diverse isoform proteins. The synthesis of these isoform proteins is often specific to tissue types, development stages and disease states. At least 15% of human disease-causing mutations occur at splice sites and mediate formation of alterate transcripts and hence isoform proteins. Thus, it is important to characterise functional changes in isoform proteins and to understand the association between the pathological states of the cells and the synthesised protein isoforms; this will help in developing novel peptide-based probes and targets for identifying and treating human diseases. We have now identified a set of disease genes which are alternatively spliced to encode protein isoforms with changes in the organisation/structure of domains and functional signatures. Database on splice-mediated changes in protein isoform sequences. The above work has led to a database SpliVaP (Splicing and variant proteins) accessible from here.