TTNPred · Development of novel computational biology pipeline for the efficient classification of titin SNPs for clinical use

Development of novel computational biology pipeline for the efficient classification of titin SNPs for clinical use

Mutations in the giant muscle protein titin are a major cause of heart disorders in human populations. Routine DNA screening of patient cohorts is now becoming feasible, with a staggering number of titin truncations and missense single nucleotide polymorphisms (mSNPs) rapidly accumulating in genomics databases (>17,000 mSNPs). While the link between titin truncation and disease is now becoming clarified, detecting the pathogenic potential of mSNPs remains a substantial challenge. In mSNPs classification, bioinformatics evaluation is a necessary first filtering step, but existing predictors are poorly reliable. To address this problem, we aim to develop a new titin-centric scoring function that predicts the mechanistic effect of an mSNP exchange in the titin protein by considering the specific characteristics of its poly-domain chain. For this work, we built a medium-throughput molecular diagnostic pipeline that harvests existent structural models of titin components in estimating mSNPs-induced changes in free energy and conformational dynamics in the protein. To develop this methodology, we used mSNPs from a dataset of healthy people over 60 whose SNPs can be assumed to not cause disease. Identified positions which are tolerant to change will be extrapolated to the rest of the titin chain by exploiting the repetition of structural and functional loci within the chain. This allowed us to reinterpret SNP data from other public databases, as well as expand the structural knowledge from one area of titin to another. A titin map of vulnerability was then calculated and will be distributed to the research community. Ultimately, we aim to produce a tool that can aid clinicians to identify patients at risk of developing a titin-based heart condition at early disease stages, where intervention is still possible.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз