Grant: Foundation Grant

Bioinformatics; Biological Networks; Biological Pathways; Computational Biology; Disease Mechanisms; Functional Genomics; Protein Domains; Protein Interactions; Proteomics

<html> <body> <p>One of the most important challenges in human genetics is to identify all of the genomic variants that cause disease. This knowledge will help identify new therapies and make medicine more precise by enabling more specific patient diagnosis and prognosis. Traditional correlative approaches to this problem, such as genome wide association studies (GWAS), are costly and often identify only a few significant variants. Despite massive efforts on GWAS, most human genetic disease causes remain unexplained(1). This knowledge gap has been attributed to rare causal variants or variant interactions, which have proven difficult to discover by traditional methods. <strong>The overall goal of my research program is to address this challenge using an innovative computational and experimental approach that integrates &rsquo;omics data from patient samples with information about cellular mechanisms to discover novel causal mechanisms of human disease.</strong> </p> <p>Rather than considering millions of data points at the level of genetic variants, my approach organizes &rsquo;omics data into a much smaller space of biological pathways and mechanisms and associates these fewer variables with disease, thus greatly increasing statistical and interpretative power. In particular, protein, RNA and DNA binding sites, important in connecting molecules within pathways, provide key links from genetic sequences to cellular systems and phenotypes. Mutations in binding sites central to cell regulatory pathways are more likely to cause disease than those in non-functional regions. My team has successfully exploited this link to identify cancer driver and causal disease mutations not detectable by other approaches. We have also identified novel causal mechanisms in multiple cancer types and a rare skin disorder, which we are experimentally validating. I now seek to apply our approach to a wider range of cell mechanisms and information about human genetic variation, which will substantially improve our ability to discover new disease mechanisms.</p> <p>Work from two previous successful CIHR funding cycles since 2007 has enabled me to build a highly productive research program (28 CIHR funded publications, &gt;10 in progress). My program has evolved from considering protein-protein interactions (PPIs) in model organisms (in 2007), to PPIs in human cells (in 2010) and now focuses on identifying mechanisms underlying human disease. Building on this success, my team is now poised to address the following aims to discover and validate novel causes of multiple genetic diseases (Fig 1).<br> <strong>1. Expand our binding site resolution human molecular interaction network to improve our ability to find genetic causes of disease.</strong> <br> <strong>2. Develop novel methods to predict how mutations affect cellular mechanisms and cause disease.</strong> <br> <strong>3. Apply our innovative methods to all available disease-linked mutation data and experimentally study novel disease mechanisms we identify.</strong> </p> <p>Ultimately, I expect my patient &rsquo;omics data analysis approach to have the power to concretely improve patient outcomes. I have assembled a world-leading and multidisciplinary team of scientists, trainees and unique computational and experimental resources to work towards this goal. As the program evolves, causal mutations we discover are expected to impact precision medicine and drug development, increasingly leading to translational opportunities that my team will pursue via my connections with clinicians in Toronto&rsquo;s world-leading research hospitals.</p> </body> </html>