Genome-wide validation of posttranscriptional variation in selection and disease

Harvard Medical School, Boston MA

Investigators

Linked publications, trials & patents

Abstract

? DESCRIPTION (provided by applicant): An influx of genotype data from disease cohorts and diverse ethnic groups is markedly increasing the power of genome-wide scans for disease association and positive selection. These scans identify loci relevant to the pathogenesis of disease and survival in the face of historic threats such as infectious agents, climate change, and dietary limitations, setting the stage for the development of genotype-based diagnostics and personalized therapeutics to reverse inherited disease and protect against acquired disease. However, it is difficult to isolate disease-causing variants from nearby neutral variants to which they are closely linked. One potential solution is to assay all potentially causal variants for molecular function. However, it is infeasible to individually assay the thousands of variants potentially associated with disease, especially in light of the prediction that most variants responsible for selection and disease will be regulatory. We aim to elucidate novel variants underlying disease and adaptive phenotypes by developing a high-throughput screen for posttranscriptional regulatory function. To accomplish this goal, we will adapt the recently described Massively Parallel Reporter Assay (MPRA) to allow the quantification of allelic differences in expression and translation for thousands of variants in tandem. We will utilize this adapted MPRA to comprehensively assay loci implicated in disease and adaptation for variants with posttranscriptional function. Finally, after identifying variants with quantifiable effects on expression or translation, we will perform targeted follow-up studies to gain mechanistic insight into posttranscriptional processes underlying these traits. These aims will enable us to move from genome-wide scans for disease and selection to elucidation of posttranscriptional mechanisms that may be manipulated to devise novel therapeutic approaches.