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Systems Biology Programme Lea Starita

Systems Biology Programme Lea Starita

20/02/2020
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Systems Biology Programme Lea Starita

MARIE CURIE

20/02/202012:00MARIE CURIESystems Biology ProgrammeLea StaritaDepartment of Genome Sciences, Brotman Baty Institute, University of Washington“Understanding the functional effects of coding variation, at scale”Host: Lehner, BenAbstract:Interpreting the effects of genetic variation is the central challenge for the progress and prospects of precision medicine. Variant-effect prediction algorithms can classify any possible genetic variation but despite substantial efforts, they do not have the accuracy to support their use in a clinical setting. On the other hand, experimentally testing the effect of each individual variant on protein function or gene expression yields high-quality information, but is low-throughput. To resolve this, we are developing multiplexed assays for variant effect to determine the impact of thousands of genetic variants on protein function and/or gene expression in a single experiment. Using this approach, we comprehensively evaluated the effects of nearly 4,000 single nucleotide variants on both mRNA splicing and protein function of BRCA1. And determined the effect of 7,801 amino acid substitutions on the stability and function of two proteins important for the etiology and treatment of cancer, PTEN and TPMT. The resulting large-scale functional data can be combined with machine learning and clinical knowledge to develop “lookup tables” of accurate pathogenicity predictions. A coordinated effort to produce, analyze and disseminate large-scale functional data generated by multiplex assays may be essential to address the variant interpretation crisis caused by the increased use of DNA sequencing in the clinic.