A functional multi-omics approach to identify… (F31HG015198) – Project Grant to The Univeristy Of Texas M.d.…

Abstract: Accurately interpreting the clinical significance of variation in the human germline is important for diagnosing genetic disorders and making informed medical decisions. Despite advancements in biobanks and predictive tools for assigning pathogenicity classifications to variants, variant interpretation is still challenging due to the incomplete manifestation (or penetrance) of phenotypes, and if phenotypes do manifest, the variability in their severity. These biological phenomena have been postulated to be in part caused by environmental factors, but the mechanisms that mediate gene-environment interactions are elusive. To improve variant interpretation, i propose to identify the origins of the environmental sensitivity of health and disease traits by capitalizing on our discovery of mutations buffered by the protein-folding chaperone HSP90. In cells, we found that HSP90 can mitigate the phenotypic effects of mutations in two disease-associated DNA repair genes, fanca and BRCA1, by creating a protein-folding buffer that stabilizes encoded mutant proteins. Moreover, proteotoxic environmental exposures, such as fever, can exhaust the HSP90 buffer and reveal the phenotypic effects of mutations. Since HSP90 assists in the folding of many proteins in the cellular proteome, HSP90 is ideally positioned to contribute to the environmental sensitivity of many health and disease traits. The goal of this proposal is to estimate the amount of variation in disease-critical genes that is HSP90-buffered and determine whether buffering has any impact on allele fitness and clinical phenotypes in human populations. Specifically, i aim to: 1) identify all HSP90- buffered and non-buffered single-nucleotide fanca variants using an innovative unbiased high-throughput and cell-based functional genomics approach. Using data from population cohorts, i will compare allele frequencies and conduct genotype-phenotype analyses to determine whether HSP90 promotes mutation accumulation and alleviates the clinical phenotypes of mutations. I will also analyze if proteotoxic environmental factors influence clinical phenotypes through HSP90; 2) identify an HSP90 cofactor protein (or "CO-chaperone") that selectively associates with HSP90-buffered fanca mutants in protein-protein interaction assays and can thus serve as a biomarker for HSP90 buffering across diverse disease-critical genes. The biomarker will be used to map HSP90- buffered mutations in BRCA1 stored in clinvar. This research is important because IT will evaluate HSP90's significance in the environmental sensitivity of genetic variation, revolutionizing variant interpretation and preci- sion medicine by defining a mechanism that predictably modulates the phenotypes of many genetic disorders in response to clinically relevant environmental exposures. Such research could also increase the statistical power of genome-wide association studies by grouping variation into HSP90-buffered categories. Furthermore, this proposal is designed to provide the principal investigator with a unique multidisciplinary training experience that will foster his development into an independent scientist advancing precision medicine for genetic disorders and studies of the human genome.

A functional multi-omics approach to identify HSP90-buffered genetic variation

Award facts

Description

Quick answers

Who received award F31HG015198?

How much is award F31HG015198 worth?

See this award's full record