Abstract
Understanding the impact of common germline variants on protein structure, function, and disease progression is crucial in cancer research. This study presents a comprehensive analysis of the EXO5 gene, which encodes a DNA exonuclease involved in DNA repair that was previously associated with cancer susceptibility. We employed an integrated approach combining genomic and clinical data analysis, deep learning variant effect prediction, and molecular dynamics (MD) simulations to investigate the effects of common EXO5 haplotypes on protein structure, dynamics, and cancer outcomes. We characterized the haplotype structure of EXO5 across diverse human populations, identifying five common haplotypes, and studied their impact on the EXO5 protein. Extensive, all-atom MD simulations revealed significant structural and dynamic differences among the EXO5 protein variants, particularly in their catalytic region. The L151P EXO5 protein variant exhibited the most substantial conformational changes, potentially disruptive for EXO5's function and nuclear localization. Analysis of The Cancer Genome Atlas data showed that cancer patients carrying L151P EXO5 had significantly shorter progression-free survival in prostate and pancreatic cancers and exhibited increased genomic instability. This study highlights the strength of our methodology in uncovering the effects of common genetic variants on protein function and their implications for disease outcomes.