Integrative Computational Analysis of Common EXO5 Haplotypes: Impact on Protein Dynamics, Genome Stability, and...

Area of Science:

• Genetics
• Molecular Biology
• Computational Biology

Background:

• Germline variants influence protein function and disease susceptibility.
• The EXO5 gene, encoding a DNA repair exonuclease, has been linked to cancer.
• Understanding common variants' impact is crucial for cancer research.

Purpose of the Study:

• To investigate the structural, functional, and clinical impact of common EXO5 gene haplotypes.
• To analyze how genetic variations in EXO5 affect protein dynamics and cancer patient outcomes.

Main Methods:

• Haplotype analysis of EXO5 across populations.
• Deep learning variant effect prediction.
• All-atom molecular dynamics (MD) simulations.
• Analysis of The Cancer Genome Atlas (TCGA) clinical data.

Main Results:

• Identified five common EXO5 haplotypes.
• MD simulations revealed significant structural and dynamic differences in EXO5 variants, especially in the catalytic region.
• The L151P variant showed major conformational changes, potentially impairing function and nuclear localization.
• Patients with L151P EXO5 had shorter progression-free survival in prostate and pancreatic cancers and increased genomic instability.

Conclusions:

• Common genetic variants, like those in EXO5, can significantly alter protein structure and function.
• The L151P EXO5 variant is associated with adverse cancer outcomes and genomic instability.
• The integrated methodology effectively uncovers the disease implications of common genetic variants.