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PHACT: Phylogeny-Aware Computing of Tolerance for Missense Mutations.

Nurdan Kuru1, Onur Dereli1, Emrah Akkoyun1

  • 1Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul 34956, Turkey.

Molecular Biology and Evolution
|May 31, 2022
PubMed
Summary

PHACT is a novel method predicting missense mutation pathogenicity using protein phylogenetic trees. It outperforms existing tools by considering evolutionary relationships, improving protein function loss prediction.

Keywords:
Mendelian diseasesamino acid substitutionpathogenicity scoringphylogenetics

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Area of Science:

  • Bioinformatics
  • Computational Biology
  • Genomics

Background:

  • Evolutionary conservation is crucial for predicting amino acid substitutability and protein function loss.
  • Traditional methods using multiple sequence alignment neglect evolutionary relationships, leading to redundant event counting.

Purpose of the Study:

  • To introduce PHACT, a new method for predicting missense mutation pathogenicity directly from protein phylogenetic trees.
  • To evaluate PHACT's performance against established pathogenicity prediction tools.

Main Methods:

  • PHACT traverses protein phylogenetic trees, assessing substitution deleteriousness via ancestral amino acid probability differences between nodes.
  • The method weights tree nodes based on their distance to the query organism.
  • A score is generated for each substitution to quantify its effect on protein function.

Main Results:

  • PHACT demonstrated superior predictive performance compared to SIFT and PolyPhen-2.
  • The method also outperformed other conventional statistical approaches found in dbNSFP.
  • Experiments were conducted on datasets comprising 3,023 proteins and 61,662 variants.

Conclusions:

  • PHACT offers a more accurate approach to predicting missense mutation pathogenicity by incorporating evolutionary information.
  • The method provides a valuable tool for understanding protein function loss and genetic variation impact.