PHACT: phylogeny-aware computing of tolerance for missense mutations

Kuru, Nurdan and Dereli, Onur and Akkoyun, Emrah and Bircan, Aylin and Taştan, Öznur and Adebali, Ogün (2022) PHACT: phylogeny-aware computing of tolerance for missense mutations. Molecular Biology and Evolution, 39 (6). ISSN 0737-4038 (Print) 1537-1719 (Online)

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Evolutionary conservation is a fundamental resource for predicting the substitutability of amino acids and the loss of function in proteins. The use of multiple sequence alignment alone-without considering the evolutionary relationships among sequences-results in the redundant counting of evolutionarily related alteration events, as if they were independent. Here, we propose a new method, PHACT, that predicts the pathogenicity of missense mutations directly from the phylogenetic tree of proteins. PHACT travels through the nodes of the phylogenetic tree and evaluates the deleteriousness of a substitution based on the probability differences of ancestral amino acids between neighboring nodes in the tree. Moreover, PHACT assigns weights to each node in the tree based on their distance to the query organism. For each potential amino acid substitution, the algorithm generates a score that is used to calculate the effect of substitution on protein function. To analyze the predictive performance of PHACT, we performed various experiments over the subsets of two datasets that include 3,023 proteins and 61,662 variants in total. The experiments demonstrated that our method outperformed the widely used pathogenicity prediction tools (i.e., SIFT and PolyPhen-2) and achieved a better predictive performance than other conventional statistical approaches presented in dbNSFP. The PHACT source code is available at
Item Type: Article
Uncontrolled Keywords: amino acid substitution; Mendelian diseases; pathogenicity scoring; phylogenetics
Divisions: Faculty of Engineering and Natural Sciences
Depositing User: Nurdan Kuru
Date Deposited: 21 Aug 2022 22:08
Last Modified: 21 Aug 2022 22:08

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