Comput. Biol. Med. - Cladograms with Path to Event (ClaPTE): a novel algorithm to detect associations between genotypes or phenotypes using phylogenies.

Tópicos

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Resumo

CKGROUND: Associations between genotype and phenotype provide insight into the evolution of pathogenesis, drug resistance, and the spread of pathogens between hosts. However, common ancestry can lead to apparent associations between biologically unrelated features. The novel method Cladograms with Path to Event (ClaPTE) detects associations between character-pairs (either a pair of mutations or a mutation paired with a phenotype) while adjusting for common ancestry, using phylogenetic trees.METHODS: ClaPTE tests for character-pairs changing close together on the phylogenetic tree, consistent with an associated character-pair. ClaPTE is compared to three existing methods (independent contrasts, mixed model, and likelihood ratio) to detect character-pair associations adjusted for common ancestry. Comparisons utilize simulations on gene trees for: HIV Env, HIV promoter, and bacterial DnaJ and GuaB; and case studies for Oseltamavir resistance in Influenza, and for DnaJ and GuaB. Simulated data include both true-positive/associated character-pairs, and true-negative/not-associated character-pairs, used to assess type I (frequency of p-values in true-negatives) and type II (sensitivity to true-positives) error control.RESULTS AND CONCLUSIONS: ClaPTE has competitive sensitivity and better type I error control than existing methods. In the Influenza/Oseltamavir case study, ClaPTE reports no new permissive mutations but detects associations between adjacent (in primary sequence) amino acid positions which other methods miss. In the DnaJ and GuaB case study, ClaPTE reports more frequent associations between positions both from the same protein family than between positions from different families, in contrast to other methods. In both case studies, the results from ClaPTE are biologically plausible.

Resumo Limpo

ckground associ genotyp phenotyp provid insight evolut pathogenesi drug resist spread pathogen host howev common ancestri can lead appar associ biolog unrel featur novel method cladogram path event clapt detect associ characterpair either pair mutat mutat pair phenotyp adjust common ancestri use phylogenet treesmethod clapt test characterpair chang close togeth phylogenet tree consist associ characterpair clapt compar three exist method independ contrast mix model likelihood ratio detect characterpair associ adjust common ancestri comparison util simul gene tree hiv env hiv promot bacteri dnaj guab case studi oseltamavir resist influenza dnaj guab simul data includ truepositiveassoci characterpair truenegativenotassoci characterpair use assess type frequenc pvalu trueneg type ii sensit trueposit error controlresult conclus clapt competit sensit better type error control exist method influenzaoseltamavir case studi clapt report new permiss mutat detect associ adjac primari sequenc amino acid posit method miss dnaj guab case studi clapt report frequent associ posit protein famili posit differ famili contrast method case studi result clapt biolog plausibl

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