KIT | KIT-Bibliothek | Impressum | Datenschutz

Coevolutionary Landscape Inference and the Context-Dependence of Mutations in Beta-Lactamase TEM-1

Figliuzzi, M.; Jacquier, H.; Schug, A. 1; Tenaillon, O.; Weigt, M.
1 Scientific Computing Center (SCC), Karlsruher Institut für Technologie (KIT)

Abstract:

The quantitative characterization of mutational landscapes is a task of outstanding importance in evolutionary and medical biology: It is, for example, of central importance for our understanding of the phenotypic effect of mutations related to disease and antibiotic drug resistance. Here we develop a novel inference scheme for mutational landscapes, which is based on the statistical analysis of large alignments of homologs of the protein of interest. Our method is able to capture epistatic couplings between residues, and therefore to assess the dependence of mutational effects on the sequence context where they appear. Compared with recent large-scale mutagenesis data of the beta-lactamase TEM-1, a protein providing resistance against beta-lactam antibiotics, our method leads to an increase of about 40% in explicative power as compared with approaches neglecting epistasis. We find that the informative sequence context extends to residues at native distances of about 20 Å from the mutated site, reaching thus far beyond residues in direct physical contact.

Zugehörige Institution(en) am KIT Scientific Computing Center (SCC)
Universität Karlsruhe (TH) – Zentrale Einrichtungen (Zentrale Einrichtungen)
Publikationstyp Zeitschriftenaufsatz
Publikationsjahr 2015
Sprache Englisch
Identifikator ISSN: 1537-1719
urn:nbn:de:swb:90-529055
KITopen-ID: 1000052905
HGF-Programm 46.11.01 (POF III, LK 01) Computational Science and Mathematical Methods
Erschienen in Molecular Biology and Evolution
Verlag Oxford University Press (OUP)
Band 33
Heft 1
Seiten 268-280
Schlagwörter mutational landscape, genotype–phenotype mapping, epistasis, coevolution, statistical inference
Nachgewiesen in Web of Science
Dimensions
Scopus

Volltext §
DOI: 10.5445/IR/1000052905
Originalveröffentlichung
DOI: 10.1093/molbev/msv211
Scopus
Zitationen: 177
Web of Science
Zitationen: 166
Dimensions
Zitationen: 280
Seitenaufrufe: 247
seit 06.05.2018
Downloads: 264
seit 16.03.2016
Cover der Publikation
KIT – Die Forschungsuniversität in der Helmholtz-Gemeinschaft
KITopen Landing Page