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Publication Date:
January 2011
ISSN:
1544-6115
DOI:
10.2202/1544-6115.1603

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Editor-in-Chief: Stumpf, Michael P.H.

Editorial Board Member: Beaumont, Mark / Binder, Harald / Gupta, Mayetri / Hubbard, Alan E. / Husmeier, Dirk / Ji, Hongkai / Keles, Sunduz / Kerr, Kathleen / Lazzeroni, Laura / Lin, Shili / Ma, Ping / Marjoram, Paul / Mertens, Bart / Nerman, Olle / G. Petretto, Enrico / Plagnol, Vincent / Purdom, Elizabeth / Robin, Stéphane / Rzhetsky, Andrey / Sanguinetti, Guido / van der Laan, Mark J. / von Haeseler, Arndt / Weeks, Daniel E. / Wiuf, Carsten / Zhao, Hongyu

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IMPACT FACTOR 2011: 1.517
5-year IMPACT FACTOR: 1.704
Rank 27 out of 116 in category Statistics & Probability in the 2011 Thomson Reuters Journal Citation Report/Science Edition

Learning Monotonic Genotype-Phenotype Maps

Niko Beerenwinkel / Patrick Knupfer / Achim Tresch

1ETH Zürich

1ETH Zürich

1Ludwig-Maximilians-Universität München

Citation Information: Statistical Applications in Genetics and Molecular Biology. Volume 10, Issue 1, Pages 1–27, ISSN (Online) 1544-6115, DOI: 10.2202/1544-6115.1603, January 2011

Publication History:
Published Online:
2011-01-06

Evolutionary escape of pathogens from the selective pressure of immune responses and from medical interventions is driven by the accumulation of mutations. We introduce a statistical model for jointly estimating the dynamics and dependencies among genetic alterations and the associated phenotypic changes. The model integrates conjunctive Bayesian networks, which define a partial order on the occurrences of genetic events, with isotonic regression. The resulting genotype-phenotype map is non-decreasing in the lattice of genotypes. It describes evolutionary escape as a directed process following a phenotypic gradient, such as a monotonic fitness landscape. We present efficient algorithms for parameter estimation and model selection. The model is validated using simulated data and applied to HIV drug resistance data. We find that the effect of many resistance mutations is non-linear and depends on the genetic background in which they occur.

Keywords: genotype-phenotype map; conjunctive Bayesian networks; HIV drug resistance; isotonic regression

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