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Shared Molecular Targets Confer Resistance over Short and Long Evolutionary Timescales

Journal article
Authors J. Li
I. Vázquez-García
Karl O. Persson
A. González
J. X. Yue
B. Barré
M. N. Hall
A. Long
Jonas Warringer
V. Mustonen
G. Liti
Published in Molecular biology and evolution
Volume 36
Issue 4
Pages 691-708
ISSN 1537-1719
Publication year 2019
Published at Department of Chemistry and Molecular Biology
Pages 691-708
Language en
Keywords adaptation, budding yeast, de novo mutation, drug resistance, pre-existing genetic variation
Subject categories Evolutionary Biology, Biochemistry and Molecular Biology


Pre-existing and de novo genetic variants can both drive adaptation to environmental changes, but their relative contributions and interplay remain poorly understood. Here we investigated the evolutionary dynamics in drug-treated yeast populations with different levels of pre-existing variation by experimental evolution coupled with time-resolved sequencing and phenotyping. We found a doubling of pre-existing variation alone boosts the adaptation by 64.1% and 51.5% in hydroxyurea and rapamycin, respectively. The causative pre-existing and de novo variants were selected on shared targets: RNR4 in hydroxyurea and TOR1, TOR2 in rapamycin. Interestingly, the pre-existing and de novo TOR variants map to different functional domains and act via distinct mechanisms. The pre-existing TOR variants from two domesticated strains exhibited opposite rapamycin resistance effects, reflecting lineage-specific functional divergence. This study provides a dynamic view on how pre-existing and de novo variants interactively drive adaptation and deepens our understanding of clonally evolving populations. © The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail:

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