Shared Molecular Targets Confer Resistance over Short and Long Evolutionary Timescales
Journal article, 2019

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.

de novo mutation


budding yeast

drug resistance

pre-existing genetic variation


Jing Li

University of Côte d'Azur

Ignacio Vázquez-García

Columbia University

University of Cambridge

Karl Persson

University of Gothenburg

Asier González

University of Basel

Jia Xing Yue

University of Côte d'Azur

Benjamin P. Barré

University of Côte d'Azur

Michael N. Hall

University of Basel

Anthony Long

University of California at Irvine (UCI)

Jonas Warringer

University of Gothenburg

Ville Mustonen

University of Helsinki

Gianni Liti

University of Côte d'Azur

Molecular Biology and Evolution

0737-4038 (ISSN) 1537-1719 (eISSN)

Vol. 36 4 691-708

Subject Categories

Evolutionary Biology

Biochemistry and Molecular Biology




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