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Cell Rep. 2017 Oct 17;21(3):732-744. doi: 10.1016/j.celrep.2017.09.046.

Clonal Heterogeneity Influences the Fate of New Adaptive Mutations.

Author information

1
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK; Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge CB3 0WA, UK. Electronic address: ivg@sanger.ac.uk.
2
Université Côte d'Azur, INSERM, CNRS, IRCAN, 06107 Nice, France.
3
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
4
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK; Université Côte d'Azur, INSERM, CNRS, IRCAN, 06107 Nice, France.
5
Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden.
6
Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden; Centre for Integrative Genetics (CIGENE), Department of Animal and Aquacultural Sciences, Norwegian University of Life Sciences, Ås, Norway.
7
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. Electronic address: v.mustonen@helsinki.fi.
8
Université Côte d'Azur, INSERM, CNRS, IRCAN, 06107 Nice, France. Electronic address: gianni.liti@unice.fr.

Abstract

The joint contribution of pre-existing and de novo genetic variation to clonal adaptation is poorly understood but essential to designing successful antimicrobial or cancer therapies. To address this, we evolve genetically diverse populations of budding yeast, S. cerevisiae, consisting of diploid cells with unique haplotype combinations. We study the asexual evolution of these populations under selective inhibition with chemotherapeutic drugs by time-resolved whole-genome sequencing and phenotyping. All populations undergo clonal expansions driven by de novo mutations but remain genetically and phenotypically diverse. The clones exhibit widespread genomic instability, rendering recessive de novo mutations homozygous and refining pre-existing variation. Finally, we decompose the fitness contributions of pre-existing and de novo mutations by creating a large recombinant library of adaptive mutations in an ensemble of genetic backgrounds. Both pre-existing and de novo mutations substantially contribute to fitness, and the relative fitness of pre-existing variants sets a selective threshold for new adaptive mutations.

KEYWORDS:

adaptation; clonal heterogeneity; drug resistance; genetic variation; genome evolution; mutation; population dynamics; quantitative traits

PMID:
29045840
PMCID:
PMC5656752
DOI:
10.1016/j.celrep.2017.09.046
[Indexed for MEDLINE]
Free PMC Article

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