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Clonal heterogeneity influences the fate of new adaptive mutations

View ORCID ProfileIgnacio Vázquez-García, Francisco Salinas, Jing Li, Andrej Fischer, Benjamin Barré, Johan Hallin, Anders Bergström, Elisa Alonso-Perez, View ORCID ProfileJonas Warringer, Ville Mustonen, View ORCID ProfileGianni Liti
doi: https://doi.org/10.1101/039859
Ignacio Vázquez-García
1Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom
2Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge CB3 0WA, United Kingdom
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  • ORCID record for Ignacio Vázquez-García
  • For correspondence: ivg@sanger.ac.uk v.mustonen@helsinki.fi gianni.liti@unice.fr
Francisco Salinas
3Université Côte d’Azur, INSERM, CNRS, IRCAN, 06107 Nice, France
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Jing Li
3Université Côte d’Azur, INSERM, CNRS, IRCAN, 06107 Nice, France
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Andrej Fischer
1Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom
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Benjamin Barré
3Université Côte d’Azur, INSERM, CNRS, IRCAN, 06107 Nice, France
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Johan Hallin
3Université Côte d’Azur, INSERM, CNRS, IRCAN, 06107 Nice, France
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Anders Bergström
1Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom
3Université Côte d’Azur, INSERM, CNRS, IRCAN, 06107 Nice, France
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Elisa Alonso-Perez
4Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
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Jonas Warringer
4Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
5Centre for Integrative Genetics (CIGENE), Department of Animal and Aquacultural Sciences,Norwegian University of Life Sciences, Ås, Norway
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Ville Mustonen
1Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom
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  • For correspondence: ivg@sanger.ac.uk v.mustonen@helsinki.fi gianni.liti@unice.fr
Gianni Liti
3Université Côte d’Azur, INSERM, CNRS, IRCAN, 06107 Nice, France
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  • ORCID record for Gianni Liti
  • For correspondence: ivg@sanger.ac.uk v.mustonen@helsinki.fi gianni.liti@unice.fr
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Abstract

In Brief Vázquez-García et al. examine the role of clonal heterogeneity in the acquisition of antimicrobial resistance. They report that pre-existing and de novo genetic variation jointly contribute to clonal evolution. By building a library of adaptive mutations in multiple genetic backgrounds, they resolve the fitness effects of mutations in a clonal lineage.

  • Clonal heterogeneity influences the acquisition of antimicrobial resistance

  • Joint role of pre-existing and de novo genetic variation in clonal evolution

  • Clonal dynamics are shaped by background-dependent fitness effects of mutations

  • Loss of clonal heterogeneity is balanced by genomic instability and diversification

Summary The joint contribution of pre-existing and de novo genetic variation to clonal adaptation is poorly understood, but essential to design 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.

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Posted October 15, 2017.
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Clonal heterogeneity influences the fate of new adaptive mutations
Ignacio Vázquez-García, Francisco Salinas, Jing Li, Andrej Fischer, Benjamin Barré, Johan Hallin, Anders Bergström, Elisa Alonso-Perez, Jonas Warringer, Ville Mustonen, Gianni Liti
bioRxiv 039859; doi: https://doi.org/10.1101/039859
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Clonal heterogeneity influences the fate of new adaptive mutations
Ignacio Vázquez-García, Francisco Salinas, Jing Li, Andrej Fischer, Benjamin Barré, Johan Hallin, Anders Bergström, Elisa Alonso-Perez, Jonas Warringer, Ville Mustonen, Gianni Liti
bioRxiv 039859; doi: https://doi.org/10.1101/039859

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