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In Brief

Vázquez-García et al. examine the role of clonal heterogeneity in the acquisition of antimicrobial resistance. They report that pre-existing andde novogenetic 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.

Highlights

• Clonal heterogeneity influences the acquisition of antimicrobial resistance

• Joint role of pre-existing andde novogenetic 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 andde novogenetic 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 byde novomutations, but remain genetically and phenotypically diverse. The clones exhibit widespread genomic instability, rendering recessivede novomutations homozygous and refining pre-existing variation. Finally, we decompose the fitness contributions of pre-existing andde novomutations by creating a large recombinant library of adaptive mutations in an ensemble of genetic backgrounds. Both pre-existing andde novomutations substantially contribute to fitness, and the relative fitness of pre-existing variants sets a selective threshold for new adaptive mutations.