Background-dependent effects of selection on subclonal heterogeneity

Abstract

In BriefVazquez-Garcia 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.\n\nHighlightsO_LIClonal heterogeneity influences the acquisition of antimicrobial resistance\nC_LIO_LIJoint role of pre-existing and de novo genetic variation in clonal evolution\nC_LIO_LIClonal dynamics are shaped by background-dependent fitness effects of mutations\nC_LIO_LILoss of clonal heterogeneity is balanced by genomic instability and diversification\nC_LI\n\nSummaryThe 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.