Background-dependent effects of selection on subclonal heterogeneity

BioRxiv : the Preprint Server for Biology
Ignacio Vázquez-GarcíaGianni Liti


The contribution of pre-existing and de novo genetic variation towards clonal adaptation is poorly understood, but essential to design successful antibiotic or cancer therapies. To address this, we evolved genetically diverse populations of budding yeast, S. cerevisiae , consisting of ∼107 diploid cells with unique haplotype combinations. We studied the asexual evolution of these populations under selective inhibition of DNA replication and cell metabolism by time-resolved whole-genome sequencing and phenotyping. All populations underwent clonal expansions driven by de novo mutations, but remained genetically and phenotypically diverse. Despite the genetic diversity of the founder cells, we observed recurrent adaptive mutations. However, the founding fitness variance limited the scope for adaptive mutations to expand. The clones exhibited continued evolution by widespread genome instability, rendering recessive de novo mutations homozygous and refining pre-existing variation. Our results show that three intertwined processes dominate the adaptive response: exploiting genetic backgrounds, de novo mutations and genome instability.

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