RT Journal Article
SR Electronic
T1 Background-dependent effects of selection on subclonal heterogeneity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 039859
DO 10.1101/039859
A1 Ignacio Vázquez-García
A1 Francisco Salinas
A1 Jing Li
A1 Andrej Fischer
A1 Benjamin Barré
A1 Johan Hallin
A1 Anders Bergström
A1 Elisa Alonso-Perez
A1 Jonas Warringer
A1 Ville Mustonen
A1 Gianni Liti
YR 2016
UL http://biorxiv.org/content/early/2016/07/27/039859.abstract
AB 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.