Complex Evolution of Resistance in Spatially Structured Populations
Final Report Abstract
Cellular evolution is one of the primary causes for the failure of modern antibiotic and chemotherapeutic treatments. As pathogenic cellular populations grow, they can acquire mutations in their genome, some of which may render their carriers resistant to one or even multiple drugs. Leveraging the power of DNA sequencing and genetic reconstitution, recent work has yielded enormous progress in our understanding of the mechanisms of resistance and their fitness effects in different environments. Notably, many drug resistance mutations are associated with a fitness cost in the absence of the drug and therefore subject to purifying selection. It has been speculated that such resistant clones may escape being purged from the population via natural selection by acquiring subsequent compensatory mutations. My postdoctoral research showed that the collective motion of cells in compact population can substantially evolutionary outcomes by hampering purging selection and, as a result, accelerate drug resistance evolution. Growing colonies of genetically tailored cells of the yeast S. cerivisiae, featuring synthetic mutations that can be tuned in rate and effect, allowed me to spatio-temporally track lineage fates and evolutionary rescue dynamics with unprecedented accuracy. Comparing empirical results to computer simulations and mathematical models revealed that collective effects can aggravate drug resistance evolution. The uncovered mechanisms have to be considered when predicting the rate of drug resistance evolution in dense cellular populations, including microbial biofilms and solid tumors, and might crucially inform novel treatment strategies, such as adaptive therapy.
Publications
- Excess of mutational jackpot events in expanding populations revealed by spatial Luria-Delbruck experiments. Nature Communications, 7, 2016
Diana Fusco, Matti Gralka, Jona Kayser, Alex Anderson, and Oskar Hallatschek
(See online at https://doi.org/10.1038/ncomms12760) - SCWISh network is essential for survival under mechanical pressure. Proceedings of the National Academy of Sciences, 114(51):13465– 13470, 2017
Morgan Delarue, Gregory Poterewicz, Ori Hoxha, Jessica Choi, Wonjung Yoo, Jona Kayser, Liam Holt, and Oskar Hallatschek
(See online at https://doi.org/10.1073/pnas.1711204114) - Emergence of evolutionary driving forces in pattern-forming microbial populations. Philosophical Transactions of the Royal Society B: Biological Sciences, 373(1747):20170106, 2018
Jona Kayser, Carl F Schreck, QinQin Yu, Matti Gralka, and Oskar Hallatschek
(See online at https://doi.org/10.1098/rstb.2017.0106) - Collective motion conceals fitness differences in crowded cellular populations. Nature Ecology & Evolution, 3(1):125–134, 2019
Jona Kayser, Carl S Schreck, Matti Gralka, Diana Fusco, and Oskar Hallatschek
(See online at https://doi.org/10.1038/s41559-018-0734-9) - Impact of crowding on the diversity of expanding populations. Proceedings of the National Academy of Sciences
Carl F Schreck, Diana Fusco, Yuya Karita, Stephen Martis, Jona Kayser, Marie-Cecilia Duvernoy, and Oskar Hallatschek
(See online at https://doi.org/10.1101/743534)
