Cooperative mechanical effects hinder natural selection in dense cellular populations

Many cellular populations exist in a densely packed state where cells must physically push aside their neighbors in order to proliferate. Using S. cerivisiae experiments and computational models, we show that these growth-induced forces generate an effective surface-tension that flattens the surface of expanding colonies. This effective surface tension couples the evolutionary fate of phenotypes across mesoscopic length-scales, strongly attenuating selective efficiency in comparison to previous non-mechanical spatial models. As a consequence, deleterious (slower growing) mutants are purged from the population much more slowly than predicted by previous models. We show that this slow purging facilitates the rescue of costly alleles upon a subsequent adaptive gain. Due to its purely mechanical nature, we expect this effect to be present in a wide range of sufficiently dense cellular populations. Our finding is particularly relevant to the emergence of antibiotic resistance, where mechanical-attenuated selection is expected to promote the emergence of drug resistant phenotypes associated with a fitness cost prior to treatment.