The inevitability of unconditionally deleterious substitutions during adaptation

TL;DR

This paper demonstrates that during adaptation, the initial genetic substitutions are often deleterious, challenging the assumption that only beneficial mutations fix, with implications for understanding evolutionary dynamics.

Contribution

It proves that unconditionally deleterious substitutions frequently occur during early adaptation under various models, including house-of-cards and Fisher's geometric model.

Findings

First substitutions are often deleterious during adaptation.

Deleterious substitutions occur even on smooth fitness landscapes.

Ignoring deleterious mutations leads to incorrect evolutionary predictions.

Abstract

Studies on the genetics of adaptation typically neglect the possibility that a deleterious mutation might fix. Nonetheless, here we show that, in many regimes, the first substitution is most often deleterious, even when fitness is expected to increase in the long term. In particular, we prove that this phenomenon occurs under weak mutation for any house-of-cards model with an equilibrium distribution. We find that the same qualitative results hold under Fisher's geometric model. We also provide a simple intuition for the surprising prevalence of unconditionally deleterious substitutions during early adaptation. Importantly, the phenomenon we describe occurs on fitness landscapes without any local maxima and is therefore distinct from "valley-crossing". Our results imply that the common practice of ignoring deleterious substitutions leads to qualitatively incorrect predictions in many regimes. Our results also have implications for the substitution process at equilibrium and for the response to a sudden decrease in population size.