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Experiments on the Role of Deleterious Mutations As Stepping Stones In Experiments on the role of deleterious mutations as PNAS PLUS stepping stones in adaptive evolution Arthur W. Covert IIIa,b,c,d, Richard E. Lenskia,c,e,1, Claus O. Wilkec,d, and Charles Ofriaa,b,c,1 aProgram in Ecology, Evolutionary Biology and Behavior, Departments of bComputer Science and Engineering and eMicrobiology and Molecular Genetics, and cBEACON Center for the Study of Evolution in Action, Michigan State University, East Lansing, MI 48824; and dCenter for Computational Biology, Institute for Cellular and Molecular Biology, and Department of Integrative Biology, University of Texas at Austin, Austin, TX 78712 Contributed by Richard E. Lenski, July 16, 2013 (sent for review April 22, 2013) Many evolutionary studies assume that deleterious mutations spread unless they are tightly linked (5, 6). In an asexual pop- necessarily impede adaptive evolution. However, a later mutation ulation, however, the fortuitous combination, once formed, will that is conditionally beneficial may interact with a deleterious be stably inherited, thereby providing a simple way to traverse a predecessor before it is eliminated, thereby providing access to fitness valley (5–10). adaptations that might otherwise be inaccessible. It is unknown Previous research on a variety of systems, both biological and whether such sign-epistatic recoveries are inconsequential events computational, has documented many examples of epistatic inter- or an important factor in evolution, owing to the difficulty of actions between mutations (3, 6, 11, 14–24), including a few cases monitoring the effects and fates of all mutations during experi- of mutational pairs that are individually deleterious but jointly ments with biological organisms. Here, we used digital organisms beneficial (11, 12). Nonetheless, it remains unclear, even in digital to compare the extent of adaptive evolution in populations when systems, whether these cases have a significant impact on the rate deleterious mutations were disallowed with control populations of adaptive evolution or, alternatively, are mere curiosities of little in which such mutations were allowed. Significantly higher fitness overall importance. Even theoretical studies are often limited to levels were achieved over the long term in the control populations simple two-mutation, two-allele models of evolution, which because some of the deleterious mutations served as stepping may not capture the more complex adaptive dynamics on a high- stones across otherwise impassable fitness valleys. As a conse- dimensional fitness landscape. quence, initially deleterious mutations facilitated the evolution of Here, we use the Avida platform (version 2.6; http://devolab. complex, beneficial functions. We also examined the effects of msu.edu) to study the importance of deleterious mutations in disallowing neutral mutations, of varying the mutation rate, and adaptive evolution (11, 25). In Avida, self-replicating computer of sexual recombination. Populations evolving without neutral programs called digital organisms compete for energy that allows mutations were able to leverage deleterious and compensatory them to execute the behaviors encoded by their genomes. Each mutation pairs to overcome, at least partially, the absence of single-instruction processing unit, or SIP, of energy allows a digital neutral mutations. Substantially raising or lowering the mutation organism to execute one instruction in its genome. As popu- rate reduced or eliminated the long-term benefit of deleterious lations of digital organisms evolve, they may become more ef- EVOLUTION mutations, but introducing recombination did not. Our work dem- ficient, requiring fewer SIPs to replicate, and they may acquire onstrates that deleterious mutations can play an important role in new computational functions that allow them to obtain more adaptive evolution under at least some conditions. SIPs. As in nature, selection acts on the phenotype rather than directly on the genome, and many or most mutations have del- epistasis | experimental evolution | genetic drift eterious effects, whereas beneficial mutations are less common (19). Mutations in digital organisms often interact epistatically volutionary biologists usually assume that increased perfor- rather than multiplicatively, once again as observed in many Emance, including the origin of new traits, arises via a hill- climbing process, such that a population evolves toward a local Significance fitness peak. Mutational paths through fitness valleys are often viewed as inaccessible (1, 2), and even nonlethal deleterious It might seem obvious that deleterious mutations must impede mutations are seen as dead ends that can be ignored when evolution. However, a later mutation may interact with a del- considering the rate of improvement and the distribution of eterious predecessor, facilitating otherwise inaccessible adap- adaptive outcomes (3). Wright’s shifting-balance theory offers tations. Although such interactions have been reported before, one possible dynamic for a sexually reproducing metapopulation it is unclear whether they are rare and inconsequential or, al- (comprising many demes or subpopulations) to traverse a fitness ternatively, are important for sustaining adaptation. We stud- valley, but its efficacy is disputed (4). In asexually reproducing ied digital organisms—computer programs that replicate and organisms, however, there exists a simpler mechanism for crossing evolve—to compare adaptation in populations where delete- a fitness valley. Provided that a deleterious mutation is not lethal, rious mutations were disallowed with unrestricted controls. the genome carrying it has some expected “half life” and a cor- Control populations achieved higher fitness values because responding chance of reproducing one or more times before some deleterious mutations acted as stepping stones across going extinct (2, 5–10). Occasionally, the mutant subpopulation otherwise impassable fitness valleys. Deleterious mutations can might acquire a second, hypercompensatory mutation that pro- thus sometimes play a constructive role in adaptive evolution. vides a net advantage (11, 12). Although such mutations are expected to be rare, new detrimental mutations are constantly Author contributions: A.W.C., R.E.L., and C.O. designed research; A.W.C. performed re- search; A.W.C. and C.O.W. analyzed data; and A.W.C., R.E.L., C.O.W., and C.O. wrote generated, thus providing a multitude of potential stepping stones. the paper. If the second mutation would also have been deleterious had it The authors declare no conflict of interest. fi appeared without the preceding mutation, then the bene cial Data deposition: Summary data and analysis scripts have been deposited at the Dryad combination is said to have a “sign-epistatic” interaction (3, 13)— Digital Repository, http://datadryad.org (DOI: 10.5061/dryad.4hp5n). two wrongs, in effect, make a right. In a sexual population, such 1To whom correspondence may be addressed. E-mail: [email protected] or [email protected]. fi interacting mutations will often nd themselves becoming dis- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. sociated so long as they are rare, making it difficult for them to 1073/pnas.1313424110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1313424110 PNAS | Published online August 5, 2013 | E3171–E3178 Downloaded by guest on September 26, 2021 natural systems (3, 14–18, 21–24). The digital organisms in this (RpDL). Besides eliminating deleterious mutations, these treat- study live on a toroidal grid; when an organism replicates, its ments also affected the overall mutation rate and the distribution progeny is placed at random in one of the nine neighboring cells of fitness effects (Fig. S1 B–D). All other parameters were iden- (including that occupied by the parent), replacing the previous tical across treatments, including the ancestral genotype, selective occupant. Thus, population size remains constant. In our anal- environment, population size (10,000), and duration (250,000 yses, we typically focus on the most abundant genotype in updates, typically ∼45,000 generations) (Supporting Information). a population at the end of an experimental run. We refer to this After comparing the effects of these treatments, we examine genotype as the “final dominant.” We also examine the “line of a case study in more detail, and we perform replay experiments descent” that includes every organism along the lineage from the starting from adjacent genotypes to quantify the effects of in- initial ancestor to the final dominant (11, 12, 25). dividual deleterious mutations on subsequent adaptation. Fur- Lenski et al. (11) previously found instances of deleterious ther, we compare the effects of reverting or replacing deleterious mutations acting as stepping stones while using Avida to examine mutations with the effects of similar treatments applied to neu- the origin of a complex logic function called “bitwise equals” tral mutations. Finally, we explore how mutation rate and sexual (EQU). Five of 23 replicate populations that evolved EQU had reproduction influence the effects of deleterious mutations on a deleterious mutation on the line of descent immediately before long-term adaptation. evolving the EQU phenotype. Reversion of those deleterious, penultimate mutations eliminated the EQU phenotype in three Results and Discussion of the five cases, indicating that those three mutations contrib- Effects of Reverting and Replacing Deleterious Mutations. If dele- uted to the EQU
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