Survival of the Flattest

When organisms have to evolve under high mutation pressure, their evolutionary dynamics is substantially different from that of organisms evolving under low mutation pressure, and some of the high-mutation-rate effects can appear paradoxical at first glance. Most of population genetics theory has been developed under the assumption that mutation rates are fairly low, which is justified for the majority of DNA-based organisms. However, RNA viruses, the large class of viruses that cause diseases such as the common cold, influenza, HIV, SARS, or Ebola, tend to suffer high mutation rates, up to 10^-4 substitutions per nucleotide and generation [Drake99]. The theory describing the evolutionary dynamics at high mutation rates is called quasispecies theory [Domingo01]

The main prediction for the evolutionary process at high mutation rates is that selection acts on a cloud of mutants, rather than on individual sequences. We tested this hypothesis in Avida [Wilke01]. First, we let strains of digital organisms evolve to both a high-mutation-rate and a low-mutation-rate environment. The rationale behind this initial adaptation was that strains that evolved at low mutation rate should adapt to ordinary individual-based selection, whereas strains that evolved at high mutation rate should adapt to selection on mutant clouds, which means that these organisms should maximize the overall replication rate of their mutant clouds, rather than their individual replication rates. This adaptation to maximized overall replication rate under high mutation pressure takes place when organisms trade individual fitness for mutational robustness, so that their individual replication rate is reduced but in return the probability that mutations cause further reduction in the replication rate is also reduced [Wilke03]. Specifically, we took 40 strains of already evolved digital organisms, and let each evolve for additional 1000 generations in both a low-mutation-rate and a high-mutation-rate environment. As a result, we ended up with 40 pairs of strains. The two strains of each pair were genetically and phenotypically similar, apart from the fact that one was adapted to low and one to high mutation rate. As expected, we found that in the majority of cases the strains evolved at high mutation rate had lower replication speed than the ones evolved at low mutation rate.

Next, we let the two types of strains compete with each other, in a setup where both strains would suffer from the same mutation rate, which was either low, intermediate, or high. Not surprisingly, at low mutation rate the strains adapted to low mutation rate consistently outcompeted the ones adapted to high mutation rate, since after all they had the higher replication rate (we excluded those cases in which the strain evolved at low mutation rate had a lower or almost equal fitness to the strain evolved at high mutation rate). However, without fail the strain adapted to a high mutation rate could win the competition if the mutation rate during the competition was sufficiently high. This result may sound surprising at first, but has a very simply explanation. At a high mutation rate (1 mutation per genome per generation or higher), the majority of an organism's offspring differ genetically from their parent. Therefore, if the parent is genetically very brittle, so that most of these mutants have a low replication rate or are even lethal, then the overall replication rate of all the organism's offspring will be fairly moderate, even though the organism itself may produce offspring at a rapid paste. If a different organism produces offspring at a slower paste, but is more robust towards mutations, so that the majority of this organism's offspring have a replication rate similar to that of their parent, then the overall replication rate of this organism's offspring will be larger than the one of the first organism. Hence, this organism will win the competition, even though it is the slower replicator. We termed this effect the "survival of the flattest", because at a sufficiently high mutation rate a strain that is located on a low but flat fitness peak can outcompete one that is located on a high but steep fitness peak.