Evolutionary biologists have argued adaptation to changing circumstances is not merely a matter of accumulation. While discernible changes in fitness often depend on many mutations, which occur in sequence, these mutations are not independent of each other. The temporal order of mutations matters, as does the combination of mutations at any given time. These constraints give adaptive processes the quality of historical contingency.

But does historical contingency also characterize purifying selection? Purifying selection, which is actually far more common than adaptive substitution, favors mutations that have little or no effect in a fixed environment.

It turns out, say researchers at the University of Pennsylvania, that historical contingency is also relevant to purifying selection. These researchers—Premal Shah, Ph.D., David M. McCandlish, Ph.D., and Joshua B. Plotkin, Ph.D.—used simulations of an evolving protein to show that the genetic mutations that are accepted by evolution are typically dependent on mutations that came before. The researchers also demonstrated that the mutations that are accepted become increasingly difficult to reverse as time goes on.

These findings appeared online June 8 in the Proceedings of the National Academy of Sciences, in an article entitled, “Contingency and entrenchment in protein evolution under purifying selection.”

“Here we use computational models of thermodynamic stability in a ligand-binding protein to explore the structure of epistasis in simulations of protein sequence evolution,” wrote the authors. “Even though the predicted effects on stability of random mutations are almost completely additive, the mutations that fix under purifying selection are enriched for epistasis.”

Epistasis refers to mutations that are dependent on one another. To explain how epistasis could be enriched in the current study, Dr. Plotkin noted that in purifying selection, mutations that have a small effect are favored. Either a mutation can have a small effect on its own, or it can have a small effect because another, earlier mutation ameliorated the effects of the current mutation.

“In particular, the mutations that fix are contingent on previous substitutions,” explained the authors of the PNAS article. “Although nearly neutral at their time of fixation, these mutations would be deleterious in the absence of preceding substitutions. Conversely, substitutions under purifying selection are subsequently entrenched by epistasis with later substitutions: They become increasingly deleterious to revert over time.”

The concepts of contingency and entrenchment were well known to be present in adaptive evolution, but it came as a surprise to the researchers to find them under purifying selection.

“Our study shows, and this has been known for a long time, that most of the substitutions that occur are substitutions that have small effects,” Dr. McCandlish observed. “But what's interesting is that we find that the substitutions that have small effects change over time.”

An implication of these findings is that predicting the course of evolution, as one might wish to do, say, to make an educated guess as to what flu strain might arise in a given year, is not easy.

“The way these substitutions occur, since they're highly contingent on what happened before, makes predictions of long-term evolution extremely difficult,” Dr. Plotkin noted.

The researchers hope to partner with other groups in the future to conduct laboratory experiments with microbes to confirm that real-world evolution supports their findings.

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