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Studies Suggest Epistatic Interactions Put Brakes on Rate of Adaptation Involving Beneficial Mutations

By Andrea Anderson

NEW YORK (GenomeWeb News) – The rate of adaptation resulting from beneficial mutations tends to dwindle as organisms become more genetically suited to their environments, according to a pair of studies appearing online today in Science.

In the first of these, researchers from Harvard and Boston Universities focused on four beneficial mutations in a metabolic pathway linked to growth in methanol. The team added combinations of these genetic changes — identified by sequencing the genome of a genetically engineered bacterial species that had become adapted to growth in methanol — into non-methanol adapted bacteria from the same strain.

Each mutation improved the bug's growth rates in methanol. But for three of the alleles, the degree of this improvement decreased as strains took on other beneficial changes and became more fit.

"Our data suggests that epistasis is at least part of why adaptation slows down [over time]," senior author Christopher Marx, an organismic, evolutionary biology, and systems biology researcher at Harvard told GenomeWeb Daily News. "Our mutations behave in a very generic, diminishing returns sort of way, where they become less and less useful on more and more fit backgrounds."

In contrast to results from studies of individual proteins, he noted, the work suggests that beneficial mutations remain beneficial regardless of how they are combined. On the other hand, results of previous studies have shown that beneficial mutations within a single protein can interact to produce myriad effects ranging from beneficial to neutral to deleterious.

Marx and his co-workers set out to investigate the effects that epistasis has on beneficial mutations by using a genetically engineered bacterial strain known as Methylobacterium extorquens AM1.

By growing this bug in methanol, the team selected for bugs that could oxidize formaldehyde to produce formate — a feat that requires a metabolic pathway found in wild type Methylobacterium but is absent from the engineered M. extorquens strain they used.

The strain contains a glutathione-dependent pathway transplanted from another bacterial species, researchers explained. Consequently, it can grow in methanol, but grows much more slowly unless it has become adapted to these conditions.

To look at the sorts of mutations linked to such adaptation, the team used the Illumina Genome Analyzer to sequence a particularly fit M. extorquens strain that had been grown in methanol for hundreds of generations, identifying nine new mutations in its genome.

They then explored the consequences of introducing combinations of four apparently beneficial mutations into M. extorquens strains, looking at how each allele affected bacterial growth rates in methanol alone or in combination.

"We took a strain that had evolved for a period of time, sequenced it to find the changes that had occurred, and then made all the possible combinations [of these mutations]," Marx explained, noting that the genetic changes were introduced in pairs, trios, and in a foursome.

Each of the alleles did lead to enhanced growth in methanol — but only up to a point. The researchers found increasingly less benefit for three of four mutations when they added them into strains that were already fairly fit.

Based on their findings, they speculated that these three mutations likely influence a similar process in the cell, while the fourth mutation — which seemed to improve growth by around 10 percent regardless of other mutations introduced with it — might confer a growth advantage through a distinct pathway.

A second study by researchers in the US and France, meanwhile, pointed to similar patterns in another bacterial species, Escherichia coli. That group looked at the fitness effects of five beneficial mutations in an E. coli population from an ongoing evolution experiment.

"The way that these mutations interact is really quite simple," senior author Tim Cooper, a biology and biochemistry researcher at the University of Houston, told GWDN. "We get this very simple pattern of diminishing returns — interference between mutations where it becomes harder and harder for mutations to confer a big fitness benefit when they're added to strains that are closer and closer to the fitness optimum of that population."

Researchers found dozens of mutations in their E. coli population of interest by using the Illumina platform to sequence the genome of an E. coli clone from population grown in glucose-limited culture for 20,000 generations. They narrowed in on the five mutations that appeared to have become fixed first, Cooper explained, while the bugs were rapidly adapting to their environments.

"The motivation was really to try to understand how the genetic changes that confer fitness increases work — how they interact with each other, what they look like, how big their effects are," he said.

They then introduced combinations of these five genetic changes into ancestral versions of E. coli with known variations. Again, the team found that four of five beneficial mutations improved E. coli fitness in a manner that depended on how well the cells had already become adapted.

"Epistasis … tended to produce diminishing returns with genotype fitness, although interactions involving one particular mutation had the opposite effect," Cooper and his co-authors explained. "These data support models in which negative epistasis contributes to declining rates of adaptation over time."

Both Marx and Cooper said that their teams plan to do additional experiments looking at whether it might be possible to predict such genetic interactions and their effects on adaptation and evolution.

In an accompanying editorial in the same issue of Science, a trio of researchers from the University of Pennsylvania and Harvard University noted that questions remain about how the epistatic influence detected in the lab contributes to evolution for organisms in the wild.

Even so, corresponding author Joshua Plotkin, a biologist at the University of Pennsylvania, and his co-authors said, "[t]hese studies, and the long-term laboratory evolution experiments from which they derive, represent a resounding achievement for the reductionist approach to studying biology."

"The mechanistic picture they paint of evolution is complex but not incomprehensible," they wrote, "although epistatic interactions lead to surprising phenomena, the advantages of a frozen 'fossil record' of laboratory raised isolates, and the ease of manipulating — and, now, fully sequencing — evolved strains enables researchers to tease apart and examine the underlying causes of these phenomena."

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