The new results have far-reaching implications. Kishony and Leibler's work is based on an assessment of what the average mutation achieves, and for various fundamental questions in evolution it really matters what happens on average. One critical area is that of trying to make sense of the advantages conveyed by sexual reproduction.
There is an unchallenged dogma that sexual reproduction must have significant biological benefits: otherwise it would not be so widespread, particularly given that there are distinct costs associated with maintaining it within a population. The problem is determining exactly what that advantage is. All the current models look at sex as purely a process of genetic recombination, and consequently the question of why sex is advantageous comes down to one of why recombination is a good thing. The assumption is that any given population is not fully adapted to its environment, and that recombination will help it to adapt faster. There are two basic reasons why the population may not be fully adapted. First, the environment may have changed since the population last tweaked its genetic composition; and second, spontaneous deleterious mutations arise. So, it is argued, sexual reproduction allows genetic recombination to purge deleterious mutations from the population.
The theory that has tried to make biological sense of this is known as mutational determinism, and in 1998 Kondrashov [4
] showed that for sex to confer an advantage, the effect of having two deleterious mutations must be more harmful than would be predicted from the effect of each alone – an effect called 'synergistic epistasis
'. A crude example of this is that if you had one 'mutation' that knocked out an organism's left eye and a second that knocked out the right eye, the effect of the two added together is considerably greater than either on its own.
For Kishony and Leibler this boils down to a question of what happens in the average situation. Is there a bias towards either positive or negative synergy, or no effect at all? Prior to their article, the most direct measurement of epistasis between random mutations was in work conducted with bacteria by Elena and Lenski [5
]. This showed no evidence for average epistasis between mutations, indicating that there is no synergy and thus starting to chip away at Kondrashov's basic requirement.
And now Kishony and Leibler's work strikes another blow at mutational determinism, this time showing that particular stresses can lessen the effect of the average mutation. Theoretically, if you added enough deleterious mutations together then the average multiply-damaged organism would perform better when put under the (antibiotic) stress than its wild-type progenitor – but this doesn't make sense. Kishony and Leibler explain that their data suggest either that diminishing-return epistasis occurs under favorable conditions or that synergistic epistasis would occur under mutation-alleviating stresses, but as yet the data do not allow them to distinguish between these two possibilities. This suggestion of epistasis, they stress, is by inference, rather than from direct observation.
Kishony and Leibler's work, therefore, does not directly contradict Lenski and Elena's 1997 paper [5
]. Rather, it gives an argument to imply that average epistasis must exist, but at the same time that its existence may depend on environmental conditions and particularly on the presence of stresses that alleviate the average mutation effect. Kishony and Leibler's work could therefore motivate researchers to repeat Lenski and Elena's approach under various environmental conditions and, in particular, under environmental stresses that alleviate average mutation effects.
"This work adds to the growing body of data showing that we still don't have a handle on the environmental effects, and how environment changes mutational effects. That is a wide open area of research and a difficult one to address. There is a need for novel approaches to assessing how the environment modulates mutational effect," says Blanchard. Kishony and Leibler may have added such an approach to the evolutionary biologist's toolkit, and at the least they have opened some new avenues for exploration.