Hidden diversity sparks adaptation

Although some genetic mutations have clear effects, others have been considered neutral and inconsequential. Such cryptic mutations can nonetheless facilitate adaptation to new environments. See Letter p.92

Is genetic variation primarily neutral, or is it predominantly shaped by natural selection? Biologists have debated this question for decades. And although the neutralist–selectionist argument has fuelled advances in our understanding of molecular evolution, it has contributed less to our knowledge of how organisms adapt to changing environments. Recent theories about robustness and evolvability, as well as experiments with enzymes and with microbes, suggest that adaptation may depend on a deep and largely unappreciated interaction between neutral and beneficial mutations. On page 92 of this issue, Hayden et al.¹ describe an empirical test of this hypothesis.

When exposed to a new environment, a microbial population will rapidly adapt through the emergence and fixation of beneficial mutations². Nevertheless, microbial-evolution experiments have uncovered factors that complicate this simple picture. One such factor, called epistasis — whereby the effects of one mutation are modified by other mutations — explains why some populations adapt faster or more predictably than others. These differences in evolvability, or in the propensity to produce beneficial mutations, account for several surprising results (such as the sudden emergence of a major metabolic adaptation³ or the long-term coexistence of lineages in a population⁴). The renewed interest in epistasis also points to an exciting and constructive role for neutral mutations in the process of adaptation.

The key finding that links neutral mutations to beneficial changes is that neutrality is often conditional: a mutation may have no detectable effect when it arises in a given environment and against a specific genetic background, but subsequent changes to the environment or genome may reveal hidden fitness effects⁵. Theoretical work suggests that conditionally neutral, or 'cryptic', mutations may accumulate within a population and later be expressed after an environmental change, either directly in response to the new environment⁶, or by epistatic interactions with subsequent mutations⁷ (Fig. 1). Hayden et al.¹ test this theory by direct experimentation.

Figure 1: Role of cryptic genetic variation in adaptation.

In this depiction, genotypes (nodes) are separated by mutations (lines). Node size indicates the frequency of a genotype in the population, and background colour shows the phenotype in a given environment. a, A population under selection for the blue phenotype occupies a network of equally fit genotypes. b, When the population is challenged with a new selective environment (red box), some of the previously neutral genotypes may already express the adaptive phenotype (green). Adaptation to the new environment is also facilitated by epistasis between a beneficial mutation (red) and a mutation that was neutral in the original environment. Hayden et al.¹ confirm that neutral genetic variation accumulated in one environment can facilitate adaptation to a novel environment, either through interaction between genotype and the environment or by epistasis.

The authors evolved two populations of a ribozyme (RNA enzyme) under selection for activity with its native substrate; one population was subject to strong selection, the other to weaker selection. The populations accumulated cryptic genetic variation that was later revealed when they were challenged to catalyse a different substrate. By measuring the increase in catalytic activity over time in this new selective environment, Hayden and colleagues found that the rate of adaptation was proportional to the amount of cryptic variation present in each population. In other words, cryptic genetic variation that had accumulated in one environment facilitated adaptation to a new environment.

This in vitro ribozyme system facilitates precise measurements of genetic variation throughout experiments. It also allows the mutations responsible for adaptation to be identified, sequenced and reconstructed in the ancestral ribozyme strain. To interrogate the genetic basis of adaptation, Hayden et al. took advantage of these features. They confirmed that the beneficial genotypes arose from previously cryptic genetic variation, supporting a causal connection between neutral mutations and adaptation.

The analysis¹ further revealed a complex, ecological dynamic: in one of the populations, the proper functioning of an evolved genotype depended on the presence of other genotypes in the population. So by tracking population variation through deep sequencing, the researchers were able to capture a more detailed picture of the underlying genetics and ecology than is feasible in most evolution experiments using organisms with large genomes.

Hayden et al.¹ applied a very high per-base mutation rate to their short ribozyme sequence to approximate the typical genomic mutation rate of a living organism. But extrapolating their results to real organisms is not straightforward, because there might be different patterns of epistasis among the sites of a single enzyme from those among the genes in a large genome. Nevertheless, other work^8,9,10 suggests that epistasis is prevalent at the genomic scale, and that novel environments reveal previously cryptic phenotypic variation in complex organisms. Together with Hayden and colleagues' work, these studies of natural populations suggest a general and important role for cryptic variation in determining a population's adaptive potential.

Sewall Wright, a vigorous proponent of the importance of epistasis in evolution, presaged the modern view in his comment¹¹ on Kimura's neutral theory: “Changes in wholly nonfunctional parts of the molecule would be the most frequent ones but would be unimportant, unless they occasionally give a basis for later changes which improve function in the species in question which would then become established by selection.” Indeed, Hayden et al.¹ have now verified that cryptic variation can shape the process of adaptation. We can hope that future studies of this type will elucidate the specific mechanisms by which neutral mutations potentiate adaptation (see ref. 12, for instance), and so eventually lead to a quantitative understanding of a population's rate of adaptation.

As climate change brings organisms into new environments and facilitates contact between novel pathogens and humans, a comprehensive theory for how populations adapt will have pay-offs for conservation and public health, as well as for our understanding of the diversity of life.