The inner life of proteins

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A quantitative analysis shows that epistasis — the fact that genetic background determines whether a mutation is beneficial, deleterious or inconsequential — is the main factor regulating evolution at the level of proteins. See Letter p.535

There is a long-standing controversy in evolutionary biology about the relative importance of 'internal' versus 'external' factors in determining the rate and outcomes of evolution. Is evolution primarily determined by ecology and the environment, or do an organism's own functional and developmental features make a substantial contribution? Now, at least at the level of proteins, it seems we have an answer. On page 535 of this issue, Breen et al.1 present a rigorous statistical analysis of protein sequences that suggests that functional interactions among amino acids are a major determinant of protein-sequence evolution.

Most people are familiar with the principle of adaptive evolution, which underlies Charles Darwin and Alfred Russel Wallace's theories of natural selection. This model describes how organisms change in response to biotic or abiotic variations in their environment — familiar examples include the large body size and white fur of the polar bear, where the body size helps to retain heat and the fur colour provides camouflage. In fact, responses to environmental conditions have been so successful in explaining biological diversity that it became tempting to see adaptation as the only factor determining evolutionary outcomes and patterns. In its extreme, this view leads to what philosophers call the functionalist interpretation of life — the idea that the function of body parts explains their existence and structure.

However, evolutionary biologists know that factors internal to organisms also contribute to biological diversity. Darwin himself discussed the 'law of correlated growth', which states that size changes in various body parts do not occur independently of each other but are subject to limitations that result from the integrated nature of development and growth. In contemporary language, these factors are considered constraints that arise from functional or developmental interdependencies between parts of the organism.

Fundamentally, these constraints manifest themselves as interactions between genes. Here, a key concept is epistasis, the term used to describe the context dependency of mutation effects — in other words, that the genetic background on which a mutation occurs determines whether the mutation has any effect and, if so, whether it is beneficial or deleterious. A frequently observed manifestation of epistasis occurs between the sex-determining factors (in mammals, the X and Y chromosomes) and some disease risk factors. For instance, in men the ε3/ε2 genotype at the gene encoding the protein ApoE leads to an earlier onset of coronary artery disease, compared to the ε3/ε3 genotype2. But in women, no such effect is observed.

In evolutionary theory, however, epistasis has a curious status. One of the pillars of population genetics is the 'fundamental theorem' of natural selection, which says that the response to selection, and thus the process of adaptation, depends only on the context-independent (additive) genetic effects that exist in a population; according to this theory, although epistasis exists, it is simply noise in an otherwise fairly deterministic process3. This hypothesis is widely misunderstood, even by many population geneticists, as saying that epistasis is insignificant. Breen and colleagues' results provide a convincing demonstration to the contrary, demonstrating that epistasis is the primary factor affecting the evolution of proteins.

The authors used an ingenious approach to test how epistatic interdependencies among the amino-acid residues of a protein contribute to the rate at which that protein evolves. They studied the amino-acid sequences of 16 proteins for which sequence information was available, in public databases, for at least 1,000 species. From this analysis they estimated that, on average, each position in a protein accepts around eight alternative amino-acid residues. They then reasoned that, if these alternative amino-acid residues are equally acceptable in the protein, regardless of the amino-acid composition of the rest of the protein — in other words, without epistasis — then the rate of amino-acid evolution should be about 60% of the neutral rate (the rate that would occur if all amino acids were acceptable).

“Amino-acid substitutions will persist, on an evolutionarily relevant timescale, only when the 'correct' amino acids are present elsewhere in the protein.”

However, they found instead that the rate of protein evolution is only 5% of the neutral rate. After excluding several potential sources of error that could influence this statistic, they conclude that interdependency among different amino-acid residues in a protein is the major factor determining its rate of evolution. This means that, in the vast majority of cases, amino-acid substitutions will persist, on an evolutionarily relevant timescale, only when the 'correct' amino acid, or amino acids, are present elsewhere in the protein.

It follows that internal constraints — not only internal to the organism but internal to each protein — are the dominant factor in determining the rate of protein evolution. If that is true at the level of individual proteins, then it is likely also to be true at the level of the organism. Thus, Breen and colleagues have provided convincing evidence that epistasis should be considered alongside adaptation as a key player in evolution.


  1. 1

    Breen, M. S., Kemena, C., Vlasov, P. K., Notredame, C. & Kondrashov, F. A. Nature 490, 535–538 (2012).

  2. 2

    Templeton, A. R. in Epistasis and the Evolutionary Process (eds Wolf, J. B., Brodie, E. D. III & Wade, M. J.) 41–57 (Oxford Univ. Press, 2000).

  3. 3

    Fisher, R. A. The Genetical Theory of Natural Selection (Clarendon, 1930).

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Correspondence to Günter P. Wagner.

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Wagner, G. The inner life of proteins. Nature 490, 493–494 (2012) doi:10.1038/490493a

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