Interaction-based evolution: How natural selection and nonrandom mutation work together

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Background: The modern evolutionary synthesis leaves unresolved some of the most fundamental, long-standing questions in evolutionary biology: What is the role of sex in evolution? How does complex adaptation evolve? How can selection operate effectively on genetic interactions? More recently, the molecular biology and genomics revolutions have raised a host of critical new questions, through empirical findings that the modern synthesis fails to explain: for example, the discovery of de novo genes; the immense constructive role of transposable elements in evolution; genetic variance and biochemical activity that go far beyond what traditional natural selection can maintain; perplexing cases of molecular parallelism; and more. Presentation of the hypothesis: Here I address these questions from a unified perspective, by means of a new mechanistic view of evolution that offers a novel connection between selection on the phenotype and genetic evolutionary change (while relying, like the traditional theory, on natural selection as the only source of feedback on the fit between an organism and its environment). I hypothesize that the mutation that is of relevance for the evolution of complex adaptation-while not Lamarckian, or "directed" to increase fitness-is not random, but is instead the outcome of a complex and continually evolving biological process that combines information from multiple loci into one. This allows selection on a fleeting combination of interacting alleles at different loci to have a hereditary effect according to the combination's fitness. Testing and implications of the hypothesis: This proposed mechanism addresses the problem of how beneficial genetic interactions can evolve under selection, and also offers an intuitive explanation for the role of sex in evolution, which focuses on sex as the generator of genetic combinations. Importantly, it also implies that genetic variation that has appeared neutral through the lens of traditional theory can actually experience selection on interactions and thus has a much greater adaptive potential than previously considered. Empirical evidence for the proposed mechanism from both molecular evolution and evolution at the organismal level is discussed, and multiple predictions are offered by which it may be tested. Reviewers: This article was reviewed by Nigel Goldenfeld (nominated by Eugene V. Koonin), Jürgen Brosius and W. Ford Doolittle.

Original languageEnglish
Article number24
JournalBiology Direct
Issue number1
StatePublished - 18 Nov 2013
Externally publishedYes

Bibliographical note

Funding Information:
This work greatly benefited from comments by and conversations with Georgii Bazykin, Marc Feldman, Simon Levin, Noam Livnat, Amos Livnat, Steve Pacala, Christos Papadimitriou, Nick Pippenger, Günter Wagner, Kim Weaver and the three referees. Jef Akst provided invaluable editorial assistance. I would like to acknowledge financial support from the Miller Institute for Basic Research in Science and from NSF grant 0964033 to Christos Papadimitriou, Division of Computer Science, UC Berkeley.

Funding Information:
122. Bryson V, Vogel HJ: (Eds): Evolving Genes and Proteins: A Symposium Held at the Institute of Microbiology of Rutgers, with Support from the National Science Foundation. New York: Academic Press; 1965.


  • Adaptive evolution
  • Epistasis
  • Evolvability
  • Junk DNA
  • Mutation bias
  • Neutral theory
  • Sex and recombination
  • Transcriptional promiscuity
  • de novo genes

ASJC Scopus subject areas

  • Immunology
  • Ecology, Evolution, Behavior and Systematics
  • Modeling and Simulation
  • General Biochemistry, Genetics and Molecular Biology
  • General Agricultural and Biological Sciences
  • Applied Mathematics


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