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Research Article

Heterozygote advantage as a natural consequence of adaptation in diploids

Diamantis Sellis, Benjamin J. Callahan, Dmitri A. Petrov, and Philipp W. Messer
  1. Departments of aBiology and
  2. bApplied Physics, Stanford University, Stanford, CA 94305

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PNAS December 20, 2011 108 (51) 20666-20671; https://doi.org/10.1073/pnas.1114573108
Diamantis Sellis
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Benjamin J. Callahan
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Dmitri A. Petrov
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  • For correspondence: dpetrov@stanford.edu messer@stanford.edu
Philipp W. Messer
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  • For correspondence: dpetrov@stanford.edu messer@stanford.edu
  1. Edited* by Boris I. Shraiman, University of California, Santa Barbara, CA, and approved November 2, 2011 (received for review September 7, 2011)

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Abstract

Molecular adaptation is typically assumed to proceed by sequential fixation of beneficial mutations. In diploids, this picture presupposes that for most adaptive mutations, the homozygotes have a higher fitness than the heterozygotes. Here, we show that contrary to this expectation, a substantial proportion of adaptive mutations should display heterozygote advantage. This feature of adaptation in diploids emerges naturally from the primary importance of the fitness of heterozygotes for the invasion of new adaptive mutations. We formalize this result in the framework of Fisher's influential geometric model of adaptation. We find that in diploids, adaptation should often proceed through a succession of short-lived balanced states that maintain substantially higher levels of phenotypic and fitness variation in the population compared with classic adaptive walks. In fast-changing environments, this variation produces a diversity advantage that allows diploids to remain better adapted compared with haploids despite the disadvantage associated with the presence of unfit homozygotes. The short-lived balanced states arising during adaptive walks should be mostly invisible to current scans for long-term balancing selection. Instead, they should leave signatures of incomplete selective sweeps, which do appear to be common in many species. Our results also raise the possibility that balancing selection, as a natural consequence of frequent adaptation, might play a more prominent role among the forces maintaining genetic variation than is commonly recognized.

Footnotes

  • ↵1To whom correspondence may be addressed. E-mail: dpetrov{at}stanford.edu or messer{at}stanford.edu.
  • Author contributions: D.A.P. and P.W.M. designed research; D.S., B.J.C., and P.W.M. performed research; D.S., B.J.C., and P.W.M. contributed new reagents/analytic tools; D.S., B.J.C., D.A.P., and P.W.M. analyzed data; and D.S., B.J.C., D.A.P., and P.W.M. wrote the paper.

  • The authors declare no conflict of interest.

  • *This Direct Submission article had a prearranged editor.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1114573108/-/DCSupplemental.

Freely available online through the PNAS open access option.

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Heterozygote advantage as a natural consequence of adaptation in diploids
Diamantis Sellis, Benjamin J. Callahan, Dmitri A. Petrov, Philipp W. Messer
Proceedings of the National Academy of Sciences Dec 2011, 108 (51) 20666-20671; DOI: 10.1073/pnas.1114573108

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Heterozygote advantage as a natural consequence of adaptation in diploids
Diamantis Sellis, Benjamin J. Callahan, Dmitri A. Petrov, Philipp W. Messer
Proceedings of the National Academy of Sciences Dec 2011, 108 (51) 20666-20671; DOI: 10.1073/pnas.1114573108
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Proceedings of the National Academy of Sciences: 108 (51)
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