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Universal pleiotropy is not a valid null hypothesis: reply to Hill and Zhang

Nature Reviews Genetics volume 13, page 296 (2012)Cite this article

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Relating to our recent Review (The pleiotropic structure of the genotype–phenotype map: the evolvability of complex organisms. Nature Reviews Genetics 12, 204–213 (2011))1, Hill and Zhang argue in their Correspondence (Assessing pleiotropy and its evolutionary consequences: pleiotropy is not necessarily limited, nor need it hinder the evolution of complexity. Nature Reviews Genetics 21 Feb 2012 (doi:10.1038/nrg2949-c1))2 that the experimental data summarized and discussed in our article are unable to reject the hypothesis of universal pleiotropy (HUP), which asserts that every mutation (or gene) affects every trait. This influential idea originated from Fisher's geometric model of evolution3. Hill and Zhang2 argue that any empirical detection of a gene effect relies on some statistical significance threshold and is thus likely to underestimate the true degree of pleiotropy. We agree with the substance of this argument and have discussed its implications in our paper1. However, we disagree with the conclusion that the HUP is a viable model of genetic architecture. We think this disagreement has deeper methodological roots, which we discuss below.

Hill and Zhang2 use the HUP as their null hypothesis and request evidence to reject this hypothesis. However, any real experiment has a detection limit. If the HUP allows for arbitrarily small effect sizes, this hypothesis could never be falsified and thus does not rise to the level of a scientific hypothesis. That this incarnation of the HUP is what Hill and Zhang2 have in mind is reflected in the mathematical structure of their model, which has an effect size distribution with a mode of zero4. Hence, most effects are assumed to be small to start with. Of course, it follows that a lower threshold for detection will quickly lead to a higher degree of pleiotropy. We think that Hill and Zhang will agree that the published data1 show that each mutation has few large effects and many effects that fall anywhere between 'small' and 'zero'.

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References

  1. Wagner, G. P. & Zhang, J. The pleiotropic structure of the genotype–phenotype map: the evolvability of complex organisms. Nature Rev. Genet. 12, 204–213 (2011).

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  2. Hill, W. G. & Zhang, X.-S. Assessing pleiotropy and its evolutionary consequences: pleiotropy is not necessarily limited, nor need it hinder the evolution of complexity. Nature Rev. Genet. 21 Feb 2012 (doi:10.1038/nrg2949-c1).

    Article  CAS  Google Scholar 

  3. Fisher, R. A. The Genetic Theory of Natural Selection (Clarendon, Oxford, 1930).Article

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  4. Hill, W. G. & Zhang, X. S. On the pleiotropic structure of the genotype-phenotype map and the evolvability of complex organisms. Genetics 3 Jan 2012 (doi:10.1534/genetics.111.135681).

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Authors and Affiliations

  1. Günter P. Wagner is at the Yale Systems Biology Institute and Department of Ecology and Evolutionary Biology, Yale University, 165 Prospect Street, POB 208106 New Haven, Connecticut 06405–8106, USA.,

    Günter P. Wagner

  2. Jianzhi Zhang is at the Department of Ecology and Evolutionary Biology, University of Michigan, 830 North University, Ann Arbor, Michigan 48109–1048, USA.,

    Jianzhi Zhang

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  1. Günter P. Wagner
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  2. Jianzhi Zhang
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Correspondence to Günter P. Wagner or Jianzhi Zhang.

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Wagner, G., Zhang, J. Universal pleiotropy is not a valid null hypothesis: reply to Hill and Zhang. Nat Rev Genet 13, 296 (2012). https://doi.org/10.1038/nrg2949-c2

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