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

Abstract

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.