  Regulatory networks have evolved to allow gene expression to rapidly track
changes in the environment as well as to buffer perturbations and maintain
cellular homeostasis in the absence of change. Theoretical work and empirical
investigation in Escherichia coli have shown that negative autoregulation
confers both rapid response times and reduced intrinsic noise, which is
reflected in the fact that almost half of Escherichia coli transcription
factors are negatively autoregulated. However, negative autoregulation is
exceedingly rare amongst the transcription factors of Saccharomyces cerevisiae.
This difference is all the more surprising because E. coli and S. cerevisiae
otherwise have remarkably similar profiles of network motifs. In this study we
first show that regulatory interactions amongst the transcription factors of
Drosophila melanogaster and humans have a similar dearth of negative
autoregulation to that seen in S. cerevisiae. We then present a model
demonstrating that this fundamental difference in the noise reduction
strategies used amongst species can be explained by constraints on the
evolution of negative autoregulation in diploids. We show that regulatory
interactions between pairs of homologous genes within the same cell can lead to
under-dominance - mutations which result in stronger autoregulation, and
decrease noise in homozygotes, paradoxically can cause increased noise in
heterozygotes. This severely limits a diploid's ability to evolve negative
autoregulation as a noise reduction mechanism. Our work offers a simple and
general explanation for a previously unexplained difference between the
regulatory architectures of E. coli and yeast, Drosophila and humans. It also
demonstrates that the effects of diploidy in gene networks can have
counter-intuitive consequences that may profoundly influence the course of
evolution.
