Evolution: Boom and Robust

RESEARCH HIGHLIGHTS

Nature Reviews Genetics | AOP, published online 4 March 2014; doi:10.1038/nrg3703

EVOLUTION For each transcription factor, they bound by a given transcription factor assembled genotype–phenotype maps. to be instead bound by a different In these network maps, each bound transcription factor following a Boom and robust sequence is depicted by a node, and single-nucleotide mutation was used connections (that is, ‘edges’) between as a proxy for evolvability. The authors In the face of mutations, biological nodes represent one-step mutational found extensive evolvability; for systems can gain from two seemingly routes (single-nucleotide substitutions, example, for FOXA2‑bound sequences, opposite phenomena: robustness, insertions or deletions) between every possible mutation resulted in a which buffers the effects of otherwise different binding sites. binding sequence for at least one other deleterious mutations to preserve The genotype–phenotype maps transcription factor. phenotypes and survival; and revealed various interesting properties. Crucially, among the transcription evolvability, in which mutations alter Each map was typically large and highly factors assessed, as the number of phenotypes to provide potential interconnected (more so than expected different binding sites increased, so adaptive benefits. Theoretical by chance). This indicates robustness did both robustness and evolvability. modelling studies have suggested for transcription factor binding, as Thus, for transcription factor binding systems may that robustness and evolvability many binding-site mutations can sites, robustness and evolvability are can actually be parallel (rather than be tolerated to maintain this in vitro intrinsically interconnected, rather than be ‘wired’ conflicting) phenomena; a new study phenotype of transcription factor conflicting, and the degree of sequence in both a now provides experimental support binding. For example, for the mouse specificity in transcription factors can robust and an for the simultaneous robustness and forkhead box protein A2 (FOXA2) ‘fine-tune’ the levels of both robustness evolvability of transcription factor transcription factor, bound sites and evolvability. evolvable way binding sites. can tolerate on average 37% of all This study shows that, at least for To interrogate the sequence possible single-nucleotide mutations. the simple molecular phenotype of specificities of 104 mouse and 89 yeast Additionally, the sequences with transcription factor binding, systems transcription factors, Payne and Wagner highest in vitro binding affinity may be ‘wired’ in both a robust and mined data from protein-binding showed the greatest robustness; these an evolvable way, thus potentially microarray studies, in which proteins high-affinity sites were enriched for providing the evolutionary benefits of are tested for their abilities to bind to transcription factor binding in vivo both phenomena. It will be interesting all possible sequence combinations from chromatin immunoprecipitation to characterize the interplay of of short double-stranded followed by sequencing (ChIP–seq) mutational robustness and evolvability DNA oligonucleotides. data, which implies that in vivo binding for additional phenotypes, particularly sites are frequently mutationally robust. those at the organismal level. The authors assessed evolvability Darren J. Burgess by integrating maps across different transcription factors. Given that

Thinkstock ORIGINAL RESEARCH PAPER Payne, J. L. & cis-regulatory changes underlie various Wagner, A. The robustness and evolvability of morphological differences between transcription factor binding sites. Science 343, 875–877 (2014) species, the ability of a sequence

NATURE REVIEWS | GENETICS VOLUME 15 | APRIL 2014