The gene expression consequences of mammalian regulatory evolution

Numerous studies have documented the rapid evolution of mammalian transcriptional regulation, especially enhancers, and yet gene expression patterns are often conserved between species. How stable gene expression is maintained by rapidly evolving regulatory landscapes is a fundamental question in evolutionary genetics.
We tested the contributions of both complexity and conservation of regulatory elements on gene expression evolution, using an integrated dataset of active promoters, enhancers and gene expression output from the same liver samples across twenty mammalian species. Our methodology captures regulatory activities that range from essential to dispensable, and from highly-conserved across mammals to present in only one species. This analysis revealed that gene expression levels and stability are reflected by the complexity of their regulatory landscape, both within a single species and across mammals. Regulatory activities conserved across placental mammals exert a powerful stabilizing effect, associating with gene expression levels that are simultaneously high and evolutionarily stable. In contrast, recently-evolved enhancers contribute weakly to gene expression and transcriptional stability, consistent with a model whereby a sizable fraction of new-born enhancer elements have a neutral role on gene expression evolution. Our results underscore how the evolutionary stability of gene expression is profoundly entwined with both the number and conservation of surrounding promoters and enhancers.