Fig. 3.

Evolutionary mechanisms at the level of gene regulatory regions. a An example of accelerated sequence evolution affecting one enhancer in a locus and leading to gain of an expression domain in the developing forebrain. We characterized one such gain of function HAR in Kamm et al. [57]. b Shadow enhancers are multiple enhancers that direct a similar gene expression pattern and thus overlap in function. As such, they can act cooperatively to confer robustness in different physiological situations [77, 78]. The example shown is based on the work of Lam et al. [78], where two enhancers direct expression to the Arcuate Nucleus and both must be deleted in mice to produce a dramatic change in expression and phenotype. c Enhancer turnover is when one enhancer disappears and a new one appears in the same regulatory region, replacing the lost function. In the example shown by Domené et al. [72], turnover resulted in no net change in expression or phenotype