Fig. 6: Evolutionary co-option of the HoxD 5DOM regulatory landscape.

Schematic representation of posterior Hoxd gene regulation by the 5DOM regulatory landscape (top left) and (at least) three developmental contexts in which this landscape is functional (top right). On the left are shown the phylogenetic relationships between taxa where distal fins, distal limbs and external genitals emerged, whereas on the right, the corresponding 5DOM regulatory contributions to these structures are indicated; ‘0’ denotes the absence of any given structure. In this hypothetical view, the 5DOM cloacal regulation is an ancestral feature. In actinopterygian fishes, 5DOM lightly contributes to hoxda gene regulation in the postaxial and distal territories of paired fin buds. The regulatory importance of 5DOM in distal fin territories has increased in sarcopterygian fishes. In amniotes, the 5DOM contribution expands to take over the entire regulation of posterior Hoxd genes in digits, as suggested by many enhancers with mixed specificities. Similarly, a distinct yet overlapping set of 5DOM-located enhancers entirely control Hoxd gene expression in the genital tubercle. It is difficult to infer the temporal sequence of the latter two co-options of this regulatory landscape. However, because genitalia are late amniote specializations, it is conceivable that elaboration of digital character arose initially, a sequence also supported by the appearance of digits in sarcopterygian fishes. A second co-option of this multifunctional regulatory landscape might have occurred along with the evolution of external genitals, facilitated both by the developmental proximity between external genitals and the embryonic cloacal region where posterior Hox genes are initially expressed⁵², and by the tight developmental relationships between amniote limbs and genitals^27,52.