In my earlier post, I documented how the Discovery Institute has failed to keep up with the literature on the evolution of developmental gene regulatory networks (dGRNs). In today’s post, I’d like to illustrate my case by looking at a creature whose embryological development has been documented in minute detail: the humble lancelet (also known as amphioxus), a fish-like creature belonging to the subphylum Cephalochordata, whose ancestors diverged from other chordates either before or during the Cambrian period. Before I do so, however, I’d like to quote some insightful excerpts from a comment by Rumraket on my earlier post, which explain how developmental gene regulatory networks are able to evolve, in the first place.

Rumraket described how a phenomenon known to biologists as retrenchment can turn a novel, redundant biochemical interaction into an indispensable one:

Another factor to consider is that various forms of what biologists call entrenchment, has been observed to evolve in experiments. It has also been shown to have evolved using ancestral sequence reconstruction.

It’s basically a form of constructive neutral evolution. A novel interaction emerges between the proteins A and B (for example), which is initially entirely neutral. Then in protein A a function is lost, but the neutral interaction with B having previously evolved turns out to compensate for the loss of function in A. The initially entirely dispensable interaction (which could be considered a plastic trait) is now suddenly necessary and can no longer be lost. It has become entrenched…

After citing an example relating to the evolution of increasing complexity in the V-type ATP-synthetases which was documented by the Thornton lab back in 2012, Rumraket continued:

Similar principles apply to gene regulatory networks. The entrenchment builds up over time as novel interactions and components emerge in the network, which makes subsequent changes more difficult as the different components of the system has become increasingly dependent on each other.

Rumraket then proceeded to cite a more recent study by the Thornton lab in 2018, showing how protein sequences are capable of evolving over the course of time when (as he put it) “mutations in the ancestral protein sequence (experimentally confirmed to have been functional at some point in the past) eventually became deleterious in the modern genetic background.” Finally, he quoted a passage from the study itself, highlighting a crucial sentence:

Overall, more than 75% of historical substitutions were contingent on permissive substitutions that rendered the derived state nondeleterious, became entrenched by subsequent restrictive substitutions that made the ancestral state deleterious, or both.

Putting it in a nutshell, we might say that the reason why developmental gene regulatory networks are able to evolve is that redundant biochemical interactions can be transformed by changing circumstances into interactions that are essential for an organism’s survival.

Consider the lancelet

A 2024 paper by Chenggang Shi et al., titled, “Evolution of the gene regulatory network of body axis by enhancer hijacking in amphioxus” (eLife 13:e89615) investigated the developmental gene regulatory network of the lancelet (amphioxus), which, like other chordates as well as echinoderms and hemichordates, belongs to a group of animals known as deuterostomes. In these animals, a signaling pathway known as the Nodal signaling pathway plays a crucial role in embryonic development. According to Proteopedia, the Nodal family of proteins “is responsible for mesoendoderm induction, patterning of the nervous system, and determination of dorsal- ventral axis in vertebrate embryos.” Another group of proteins named Lefty helps to determine left-right asymmetry in organ systems during embryonic development. Yet another protein, called Growth differentiation factor 1 (GDF1), which is found in the brain, spinal cord and peripheral nerves of embryos, plays a role in left-right patterning and mesoderm induction during embryonic development. A related protein, GDF3, has been shown to negatively and positively control differentiation of embryonic stem calls in mammals. Each of these different proteins is encoded by genes. Having defined the key terms, we are now in a position to appreciate the significance of the new paper’s findings, summarized in its abstract:

The Nodal signaling that governs the body axes of deuterostomes exhibits a conserved GRN orchestrated principally by Nodal, Gdf1/3, and Lefty. Here we show that this GRN has been rewired in cephalochordate amphioxus. We found that while the amphioxus Gdf1/3 ortholog exhibited nearly no embryonic expression, its duplicate Gdf1/3-like, linked to Lefty, was zygotically expressed in a similar pattern as Lefty. Consistent with this, while Gdf1/3-like mutants showed defects in axial development, Gdf1/3 mutants did not. Further transgenic analyses showed that the intergenic region between Gdf1/3-like and Lefty could drive reporter gene expression as that of the two genes. These results indicated that Gdf1/3-like has taken over the axial development role of Gdf1/3 in amphioxus, possibly through hijacking Lefty enhancers. We finally demonstrated that, to compensate for the loss of maternal Gdf1/3 expression, Nodal has become an indispensable maternal factor in amphioxus and its maternal mutants caused axial defects as Gdf1/3-like mutants. We therefore demonstrated a case that the evolution of GRNs could be triggered by enhancer hijacking events. This pivotal event has allowed the emergence of a new GRN in extant amphioxus, presumably through a stepwise process.

In the lancelet, a duplicate gene has taken over a key role in the development of the embryo’s body axis, while the loss of expression of one maternal factor caused another factor to become indispensable. A new gene regulatory network emerged in the process. This is a beautiful illustration of the phenomenon of entrenchment, highlighted above by Rumraket. The authors of the 2024 paper even included a figure, showing how Nodal signaling evolved in the lancelet, in three steps: (i) Gdf1/3-like originated and hijacked the enhancers of Lefty; (ii) Gdf1/3 retreated from the Nodal signaling; and (iii) Nodal became maternally expressed.

Conclusion

The evolution of developmental gene regulatory networks is now no longer in the realm of theory; it is an established fact. Sadly, however, the Discovery Institute appears to be completely unaware of this fact. Its members are stuck in a time-warp, deluded by an argument purporting to demonstrate that dGRNs cannot evolve, whose major premise is empirically false, and which also overlooks the scenario explaining how they could evolve over time, as described above. Once again, a little research could have easily pointed them in the right direction. Will the Discovery Institute now acknowledge its error? The ball is in their court.