Dismantling the retinoic acid synthesis pathway in chordate evolution

Retinoic acid (RA) is a molecule derived from vitamin A (retinol), which is fundamental in the physiology and embryonic development of human beings and our phylogenetic line. Gene loss would have enabled O. dioica to develop without vitamin A, which would be a new example of how gene loss can be an evolutionary strategy that allows the adaption of species to biological situations in a beneficial way.

The new study has been carried out by the researchers Josep Martí-Solans, Núria P. Torres-Àguila, Ricard Albalat and Cristian Cañestro from the Department of Genetics, Microbiology and Statistics and the Biodiversity Research Institute (IRBio) of the University of Barcelona, with the collaboration of the researchers Olga V. Belyaeva and Natalia Y. Kedishvili from the University of Alabama, USA.

When evolution is regressive

Retinoic acid (RA) is an essential factor in chordates to regulate the expression of genes involved in processes of cell proliferation and differentiation, like those occurring during the embryonic development of organs and systems, or during body patterning. Moreover, some genetic diseases that cause alterations in RA action can alter cell proliferation and lead to cancer development such as acute promyelocytic leukemia.

The chordate O. dioica is an organism evolutionary close to vertebrates. They both share a similar body plan and some organs or homologue structures like heart, brain or skeleton musculature, which have a RA-dependent development. A big challenge of this study has been to prove that these organs develop in O. dioica without RA due to the massive loss of genes involved in its synthesis and to demonstrate the absence of alternative pathways. According to Professor Ricard Albalat, "our results are compatible with the loss of genes related to RA in Oikopleura dioica happened in an scenario of regressive evolution, in which the lost functions were not essential for the organism."

"In humans, -continued Albalat- as in the rest of the chordate species, there are multiple enzymes that regulate the synthesis and degradation of RA. Understanding how these enzymes are regulated is important for our health. Everything points to the RA metabolic machinery is a genetically robust system, forming a pathway which is hard to modify in which several enzymes encoded by multiple genes can do the same function in a redundant way. Moreover, to discover that RA was also important for non-vertebrate animals means that RA metabolic machinery could be ancient, early originated during animal evolution."

How can it be possible to create a heart without retinoic acid?

According to Professor Cristian Cañestro, "these results show an example of what has been called the 'reverse paradox' of evolutionary and developmental biology (evo-devo), in which morphologically similar structures differ in the genes responsible for their development."

"The heart is another paradigmatic example we try to understand: how is it possible that O. dioica generates a heart without RA, whereas RA is essential to create this organ in all other chordates? We soon hope to find some answers and assess the impact that RA loss caused in the cardiogenic gene function" said Cañestro.

Biological innovation is not necessarily linked to an increase of functional complexity or number of genes, according to the authors. Genomic rearrangements, changes in epigenetics mechanisms, loss of light-receptor organs, decrease of body complexity and size, or increase of the speed of embryonic development and life cycle of O. dioica are some situations that might have allowed the evolution of new ways to create a heart without the requirement of RA.

Rebuilding genic evolution as a lost train route

According to Albalat and Cañestro, "results show that gene loss can follow non-random patterns, like the co-elimination of all genes related to a function no longer useful during the evolution of a certain species, such as the case of retinoic acid in O. dioica."

"It is like imagining that a certain train route stopped being useful, and the maintenance of its structure was no longer taken care of. If several years later, a historian discovered remains of some abandoned train stations in different parts of a territory, he could rebuild the old train route."

"The discovery of this lost gene route in O. dioica provides experimental evidence showing that the identification of co-eliminated genes (abandoned train stations) is a useful strategy to identify genes functionally related (train routes). On the other hand, if one of the stations had "survived" in a good shape, we could say that this station is still probably connected to another route that has been active during all this time."

"The work published in the journal Molecular Biology and Evolution shows that the identification of "surviving" genes of a dismantled pathway is useful to discover new functions that were previously left unnoticed. In the case of O. dioica, the maintenance and extensive duplication of a couple of genes linked to RA pathway (Cco and RdhE2 genes) allowed us discovering their relevance in the compartmentalization of the digestive system (at least in this organism). Simultaneously, we have shown that if the Aldh8a gene has "survived" in O. dioica is at least thanks to its function responding to the impact of environmental toxins, like those released by marine micro-algae" say Albalat and Cañestro.