Giant Rodents Provide Insight into Cancer Paradox
By Julia Wong
Capybaras have recently taken the internet by storm. Not only are these giant guinea pig relatives undeniably cute, but they also have the personalities to match. Nicknamed the “coconut doggy” for its friendly disposition and coconut-like fur, the capybara gained traction across social media for its pacific temperament and unique size.
But what exactly is evolutionary advantageous about a 150-lb guinea pig? How did this species overcome the multitude of trade-offs associated with its size?
A group of researchers affiliated with the Universidad de Los Andes and the Broad Institute of MIT and Harvard sought to answer these questions by developing a genome sequence of a capybara.
The purpose of the study was to investigate the mechanism of gigantism in rodents and its associated “genomic signatures.” In addition, the study aimed to explore how this is related to Peto’s Paradox—a phenomenon describing the puzzling absence of correlation between an organism’s body size and cancer risk. That is, if tumors are developed through random errors in cell division, then species with higher body mass should theoretically have higher risks of developing cancer simply because they have more cells. But, evidently, this is not the case, or else giants such as elephants and capybaras would not be prevalent species.
Researchers developed a genome sequence of a female capybara using a genome assembler called DISCOVAR de novo. Using the genome assembler, researchers searched for putative genes, meaning gene sequences that were previously found to cause specific traits (such as body size regulation). The putative genes were identified within the genome by homologous comparison to the known genomes of related rodents, including mice, rats, and guinea pigs. To identify occurrences of evolutionary splits specific to the capybara genome, researchers performed a comparative analysis of the capybara genome against a library of other rodent gene sequences. When a capybara protein sequence matched the evolutionary homology of the other rodents, the AED (annotation edit distance) returned a 0. In order for a gene to be flagged as having significant variation from the other rodent gene sequences, it had to return an AED of over 0.5 (with an AED of 1 being the measurement’s upper bound).
The study found that 92.5% of capybara protein sequences returned an AED below 0.5, which was to be expected due to the ancestral traits capybaras share with other rodents. The remaining protein sequences that showed capybara lineage-specific positive selection were analyzed in a gene interaction network.
The comparative genomic analysis found a key variation in capybara gene families associated with growth factor signaling pathways. These growth factor signaling pathways modify bone growth and musculoskeletal development, which would explain the unusual size of capybaras in comparison to the rest of the rodent order. The results suggest that capybara gigantism could be a result of a longer or quicker period of postnatal bone growth, which is consistent with previous research on other giant species.
But the growth factor signaling in capybaras may be responsible for more than just their body size. Within the capybara gene families involved in growth regulation, the analysis also found three expanded gene families previously found to promote tumor suppression and reversal in rodents.
These expanded gene families regulate the T-cell receptor signaling pathway, which plays a vital role in identifying and eradicating cancer cells. Although the capybara-specific protein sequences for higher body mass were indeed correlated with a higher level of nonsynonymous substitutions (meaning an increased risk of mutation correlated with tumors), the findings suggest that these risk factors may be mediated by evolution in the capybara’s T-cell receptor signaling pathway. In regards to Peto’s Paradox, this anticancer adaptation could explain why the capybara does not have a higher incidence of cancer in comparison to its smaller relatives in the rodent order.
It is worth noting that the protein sequences identified as unique to capybaras were compared against a genome library that excludes its closest living relative, the rock cavy, which does not display gigantism. Therefore, the location of evolutionary changes leading to the increase in capybara body mass cannot be determined with certainty (i.e. which genetic changes are specific to the capybara and not rock cavies). Future comparative analysis using the genome of a rock cavy would provide clarification.
With this limitation in mind, this study provides insight into the trade-offs of gigantism and the remarkable adaptability of species. If the very growth pathways that produce large body mass, often associated with tumor development, are the same pathways that allow it to overcome those tumors, the capybara is a living tale of weakness turned into a hidden strength.
Herrera-Álvarez, S., Karlsson, E., Ryder, O. A., Lindblad-Toh, K., & Crawford, A. J. (2021). How to make a rodent giant: Genomic basis and tradeoffs of gigantism in the capybara, the world’s largest rodent. Molecular Biology and Evolution, 38(5), 1715–1730. https://doi.org/10.1093/molbev/msaa285
Image source: ericeven1. (2021, March 16). Pixabay. https://pixabay.com/images/id-6091872/