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Frugivore Evolution

The GULO Pseudogene in Humans: A Unique Mutation to Frugivores!

Did you know that most animals do not have to get vitamin C via food? They produce the essential molecule internally because they have the genes to do so. Vitamin C is a crucial substance for the health and even for the survival of most organisms – and here is where it gets paradoxical and mysterious: A few animals have dysfunctional vitamin C genes (the GULO gene). Humans, all other apes, most primates, some bats, guinea pigs, and some bird species do not produce vitamin C.

But how can those species lose an ancient and vital gene and component of life? The answer to this question helps us understand the natural human diet and reveal the well-kept secret of our evolutionary past as frugivores (fruit-eaters). So let’s dive right in:

What is the GULO gene?

The GULO gene is a part of vitamin C genes in animals. It codes for the L-gulonolactone oxidase – an enzyme that converts the precursor of vitamin C ( L-gulonolactone) into the final active vitamin C (L-ascorbic acid). The enzyme is the last one in a sequence of enzymes needed to produce vitamin C. In humans, the gene sequence lacks multiple exons (coding regions of the DNA).

Vitamin C in animals and plants

Vitamin C is one of the strongest antioxidants and is needed in many biochemical reactions in the body of animals and plants alike. It plays a vital role in living organisms and is known to be essential for humans.

We usually associate vitamin C with diet, especially plant foods like citrus fruits. Plants are known to synthesize vitamin C, but what is less commonly known is that there is the biosynthesis of vitamin C in animals, too! The animals that do have functional vitamin C genes have another pathway than plants, but the outcome is the same molecule.

In a few animal species, the GULO gene is broken

Most animals make their vitamin C internally: Just a few examples are dogs, cows, most birds and reptiles, and even mollusks. The few animal species that cannot make vitamin C lack a functional GULO gene: Humans, all other apes, most primates, some bats, guinea pigs, and some bird species. Those species still carry the gene, but it has mutated to the extent that it has become a dysfunctional pseudogene, now called GULOP (GULO Pseudogene). This means, at one point, our (distant) ancestors were carrying the functional gene and vitamin C pathway.

The loss of the GULO enzyme in humans means our vitamin C production is broken!

But why?

The GULO gene is important for life

The GULO gene has been kept throughout evolution by most animal species, indicating its essential, vital function for life!

The types of genes that do not change much during evolutionary history are said to be conserved. The vitamin C genes are conserved. Such basic genes are also called housekeeping genes: In the same way, dietary vitamin C is vital for humans, the GULO gene is vital for most other species.

“Housekeeping genes are examples of regions in a genome that tend to be highly conserved and evolve slower than other genes such as the tissue-specific genes mainly due to their roles in the maintenance of basic cellular functions and are essential for the existence of a cell.”

Ong, 2019

So what is going on here? Why does such an ancient gene mutate and become a pseudogene in humans?

Why do humans have a broken GULO gene? Revealing a secret…

Why is the GULO gene conserved in most animals but “broken” in humans and apes – making them auxotrophs for vitamin C?

Some animals, like most primates, birds, some bats, guinea pigs, and even some invertebrates, do not produce vitamin C.

The question here arises: What do those animals have in common, which have to take in vitamin C from external sources? Yes, they have a high intake of fruits and, thus, sufficient vitamin C from their diet.

Figure: Vitamin C gene loss has occurred independently in species with a frugivorous diet (with a high vitamin C intake). This phylogenetic tree by Drouin et al. (2011) illustrates the ability of different mammals to produce vitamin C. Dark green species have functional genes; light green species do not. Screenshot from Scientific American, showing that Lemurs (a primate with functional vitamin C genes) consume far less fruits than other primates”.

Vitamin C-rich diets: The GULO gene has mutated in frugivores!

Animals with mutated vitamin C genes have one thing in common: Vitamin C-rich diets. They are all frugivores. Human ancestors were highly frugivorous, and the GULO gene is a hint that we actually still are frugivores! In some birds, for example, vitamin C production has re-emerged again when frugivory was lost.

Frugivores can benefit from ceasing to produce the compound internally because producing it internally is energetically costly. In a sense, the frugivores outsource the metabolic task to the plants they consume – and saves energy.

The GULO gene mutation is unique to frugivores – across the animal kingdom!

Humans come from a highly frugivorous ancestry, and, therefore, naturally must take in large amounts of vitamin C.

Find more about this apparent evolutionary paradox of broken vitamin C genes in frugivores here.

The mutated Vitamin C gene is the reason we like sour taste

Acidic taste is off-putting for most animals – but not for frugivorous humans, apes, and birds! Just like sweet taste, humans enjoy sour taste, especially sweet-sour. In contrast, most animals reject sour foods! We share our preference for slightly sour with all apes, and the frugivorous monkeys as well as birds. Once more, this is a typical feature for frugivorous species, as most fruits have some acidic, sour flavor to them. (This phylogenetic tree by Frank et al. (2022) shows acid detection and preference in different animal species.)

Being attracted to acidic foods could be linked to the vital necessity to get vitamin C (ascorbic acid) via the diet: sour is a good indication of vitamin C in the food. Thus, vitamin C detection and attraction could be vital and adaptive in species without functional vitamin C genes.

The broken GULO gene holds a message: We should not underestimate the role of fruit-rich diets for humans!

So, having broken vitamin C genes (GULO Gene) is unique for frugivores! What this means, as a logical follow-up, is that humans are supposed to be highly frugivorous: and, yes, our adaptations show that we are supposed to have a high-fruit diet naturally!

Knowing that our ancestors and closest relatives consume(d) that much vitamin C (fruits) that it led to the loss of our own vitamin C production, takes the understanding of the importance of vitamin C-rich to another level: We need much more fruits in our diet than we currently believe! This is one important lesson our broken GULO gene might teach us…

Read more about the adaptations of frugivores and the secret behind “lost” vitamin C genes.

Go to How to do the Frugivore Diet

References

  1. Gulop Gulonolactone (L-) oxidase, pseudogene [homo sapiens (human)] – gene – NCBI (no date) National Center for Biotechnology Information. Available at: https://www.ncbi.nlm.nih.gov/gene/2989 (Accessed: 25 July 2023). 
  2. Yang, H. (2013) ‘Conserved or lost: Molecular evolution of the key gene gulo in vertebrate vitamin C biosynthesis’, Biochemical Genetics, 51(5–6), pp. 413–425. doi:10.1007/s10528-013-9574-0. 
  3. M.C De Tullio, The Mystery of Vitamin C. Nature news (available at https://www.nature.com/scitable/topicpage/the-mystery-of-vitamin-c-14167861/).
  4. Henriques, S.F. et al. (2019) ‘Multiple independent L-gulonolactone oxidase (GULO) gene losses and vitamin C synthesis reacquisition events in non-deuterostomian animal species’, BMC Evolutionary Biology, 19(1). doi:10.1186/s12862-019-1454-8. 
  5. G. Drouin, J.-R. Godin, B. Page, The genetics of vitamin C loss in vertebrates. Current Genomics12, 371–378 (2011), doi:10.2174/138920211796429736.
  6. J. G. Goldman, Why lemurs have such strange diets. Scientific American (2018) (available at https://www.scientificamerican.com/article/why-lemurs-have-such-strange-diets/). 
  7. Joshi, C.J. et al. (2022) ‘What are housekeeping genes?’, PLOS Computational Biology, 18(7). doi:10.1371/journal.pcbi.1010295. 
  8. Ong, H.S. (2019a) ‘Comparative genomics analysis’, Encyclopedia of Bioinformatics and Computational Biology, pp. 425–431. doi:10.1016/b978-0-12-809633-8.20126-x. 
  9. Frank, H.E. et al. (2022) “The evolution of sour taste,” Proceedings of the Royal Society B: Biological Sciences, 289(1968). Available at: https://doi.org/10.1098/rspb.2021.1918. 

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Martina Spaeni, MSc

"We are frugivores - specialized fruit-eaters!" It was passion at first sight when I came across the intriguing concept that humans are adapted to a high-fruit diet, similar to chimpanzees...

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