MadSci Network: Molecular Biology
Query:

Re: Has the nonfunctioning vitamin c gene been identified in humans?

Date: Wed Jun 2 11:15:35 2004
Posted By: Brian Foley, Molecular Genetics Staff Scientist
Area of science: Molecular Biology
ID: 1086121254.Mb
Message:

Dear John,

Yes, the defect in the production of vitamin C in humans has been discovered and very well studied. I am excitied about answering your question, because the full story of this involves many different areas of science, from chemistry to archeology to genetics and biology and evolution. It shows how many scientists are working together to understand the many mysteries of life, even when to each of us it often seems that we are just working on our own tiny little problem.

I'd like to first note that my dictionary notes that vitamins are "any of a group of organic substances essential in small quantities to normal metabolism and health. Found in natural foodstuffs and also produced synthetically." The word "Vital" means "essential or necessary for life". Although this definition is correct, it does not make it very clear that there are thousands of other similar organic substances that are not classified as vitamins because our human bodies make them. If we did not have this defect in the manufacture of ascorbic acid (vitamin C is ascorbic acid), it would not be classified as a vitamin.

It turns out that there are several different enzymes (enzymes are proteins, encoded by genes, that act as catalysts in converting one substance into another in a biochemical reaction) needed in the biochemical pathway that produces vitamin C. I found a very nice web page that tells almost the complete story of this. The one enzyme that is defective in this pathway in humans and many other primates is L-gulonolactone oxidase.

The detail that is lacking in the story told on that page, is exactly the question you are asking. So I need to dig further, and that is where the story gets more complex and interesting. It turns out, that by knowing that humans, chimpanzees, other great apes, and many monkeys are lacking the same enzyme activity, we can go to the fossil record and other sources of information about primate evolution and see that it appears that an ancient ancestor of humans and great apes in the primate lineage lost the L-gulonolactone oxidase activity, but survived to pass on this defect to all of us because it and all of us that have survived have been able to eat enough fruits and vegetables to make up for the defect.

The gene function was lost so long ago, that there have been tens of millions of years for further damage to be done to the gene. Once a gene is defective, there is no longer any selection pressure preventing the DNA of that gene from accumulating more damage. It's like a car in a recyling center; the original defect that caused the car to get there might have been a bad oil pump, which caused the engine to get totally ruined, which caused the car to be sold for scap and get crushed and loaded on a trailer. The car is so mangled now, we have a hard time even finding the bad oil pump that started the whole problem.

The human L-gulonolactone oxidase gene has many point mutations, several deletions, and some insertions, compared to functional genes found in other primates and other lineages of mammals (rodents, felines, etc.). If we want to know which defect came first, we can't travel back in time, nor can we find the gene in fossils, the DNA does not survive in fossils that old. Instead we need to look at the gene sequences of all (or a good sampling) of the modern animals that share both the defective gene, and the evolutionary lineage with humans. If we find that all of us share a single point mutation, while we have each suffered different insertions and deletions afterward, it will give us the evidence that this point mutation was the first thing that when wrong. Or we might find that we all share a deletion and have different point mutations, indicating that the deletion was the first thing to go wrong.

If we look in the scientific literature, we can find papers such as this one:

Inai Y, Ohta Y, Nishikimi M. The whole structure of the human nonfunctional L-gulono-gamma-lactone oxidase gene--the gene responsible for scurvy--and the evolution of repetitive sequences thereon. J Nutr Sci Vitaminol (Tokyo). 2003 Oct;49(5):315-9. PMID: 14703305

Which sounds like it might tell the whole story. But I do not have this Journal of Nutritional Science of Vitaminology (Tokyo) in my library, so I can't read the paper and tell you about it. So I will keep digging.

The next place I turn is GenBank, which is the database containing all of the gene sequences that have been determined and published to date. I searched for "L-gulonolactone oxidase" and found that the complete gene has been sequenced in a few mammals such as rats, mice and humans, but only a small part of the gene has been sequenced in other primates (chimpanzees, gorillas and macaques), so far. We need the sequences from many other primates some of which have the functional gene, before we can really tell which mutation came first. All we can say at this time, is that the L-gulonolactone oxidase gene became defective tens of millions of years ago, and has thus accumulated many mutations in the surviving primate lineages that carry it.


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