Evolution's Sweet Tooth

Varki (shown above) and his colleague Pascal Gagneux conducted an extensive review of published studies that detailed the genetic differences between humans and the great apes.
Image Credit: UCSD Cancer Center

Like icing on a cake, the surfaces of most animal cells are covered with sugars. These molecular sugar chains are capped off by a kind of sugar called sialic acid. While one particular sialic acid – called N-glycolylneuraminic acid (abbreviated as "Gc" in this article) – is found on most animal cells, it is not easily detectable on human cells.

This is due to a genetic mutation that occurred many years ago, sometime after our last common ancestor with the great apes. All mammals except for humans tend to have about equal proportions of Gc and another sialic acid called N-acetylneuraminic acid ("Ac") in the body. Humans, meanwhile, only have trace amounts of Gc, but double the amount of Ac.

"Ac is the precursor to Gc," says Ajit Varki, a professor of medicine and director of the Glycobiology Research and Training Center at the University of California, San Diego. "In the cell, at the biochemical level, a portion of the Ac converts into Gc. This is an ancient function, going back at least 530 million years."

In humans, this conversion of Ac into Gc never takes place. Varki and his colleagues discovered this biochemical anomaly, and they have traced its cause to an Alu-mediated mutation. An Alu is a short DNA chain sequence that can jump from one location on a chromosome to another. An Alu often will jump right into a gene sequence, creating a mutation. In this case, an Alu jumped into the gene for a hydoxylase enzyme that normally converts Ac into Gc.

Several thousand Alu elements have become a part of the human genome since the divergence of humans and great apes. Varki has calculated that the Gc-eliminating Alu mutation occurred over 2 million years ago – sometime after our ancestors started to walk on two legs, but before the brain started to expand.

To confirm this date, Varki looked for sialic acids in the fossils of our ancestors. In Neanderthal fossils (600,000 years ago), there was Ac but no Gc, just as in modern humans. Tropical fossils ranging from 50,000 to 1.7 million years old haven’t yielded any sialic acids, possibly because the hot, humid environment may cause these sugars to break down over time.

Varki and his colleague Pascal Gagneux also conducted an extensive review of published studies that detailed the genetic differences between humans and the great apes. To date, very few differences have been discovered: some chromosomal differences here, a few different genes there. But such variations do not always translate into dramatic physical differences. For instance, genes regulating the sense of smell consist of a very large family of genes with over 1,000 members. A few alterations in the gene family won’t knock out an organism’s sense of smell – instead it will lead to very subtle differences in what they can sniff out.

"In our case, however, the hydroxylase responsible for making Gc is coded by a single gene instead of a gene family," says Varki. "So a change in this gene makes a dramatic difference."

While humans and great apes have the same amount of sialic acid in the body overall, the type of sialic acid – Gc versus Ac – is quite different. Varki says that the physical implications of this mutation are uncertain. While scientists know of several roles that sialic acids play, the functions of Gc versus Ac are less clear.

Goodman doesn’t think the loss of Gc played a major role in human brain development.
Image Credit: med. wayne. edu

One interesting fact is that the brain contains much more sialic acid than any other organ in the body. For instance, the brain has 20 times more sialic acid than the liver. Varki also notes that all animals have reduced amounts of Gc and higher amounts of Ac in the brain. Could sialic acid have something to do with brain development?

"Humans have no Gc in the brain, and animals tend to have very low amounts – despite their relatively high amounts of Gc in the body," says Varki. "The question we’re asking is, ‘What’s so bad about Gc in the brain?’ Or in other words, ‘Why has Gc expression in the brain been suppressed for the tens of millions of years of mammalian evolution?’"

Sialic acid primarily occurs in vertebrate animals. There’s hardly any sialic acid, for instance, in insects. Some people have argued that because insect brains are hard-wired and inflexible, sialic acid may be responsible for our more flexible, adaptable brains.

Morris Goodman, a professor of anatomy and cell biology at the Wayne State University School of Medicine, says that Varki’s findings do point to some role for sialic acid in brain development. However, he cautions, "to say the mutation that caused humans to lose Gc may have resulted in our unique brain evolution may be putting the cart before the horse."

Goodman doesn’t think the loss of Gc played a major role in human brain development. However, he says that such a mutation could have been one of many minor evolutionary steps. Once we have complete DNA sequences of the great apes – and once we figure out how these sequences differ between groups – then it may be possible to identify which genetic changes had a hand in human evolution.

"The genetic change that resulted in loss of Gc may well be in this list," says Goodman, "but many, many other genetic changes are also likely to be in the list. We have to get a more comprehensive picture of the full spectrum of positively selected changes in our ancestry to evaluate how big a role the loss of Gc played."

Varki agrees that, as much as we desire a single explanation for the human phenomenon, our evolution had to take multiple steps. And while one such step could have been the loss of Gc, this step may not have had any discernible affect on us at the time. Instead, the loss of Gc could have been a random oddity.

A chicken-specific disease, such as Gumboro’s Disease (shown above) will wipe out chicken populations, but humans working in infected areas will be unharmed.
Credit: afip.org

"Humans were an endangered species for 2 million years, with a population calculated to be around 10,000," says Varki. "Such a small population can get a gene knocked out by accident, rather than be a change that’s selected because it confers an evolutionary advantage. Once such a mutation became common in a population, it could have simply drifted to fixation."

Another possibility is that the loss of Gc was an advantage. Certain pathogens, for instance, prefer one sialic acid over another. By losing Gc, perhaps we became immune to a virus that wiped out others who still produced Gc.

"There’s no way to tell if there was some sort of die-off among the human ancestors who retained Gc," says Varki. "There are few fossils because they lived in moist, humid rainforests where preservation is rare. The fact that modern primates didn’t lose Gc might mean their ancestors had refuges away from the pathogen."

Also, says Varki, some pathogens are species specific: they may get inside you, but that doesn’t mean their mechanisms will be able to function. They often need specific physical chemistries to work – for instance, a chicken-specific disease will wipe out chicken populations, but humans working in infected areas will be unharmed. In the case of a pathogen that targeted Gc, our ancestors could have been the only species affected.

Goodman thinks a simpler explanation may be that the body has to expend energy to keep Gc out of the brain. By losing the ability to make Gc, our ancestors had to use less energy – a definite evolutionary advantage.

What Next?

Varki is currently conducting studies on mice to find out how Gc affects the brain. He wants to find out what happens when mice have no Gc in the brain, or when they have more than the normal amount.

If Gc is introduced into the human body, it provokes an immune response. Varki therefore is interested to see if the trace amounts of Gc in humans might stem from the ingestion of animal products.