A substance detectable in fossils millions of years old may help determine which prehuman species are direct human ancestors, according to a study led by San Diego researchers.

The substance comes from a sugar component made in apes but not humans. The study, published Monday, said testing for its presence should allow hominid fossils to be sorted into two groups:

Those with it were dead-end branches, whose lineages became extinct.

Those without it came from species closer to humans than to other apes, including our direct ancestors.

Schematic map indicating the loss of the sialic acid Neu5Gc in the hominid family tree. (Ajit Varki)

The study, which used animal fossils to demonstrate the concept, was published Monday in the Proceedings of the National Academy of Sciences. Go to j.mp/sialicfo for the study.


Tim White, a prominent paleoanthropologist at UC Berkeley, said by email that he liked the study.

“This looks like a good first step to me, and as time goes on, with independent verification and further refinement of method, ancient biomolecules promise to open even wider windows of understanding on the deep past,” White said.

White is known for his research on the 3.2 million-year-old hominid fossil “Lucy,” and the even more ancient Ardipithecus ramidus, or “Ardi,” dating back 4.4 million years ago.

Ajit Varki, M.D., was the study’s senior author. Varki is with UC San Diego and with the UC San Diego/Salk Center for Academic Research and Training in Anthropogeny, or CARTA. The group conducts and discusses research related to human origins. Anne K. Bergfeld, first author, conducted the research when she was a postdoctoral researcher at UCSD.


The remnant is a component of a certain kind of sialic acid. These sugar units play fundamental biological roles, such as in immune recognition and infection. They’re incorporated into sugars known as glycans, also important to human health.

This particular sialic acid, Neu5Gc, is made by many animals and all apes except humans.

At some point in the past, our ancestors lost the ability to make Neu5Gc, while other apes retained it. This marks a critical turning point in the path that led to modern humans, Varki said.

Varki said the animal fossil testing was the idea of coauthor Meave Leakey of the Turkana Basin Institute in Nairobi, Kenya, and Stony Brook University in New York.


White said that approach was the right one to win the confidence of museums that take great care in guarding their precious hominid fossils.

“In my experience, museums are willing to sacrifice small amounts of tissue to learn a great deal about the past,” White said.

“These authors are cognizant of this limitation, and have responsibly initially proceeded with less rare nonhuman faunal remains, which is laudable (and has not always been the case).”

Tangled ancestry


If the testing method is proven, it could give rise to what the study refers to as an “ancient glycans” approach to the molecular examination of hominid fossils. It could bring some order into the confusion about which fossils belong where on the evolutionary map.

Genetic and other biological evidence point to chimpanzees as the closest living relatives of humans. It’s uncertain when they last shared a common ancestor.

The process of separation could have begun as early as 13 million years ago, with interbreeding between the diverging lines continuing until as recently as 4 million years ago.

Sahelanthropus tchadensis is one of the oldest potential ancestors of humans and their close relatives, living between 7 and 6 million years ago. Other old potential ancestors have been assigned to the genus Ardipithecus, which originated more than 4 million years ago.


The genus Australopithecus arose a bit later. Their species existed from about 4 million to 2 million years ago.

The closest human relatives belong to the genus Homo, arising around 2.1 million years ago. This genus eventually yielded such groupings as Neanderthals, Denisovans and Homo sapiens — modern humans.

However, the record in more recent times, on the order of a few hundred thousand years ago to a few tens of thousands of years ago, is again complicated by interbreeding.

A small percentage of the genome in modern humans appears to have been inherited from Neanderthal ancestors, determined by extracting DNA from the fossils. Likewise, some modern humans have a small amount of Denisovan ancestry.


This tangled web of hominid species makes determining which fossils come from direct ancestors of modern humans and which are side branches a hotly disputed topic. And that’s where the sialic acid remnant could help.

DNA testing would provide the most indisputable evidence of ancestry. However, the hot, humid conditions in Africa destroyed the DNA in those fossils long ago. (The Neanderthal and Denisovan fossils are from sites in Eurasia, where conditions for DNA preservation are better).

The sialic acid itself, Neu5Gc, is also destroyed by these conditions. But research by Varki and colleagues demonstrated that its remnant, the unusual form of chondroitin sulfate called Gc-CS, proved remarkably durable.

Asked if the loss of Neu5Gc could have happened more than once, Varki said it was extremely unlikely on statistical grounds that the same mutation could have occurred multiple times in hominids.


Since the testing process is destructive, the method was first demonstrated on animal fossils. Varki began by testing a relatively common fossil from about 50,000 years ago, of a cave bear. He found the Gc-CS remnant.

Then Varki and study colleagues tested much older animal fossils. These included a 4-million-year old bovine-like fossil, in which the molecule was clearly present.

That fossil was discovered in a bone bed at Allia Bay, in the Turkana Basin of northern Kenya. Hominid fossils were also discovered at the same depth.

That fossil’s age of 4 million years is significant, because genetic analysis suggests human ancestors lost the ability to make Neu5Gc about 2 to 3 million years ago. So the method can work in fossils old enough to document the loss of Neu5Gc in hominids.


Coauthor Leakey, of the famous Leakey hominid-hunting family, said she suggested testing ancient animal fossils as a gateway to eventually testing on more precious prehuman fossils. Using her own connections, she helped arrange for the bovine fossil.

Varki said he and colleagues are working to improve the testing process, so smaller amounts of fossil are needed. He estimates that a more sensitive test should be ready in about five months. It would require 100 milligrams of fossil, one-tenth of what’s needed now.

Health implications

Sialic acids coat the outsides of cells, bristling from their surfaces. They help identify these cells as “self,” protecting them from attack by the immune system.

Some pathogens such as HIV make or acquire sialic acids from the host, likewise protecting themselves. Pathogens may also latch onto sialic acids to help them get inside cells.


× UCSD researcher Ajit Varki, M.D., discusses the implications of the loss of the sialic acid Neu5Gc to human health.

The reason humans stopped making the sialic acid Neu5Gc, is not known for sure. There’s evidence from Varki’s previous research that it’s related to resistance to infectious disease such as malaria.

Loss of Neu5Gc also has implications for fertility, in driving the separation of human ancestors from others; as well as for eating red meat, which may aggravate diseases such as cancer.

Because Neu5Gc is not made by the human body, the human immune system recognizes it as a foreign substance, producing antibodies against it.


“This immune response may help explain why red meat consumption can be harmful, specifically in humans,” Varki said.

Varki has been leading research for many years into the significance of Neu5Gc, and how the immune reaction in red meat might be reduced or eliminated.

Varki and colleagues demonstrated with mice that unnatural Neu5Gc can cause elevated cancer rates, in a 2014 study in the Proceedings of the National Academy of Sciences.

Varki’s team fed Neu5Gc to two groups of mice. One naturally had Neu5Gc. The other group was genetically engineered to no longer have the molecule, thus mimicking human biology in that regard.


The specially engineered mice showed a cancer rate that was more than five times that of the other rodent group.

For further reading

Why eating red meat raises cancer risk

Selected publications: Red Meat and Disease Risk

Malaria, sexual selection led to humans, UCSD research suggests


Sexual selection by female immunity against paternal antigens can fix loss of function alleles

One sugar proves not so sweet

Ancient fossils help UCSD researchers determine date humans genetically diverged from apes


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