Protein mutation’s hidden past

A single protein mutation may have had health benefits for anatomically modern humans compared to our Neanderthal cousins, researchers have found.

In a paper published in Science Advances, scientists from Karolinska Institutet in Sweden and the Max Planck Institute for Evolutionary Anthropology in Germany investigated the effects of a mutation in an enzyme called glutathione reductase.

This enzyme helps protect cells against damage from oxidative stress. Molecules known as reactive oxygen species (ROS) are normal byproducts of our cellular metabolism, but in excess they can damage the normal function of DNA, proteins and other components in our cells – this is oxidative stress.

Glutathione reductase keeps oxidative stress in check by helping another molecule called glutathione to mop up the damaging ROS. However, in certain conditions glutathione reductase can also create more ROS, in a process known as “electron leakage”.

Glutathione reductase structure
Structure of the glutathione reductase enzyme bound to glutathione. Credit: Splette / Wikimedia Commons.

By comparing DNA sequences, which form the blueprint for enzymes and other proteins, the researchers recognised that glutathione reductase in most modern humans contained a mutation that differed from corresponding enzymes in human relatives including Neanderthals, Denisovans and other primates.

However, because some humans and Neanderthals interbred in the distant past, most modern humans have a small percentage of Neanderthal-derived DNA in our genomes. According to biobank data, the ‘ancestral’ Neanderthal variant of glutathione reductase is present at low frequency in some modern-day humans, particularly in people living today on the Indian subcontinent.

Next, the researchers set out to investigate what this difference might mean for human health. In laboratory tests, human and Neanderthal versions of the enzyme had similar stability and activity, but the Neanderthal protein showed significantly more electron leakage, meaning that more reactive oxygen species are created.

That’s likely bad news for human health, because more ROS means more oxidative stress for our cells.

Bastien Llamas, a researcher in ancient DNA and human evolution at the University of Adelaide, who was not involved in the research, says the study is a very interesting addition to the burgeoning field of evolutionary medicine.

“The premise [is] that we are the product of evolution, basically, and the health issues and conditions that we can develop come from genetic background interacting with environments that change through time,” Llamas says.

“It’s trying to integrate the past with what’s happening today… so, what are the consequences for us modern humans to carry some of this genetic information [from Neanderthals] in particular environments?”

Model of neanderthal man in a museum
A reconstructed model of a Neanderthal man at London’s Natural History Museum. Credit: Mike Kemp / In Pictures via Getty Images.

In fact, the authors of the study found that the Neanderthal version of glutathione reductase was associated with immune disorders in a large database of genetic and health information from patients at the University of Michigan. Data from several other biobanks and databases indicated that the Neanderthal version of the gene is associated with peripheral vascular disease and inflammatory bowel disease – both previously linked to oxidative stress – as well as higher levels of immune cells in the blood.

“The risk increases we see are large; several times increased risk of inflammatory bowel disease and vascular disease,” says Hugo Zeberg, senior author on the paper.

However, Llamas notes that the disease association results were based on genetic data from mainly people of European ancestry, so may not be relevant to everyone with the variant enzyme.

It’s not yet clear why most modern humans carry a version of the enzyme that differs from the version shared by Neanderthals and our other relatives.

“Stopping oxidative stress is a bit like preventing something from rusting,” says Svante Pääbo, co-author on the new paper. “Perhaps the fact that we are living longer has driven these changes.”

“This new paper is definitely showing that there is a trend where people try and go beyond just observation, to see what happened in the past, where does that variant come from?” says Llamas.

“There’s two aspects to it: evolutionary medicine to solve human health today, but also to understand how Neanderthals and Denisovans actually managed to live with this particular variant that seems to create some issues in modern humans. So we can really understand a bit more about the biology of our extinct cousins.”

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