Double-edged sword: when helpful genes begin to hinder

The genetic quirk that makes some people seriously ill from COVID-19 actually protects them from HIV, according to a new Swedish study. It’s a suite of genes that was passed down to us by Neanderthals, and increased dramatically in frequency some 10,000 years ago, adding to the mystery of an already complicated genetic story. 

A person’s susceptibility to severe COVID is driven by a collection of factors including age, chronic disease, and their genes. In 2020, Swedish researchers Hugo Zeberg and Svante Pääbo of the Karolinska Institutet and the Max Planck Institute for Evolutionary Anthropology (MPI-EVA) demonstrated that the genes that put some people at high risk of severe COVID have their origins in our long-extinct ancestors, the Neanderthals.

The following year the pair began to hunt for this variant within ancient human DNA, and found a sudden, steep increase in its occurrence after the last Ice Age. It’s unusual for a gene from our Neanderthal ancestors to stick around and prosper, so the team wondered whether it might provide any benefits to its carriers.

“This major genetic risk factor for COVID-19 is so common that I started wondering whether it might actually be good for something, such as providing protection against another infectious disease,” explains Zeberg, who is the sole author of this latest study on the genetic variant. 

The gene sequence that codes for heightened COVID risk is located on chromosome 3. Several of the genes involved encode receptors in the immune system – one of those receptors, CCR5, is what the HIV virus uses to infect white blood cells. 

Zeberg found that people who carried the risk factor for COVID-19 had fewer CCR5 receptors, so he wondered whether they might be less susceptible to HIV as a result. By analysing data from three major biobanks (FinnGen, UK Biobank and Michigan Genomic Initiative), he found that carriers of the COVID-risk variant had a 27% lower risk of contracting HIV.

“This shows how a genetic variant can be both good and bad news,” says Zeberg. “Bad news if a person contracts COVID-19, good news because it offers protection against getting infected with HIV.”

But the mystery deepens; HIV only arose in the 20^th century, so protection against the disease doesn’t explain why the genetic variant became so common 10,000 years ago. 

Zeberg suspects the variant may have coded for protection against yet another disease, one that expanded rapidly after the last Ice Age. Variola – the virus that causes smallpox – is a strong candidate, as it emerged at around the same time as the explosion in this protective variant. 

The genetic variant is also unevenly distributed around the world: while 16% of Europeans carry it, some 50% of people in South Asia are carriers.

The research is published today in Proceedings of the National Academy of Sciences.