Modern humans inherited an immunity-boosting gene variant from Denisovans
Experts at the Garvan Institute of Medical Research have discovered that Denisovans passed along a gene variant to modern humans that heightened immune reactions, which was likely driven by the adaptation of the immune system to a changing environment.
Modern humans interbred with Denisovans around 50,000 years ago during migrations from Africa to what is now Papua New Guinea and Australia. Among indigenous people in Papua New Guinea today, up to five percent of the genome is derived from Denisovans.
The gene variant that modern humans inherited from Denisovans increases a range of immune reactions and inflammatory responses, including those that protect humans from disease-causing microbes.
Professor Shane Grey heads the Transplantation Immunology Laboratory at Garvan and is the study’s co-senior author.
“Our study indicates that the Denisovan gene variant heightens the inflammatory response in humans,” said Professor Grey. “Previous research has found collections of gene variants from extinct human species that appear to have provided an advantage to humans living at high altitudes or to resist viruses, but have been unable to pinpoint which if any were actually functional.”
“This study is the first to identify a single, functional variant, and suggests that it also had an evolutionary benefit on the human immune system.”
There are harmful variations of a gene called TNFAIP3 that cause the overactive immunity that is associated with autoimmune conditions, including inflammatory bowel diseases, arthritis, multiple sclerosis, and lupus. The TNFAIP3 gene codes for a protein called A20 that helps reduce immune reactions to foreign microbes.
The Garvan researchers analyzed the genomes of families in which one child had a severe and unusual autoimmune or inflammatory condition.
“Four separate families had the same DNA variant in the TNFAIP3 gene, changing one amino acid in the A20 protein from an isoleucine to a leucine (I207L),” explained co-senior author Professor Chris Goodnow. “However, the presence of this variant in healthy family members indicated it was not sufficient to cause inflammatory disease on its own.”
Immune cells extracted from the blood samples were found to produce a stronger inflammatory response than the immune cells of other individuals.
Using genome data on hundreds of diverse human populations, study co-first author Dr. Owen Siggs analyzed the distribution of the TNFAIP3 variant worldwide. The analysis revealed that the gene variant carried by the Sydney families was absent from most populations, yet was common in some people with Indigenous Australian, Melanesian, Maori, and Polynesian ancestry.
“The fact that this rare version of the gene was enriched in these populations, and displayed genetic signatures of positive selection, means it was almost certainly beneficial for human health,” said Professor Grey.
The team also found the I207L variant in genome data extracted from the 50,000-year-old bone of a Denisovan girl that had been recovered from a cave in Siberia. “Making that connection was extremely exciting,” said Dr. Siggs.
The I207L variant was notably absent from Neanderthal remains that were recovered from the same cave, which is evidence that the gene variant emerged after the Denisovan and Neanderthal lineages split around 400,000 years ago.
Using a mouse model, co-first author Dr. Nathan Zammit replicated the I207L variant to investigate its effects on the immune system.
“When exposed to a pathogenic Coxsackie virus strain – a virus which was originally isolated from a fatal case of human infant infection – mice with the Denisovan variant had stronger immune reactions and resisted the infection better than mice without the Denisovan gene,” said Dr. Zammit.
“It was previously thought that A20, a gene that’s central to the immune system, is binary – either it’s switched on or off,” said Professor Grey. “We’ve found it in fact tunes us as individuals to optimal ‘Goldilocks points’ in between – where immune reactions are neither too hot nor too cold – and that blows the field wide open.”
The study is published in the journal Nature Immunology.
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