A Mutation Distinguishing Modern Humans from Other Primates Acts to Reduce Oxidative Stress and Inflammation
Humans are long-lived in comparison to other primates, despite exhibiting broad genetic similarity to our closest neighboring species. Our comparative longevity is thought to have evolved as a consequence of our intelligence and culture, allowing grandparents to contribute to the survival of descendants, and thus increasing the selection pressure operating in later life. Here researchers identify one genetic difference in modern humans that may contribute to greater longevity. Interestingly, it is absent from Neanderthals, an ancestral subspecies of human that one would also expect to exhibit a greater life span as a result of intelligence and culture changing the landscape of later life selection pressure.
Aerobic organisms face the challenge of oxidative damage caused by reactive oxygen species produced as metabolic by-products. Glutathione reductase (GR) is a critical enzyme for preventing oxidative stress and maintaining a reduced intracellular environment. Almost all present-day humans carry an amino acid substitution (S232G) in this enzyme relative to apes and Neanderthals.
Three Neanderthal genomes and one Denisovan genome have been sequenced to high quality. This makes it possible to identify genetic changes that characterize modern humans. Among the single-nucleotide substitutions on the lineage leading to modern humans, which alter protein sequences, approximately 100 are known to occur among all or almost all humans today but not in the archaic genomes available to date. One of these affects GR, which, in present-day humans, carries a glycine residue at position 232, whereas Neanderthals, Denisovans, and other primates carry a serine residue at this position.
We express the modern human and the ancestral enzymes and show that whereas the activity and stability are unaffected by the amino acid substitution, the ancestral enzyme produces more reactive oxygen species and increases cellular levels of transcripts encoding pro-inflammatory cytokines. We furthermore show that the ancestral enzyme has been reintroduced into the modern human gene pool by gene flow from Neanderthals and is associated with multiple traits in present-day people, including increased susceptibility for inflammatory-associated disorders and vascular disease.