A number of human gene variants have been identified by scientists at the University of California San Diego School of Medicine as protective against dementia and cognitive decline in older people. In a new study published July 9, 2022 in the journal Molecular Biology and Evolution, they examine one of these mutant genes and try to determine when and why it first appeared in the human genome.
Findings that inadvertently support the existence of grandparents in human culture imply selective pressure from infectious diseases such as gonorrhea. It may facilitate the finding of this gene variant in Homo sapiens.
Most animal species have reproductive biology, often sacrificing future health and longer lifespans. The only known species to live far beyond menopause is the human race. The “grandmother hypothesis” argues that this is the case because older women play an important role in raising human infants and children who need more attention from other species than younger ones. Scientists are currently trying to understand what aspects of human biology make this long-term health possible.
When researchers previously analyzed the human and chimpanzee genomes, they discovered that it had a different variant of the CD33 gene, a receptor produced on immune cells. All human cells are coated with a form of sugar called sialic acid to which the typical CD33 receptor binds. An autoimmune reaction is avoided when the immune cell senses sialic acid via CD33 and recognizes the other cell as a component of the body and avoids attacking it.
In addition, the CD33 receptor expressed in brain immune cells known as microglia helps regulate neuroinflammation. However, microglia also play an important role in removing amyloid plaques and damaged brain cells associated with Alzheimer's disease. Regular CD33 receptors bind to sialic acids in these cells and plaques, suppressing this important microglial function and increasing the risk of dementia.
The new gene variation comes into the picture here. Somewhere along the evolutionary line, humans acquired an extra mutant version of CD33 that lacked the sugar-binding site. The sialic acids on damaged cells and plaques now cause the mutant receptor to react, allowing microglia to degrade them. Indeed, several studies have shown that this variation of CD33 is protective against late-onset Alzheimer's disease.
Ajit Varki, MD, Professor of Molecular Medicine at the UC San Diego School of Medicine, and colleagues sought to understand when this gene variant first appeared, discovering evidence of strong positive selection. This suggests that something is causing the gene to evolve faster than expected. Additionally, they found that our closest evolutionary ancestors, Neanderthals and Denisovans, did not have genomes containing this particular CD33 variant.
“Neanderthals often have the same version as humans for most genes that differ in humans and chimpanzees,” Varki said.
This was incredibly shocking to us. These findings imply that we may have gained a significant evolutionary advantage over other ancient hominin species, thanks to the care of our grandparents.
Varki oversaw the work with Pascal Gagneux, a professor of pathology and anthropology at the UC San Diego School of Medicine. The study provides further evidence in favor of the grandmother theory, according to the authors.
However, according to evolutionary theory, it is reproductive success, not post-reproductive cognitive health, that drives genetic selection. So what drives this mutant variant of CD33 frequency in humans?
Researchers think that gonorrhea, a highly contagious disease that can be harmful to reproductive health, may have an impact on human evolution. Identical sugars to which CD33 receptors bind are also found on the surface of gonorrhea bacteria. Like a wolf in sheep's clothing, bacteria can trick human immune cells into thinking they are not foreign intruders.
According to the researchers, humans have evolved the modified CD33 protein, which lacks a sugar-binding site, as a defense mechanism against the "molecular mimicry" of gonorrhea and other diseases.
In fact, they confirmed that one of the human-specific mutations completely eliminated the contact between bacteria and CD33, allowing immune cells to attack the bacteria once again.
Altogether, the authors speculate that humans originally inherited the mutant form of CD33 to protect against gonorrhea while still in their reproductive years, and then the brain co-opted this gene variant for its advantages against dementia.
According to Gagneux, “It is possible that CD33 is one of many genes selected for early life resistance to infectious diseases.
Still, they were later chosen for their ability to prevent dementia and other aging-related disorders”.