Researchers at the University of California, San Diego School of Medicine previously found a set of human genetic mutations that protect older adults from cognitive decline and dementia. In a new study, published July 9, 2022 in Molecular Biology and Evolution, they focus on one of these mutated genes and try to track its evolution -; when and why it appeared in the human genome. The findings suggest that selective pressure from infectious pathogens such as gonorrhea may have promoted the emergence of this variant of the gene in Homo sapiens and, unwittingly, supported the existence of grandparents in human society.
The biology of most animal species is optimized for reproduction, often at the expense of future health and longer shelf life. In fact, humans are one of the only known species that live beyond menopause. According to the “grandmother hypothesis,” this is because older women provide important support in raising babies and human children, who require more care than the offspring of other species. Scientists are now trying to understand what features of human biology make this long-term health possible.
When the researchers previously compared the human and chimpanzee genomes, they found that humans have a unique version of the gene for CD33, a receptor expressed in immune cells. The standard CD33 receptor binds to a type of sugar called sialic acid with which all human cells are coated. When the immune cell detects sialic acid through CD33, it recognizes the other cell as part of the body and does not attack it, preventing an autoimmune response.
The CD33 receptor is also expressed in brain immune cells called microglia, where it helps control neuroinflammation. However, microglia also play an important role in the removal of damaged brain cells and amyloid plaques associated with Alzheimer’s disease. By binding to the sialic acids of these cells and plaques, regular CD33 receptors suppress this important microglial function and increase the risk of dementia.
This is where the new variant of the gene comes in. Somewhere along the evolutionary line, humans picked up an additional mutated form of CD33 that lacks the sugar binding site. The mutated receptor no longer reacts to sialic acids in damaged cells and plaques, allowing the microglia to break them down. In fact, it was independently found that the highest levels of this variant CD33 were protective against late-onset Alzheimer’s.
In trying to understand when this variant of the gene first emerged, lead co-author Ajit Varki, MD, a distinguished professor of medicine and cellular and molecular medicine at the UC San Diego School of Medicine, and colleagues they found evidence of strong positive selection, suggesting that something was driving the gene to evolve faster than expected. They also found that this particular version of CD33 was not present in the genomes of Neanderthals or Denisovans, our closest evolutionary relatives.
For most genes that are different in humans and chimpanzees, Neanderthals usually have the same version as humans, so this surprised us. These findings suggest that the wisdom and care of healthy grandparents may have been an important evolutionary advantage we had over other ancient hominid species. “
Ajit Varki, MD, Distinguished Professor of Medicine and Cellular and Molecular Medicine at UC San Diego School of Medicine
Varki led the study with Pascal Gagneux, PhD, professor of pathology at UC San Diego School of Medicine and professor in the Department of Anthropology. The authors said the study provides new evidence to support the grandmother’s hypothesis.
However, evolutionary theory says that reproductive success is the main driver of genetic selection, not post-reproductive cognitive health. So what was driving the prevalence of this mutated form of CD33 in humans?
One possibility, the authors suggest, is that highly infectious diseases such as gonorrhea, which can be detrimental to reproductive health, may have affected human evolution. Gonorrhea bacteria are coated with the same sugars to which CD33 receptors bind. Like a wolf in sheep’s clothing, bacteria are able to trick human immune cells into not identifying them as external invaders.
The researchers suggest that the mutated version of CD33 without a sugar binding site emerged as a human adaptation against this “molecular mimicry” of gonorrhea and other pathogens. In fact, they confirmed that one of the human-specific mutations was able to completely abolish the interaction between bacteria and CD33, which would allow immune cells to attack the bacteria again.
Taken together, the authors believe that humans initially inherited the mutated form of CD33 to protect themselves from gonorrhea during reproductive age, and this variant of the gene was later co-opted by the brain for its dementia benefits.
“CD33 may be one of many genes selected for its survival benefits against early-life infectious pathogens, but then selected secondarily for its protective effects against dementia and other aging-related diseases,” he said. Winning.
Source:
University of California – San Diego
Magazine reference:
Saha, S., et al. (2022) Evolution of specific human alleles that protect the cognitive function of grandmothers. Molecular Biology and Evolution. doi.org/10.1093/molbev/msac151.