In a new study published in Molecular Biology and Evolution, researchers found a set of human gene mutations responsible for protecting older people against dementia and cognitive decline. They examined one of these mutant genes and tried to determine when and why it first emerged in the human genome. The results imply that the origin of this gene variant in Homo sapiens may have been influenced by selective pressure from contagious illnesses like gonorrhea, which unintentionally boosted the presence of grandparents in human society.

DNA Genotyping and Sequencing
(Photo: National Cancer Institute/Unsplash)
DNA Genotyping and Sequencing

CD33 Homo Sapiens Mutation in Homo Sapiens

The research aims to understand when the mutation of CD33 occurred. According to the Atlas of Hematolopathology, CD33 is a member of the immunoglobulin supergene family. It is a sialoadhesin and a receptor produced in immune cells, a marker for acute myeloid leukemia.

Initially, researchers discovered that humans have a distinct variant of the gene for CD33 when compared to chimpanzees. All human cells are covered with a sugar called sialic acid, which the typical CD33 receptor binds to. When an immune cell detects sialic acid through CD33, it recognizes the other cell as a part of the body and does not attack it, preventing an autoimmune response.

Additionally, CD33 is expressed in brain immune cells known as microglia, which aids in the regulation of neuroinflammation. However, microglia also play a significant part in the removal of Alzheimer's disease-related amyloid plaques and injured brain cells. When regular CD33 receptors attach to the sialic acids on these cells and plaques, it suppresses the crucial microglial function and raises the risk of dementia.

At this point, the new gene variation takes place. Researchers noticed that humans had acquired an additional mutated form of CD33 that lacks the sugar-binding site. The sialic acids on injured cells and plaques no longer cause the mutant receptor to react, allowing the microglia to degrade them. Indeed, this CD33 variation is protective against late-onset Alzheimer's disease.

Strong positive selection was present, indicating that something was causing the gene to evolve more quickly than was anticipated. Additionally, they found that humans' closest evolutionary ancestors, the Neanderthals, and Denisovans, did not have the genomes that included this particular variant of CD33.

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Mutated CD33: Evolutionary Theory

According to evolutionary theory, reproductive success, not post-reproductive cognitive health, drives genetic selection. So, the authors of the study suggested that gonorrhea, a highly contagious disease that can harm reproductive health, may have impacted human evolution. The identical sugars that CD33 receptors bind to are also on the surface of gonorrhea bacteria. The bacteria can deceive human immune cells into thinking they are not foreign intruders, much like a wolf in sheep's clothing.

The research showed that humans developed the altered CD33 protein without a sugar-binding site as a defense mechanism against the molecular mimicry of gonorrhea and other diseases. The researchers verified that one of the human-specific mutations could eliminate the contact between the bacteria and CD33, allowing immune cells to attack the bacteria again.

The authors think that humans originally inherited the mutant form of CD33 to guard against gonorrhea when they were still in their reproductive years. The brain then co-opted this gene variant for its advantages against dementia.

"It is possible that CD33 is one of many genes selected for their survival advantages against infectious pathogens early in life, but that are then secondarily selected for their protective effects against dementia and other aging-related diseases," Pascal Gagneux, Ph.D., professor of pathology at UC San Diego School of Medicine and professor in the Department of Anthropology, said.

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