Researchers at the University of California San Diego School of Medicine have discovered a set of human genetic mutations that prevent cognitive decline and dementia in older adults, according to a new study published July 9, 2022 in the journal Molecular Biology and Evolution. Scientists focused on one of the mutated genes and tracked its evolution through its appearance in the human genome.
The results of the study suggest that the selective pressure of infectious pathogens such as gonorrhea may have been the reason for the appearance of this variant of the gene in homo sapiens and paved the way for the existence of grandparents in the social structures of humans.
Long-term health
Interestingly, humans are the only known species that lives after menopause. To explain the reason for this, the “grandmother’s hypothesis” suggests that older women are crucial in helping to raise babies and human children, as they need more care than babies of other species.
And now, researchers are trying to understand the long-term health of humanity by examining mutated genomes. The new study is significant in revealing that humans collected an additional mutated form of CD33 that has no sugar binding site somewhere along the evolutionary line. CD33 is a receptor expressed in immune cells and usually binds to sialic acid, a form of sugar that covers all human cells.
Sialic acids in damaged cells and plaques no longer cause the mutant receptor to respond, allowing the microglia to break them down. Finally, several studies have shown that this variation of CD33 is protective against late-onset Alzheimer’s disease.
The researchers looked for clues to discover when this variation in the gene originally arose and found signs of strong positive selection, indicating that something was pushing the gene to develop faster than expected. In addition, they found that our closest evolutionary ancestors, Neanderthals and Denisovans, did not have this specific variant of CD33 in their genomes.
“For most genes that are different in humans and chimpanzees, Neanderthals usually have the same version as humans, so that really surprised us,” said lead co-author Ajit Varki, MD, a distinguished professor of medicine and cellular and molecular medicine. at the UC San Diego School of Medicine. “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.”
Influence of gonorrhea on human evolution
While this new study provides evidence that supports grandmother’s theory, evolutionary theory says that what drives genetic selection is reproductive success, not post-reproductive cognitive health. Thus, scientists suggest that gonorrhea, a highly contagious sexually transmitted infection caused by bacteria, may have influenced human evolution.
Identical sugars to which CD33 receptors bind are also found on the surface of gonorrhea bacteria, and the bacteria can trick human immune cells into thinking they are not external intruders. In light of this, the researchers indicate that humans developed the mutant form of CD33 that lacks a sugar binding site as a defense mechanism against this “molecular mimicry” for gonorrhea and other infections. They also found that one of the human-specific mutations was able to eliminate contact between bacteria and CD33, allowing immune cells to attack germs once again.
In the final analysis, the researchers claim that humans inherited the mutant version of CD33 first to protect themselves from gonorrhea when they were in reproductive age. Later, the brain co-opted this genetic variation for its benefits against dementia.
Abstract: The myelomonocytic receptor CD33 (Siglec-3) inhibits innate immune reactivity by extracellular recognition of the V-set domain of “self-associated molecular patterns” (SAMP) containing sialic acid (Sia). We previously demonstrated that the allele of the V-set domain-deficient CD33 variant, protective against late-onset Alzheimer’s disease (LOAD), is derived and specific to the hominin lineage. We now report multiple hominin-specific V-set CD33 domain mutations. Due to the fixed mutation of hominine-specific loss of function in the CMAH gene, humans lack N-glycolylneuraminic acid (Neu5Gc), the preferred Sia ligand of the ancestral CD33. Mutational analysis and MD simulations indicate that the fixed change in amino acid 21 of the hominin V-set domain and His45-related conformational changes were corrected for Neu5Gc loss by switching to acid recognition. N-acetylneuramine (Neu5Ac). We show that human-specific pathogens Neisseria gonorrhoeae and group B streptococcus bind selectively to huCD33 as part of the evasive immune molecular mimicry of host SAMPs and that this binding is significantly affected by amino acid modification 21 In addition to the LOAD protective CD33 alleles, humans harbor variants of cognition protection, universal in the population, derived from several other loci. Interestingly, 11 of the 13 SNPs of these human genes (including CD33) are not shared by archaic hominin genomes: Neanderthals and Denisovans. We present a plausible evolutionary scenario for collecting, correlating, and understanding existing knowledge about the evolution of huCD33 and suggesting that the grandmother emerged in humans.