Summary: Researchers have identified a group of genetic mutations that protect against cognitive decline in older adults. A new study suggests that selective pressure from infectious pathogens such as gonorrhea may have enhanced the emergence of this genetic variation in Homo sapiens.
source: University of California
Researchers at the University of California, San Diego School of Medicine have previously found a group of human genetic mutations that protect older adults from cognitive decline and dementia.
In a new study published on July 9, 2022 in Molecular biology and evolutionThey focus on one of these mutant genes and try to trace its evolution — when and why it appeared in the human genome.
The results suggest that selective pressure from infectious pathogens such as gonorrhea may have enhanced the emergence of this variant gene in A wise manand unintentionally supported the existence of ancestors in human society.
The biology of most animal species has been improved for reproduction, often at the cost of future health and longer life. In fact, humans are one of the only species known to have gone through menopause.
According to the “grandmother’s hypothesis”, this is because older women provide important support in raising infants and children, who need more care than younger ones of other species. Scientists are now trying to understand the characteristics of human biology that make this long-term health possible.
When researchers previously compared the genomes of humans and chimpanzees, they found that humans have a unique copy of the gene for CD33, a receptor expressed in immune cells. The standard CD33 receptor binds to a type of sugar called sialic acid that all human cells are coated with. When the immune cell senses sialic acid via CD33, it recognizes the other cell as part of the body and does not attack it, preventing the autoimmune response.
The CD33 receptor is also expressed in immune cells of the brain called microglia, where they help control neuroinflammation. However, microglia also have an important role in removing damaged brain cells and amyloid plaques associated with Alzheimer’s disease. By binding to the sialic acids on these cells and plaques, normal CD33 receptors actually inhibit this important glial function and increase the risk of dementia.
This is where the new genetic variant comes in. Somewhere along the evolutionary line, humans have picked up an additional mutated form of CD33 that is missing a sugar-binding site. The mutated receptor no longer interacts with sialic acids on damaged cells and plates, allowing microglia to break them down. Indeed, higher levels of this CD33 variant were independently found to be protective against late-onset Alzheimer’s disease.
In an effort to understand when this genetic variant first appeared, co-senior author Ajit Varkey, MD, Distinguished Professor of Medicine and Cellular and Molecular Medicine at the University of California San Diego School of Medicine, and colleagues found evidence of strong positive selection, suggesting that something What was driving the gene evolving more quickly than expected.
They also discovered that this particular copy of CD33 was not present in the genomes of Neanderthals or Denisovans, our closest evolutionary relatives.
“For most of the different genes in humans and chimpanzees, Neanderthals usually have the same version as humans, so this was really surprising to us,” Varkey said. “These findings suggest that the wisdom and care of healthy ancestors may have been an important evolutionary advantage we had over other ancient hominin species.”
Varkey led the study with Pascal Gagnot, PhD, professor of pathology at the University of California, San Diego School of Medicine and professor in the department of anthropology. The authors said the study provides new evidence supporting the novelty hypothesis.
However, evolutionary theory says that reproductive success is the main driver of genetic selection, not post-reproductive cognitive health. So what prompted the spread of this mutated form of CD33 in humans?
The authors suggest that one possibility is that highly contagious diseases such as gonorrhea, which can be harmful to reproductive health, may have an impact on human development. Gonorrhea bacteria encapsulate themselves with the same polysaccharides to which the CD33 receptor binds. Like a wolf in sheep’s clothing, bacteria can trick human immune cells into not recognizing them as outside invaders.
The researchers suggest that the modified version of CD33 without a sugar-binding site emerged as a human adaptation against “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 the bacteria and CD33, allowing immune cells to attack the bacteria again.
Altogether, the authors believe that humans initially inherited the mutated form of CD33 to protect against gonorrhea during childbearing age, and the brain subsequently selected this genetic variant for its benefits against dementia.
“CD33 is likely one of several genes that were selected for their survival advantages against infectious pathogens early in life, but are then selected secondarily for their protective effects against dementia and other diseases associated with ageing,” Gagnox said.
Co-authors are: Sudeshna Saha, Nazanin Khan, Andrea Verhagen, Aniruda Sasmal, Sandra Diaz at UCSD, Troy Comey, Joshua M. Aki at Princeton University, Hai Yu and Shi Chin at UC Davis, and Martin Frank at Biognos A. with me. .
Financing: This work was funded by the National Institutes of Health (Grant R01GM32373) and the Alzheimer’s Treatment Fund.
About this genetics and evolutionary neuroscience news
author: Scott La Vi
source: University of California
Contact: Scott La Vie – University of California
picture: Image credited to the National Institutes of Health
original search: open access.
“Evolution of human-specific alleles that protect grandmothers’ cognitive functionby Ajit Varki et al. Molecular biology and evolution
Evolution of human-specific alleles that protect grandmothers’ cognitive function
The myeloid receptor CD33 (Siglec-3) suppresses the innate immune reaction by recognizing an extracellular group V domain of sialic acid (Sia) containing ‘self-associated molecular patterns’ (SAMPs). We previously showed that the V group is deficient in domain CD33The altered allele, protective alleles of late-onset Alzheimer’s disease (LOAD), is derived and assigned to the hominin strain.
We now report multiple mutations in the CD33 V-set domain of hominins. Because of the hominin fixed-function loss mutation in CMAH Gene, humans lack n-Glycolinoraminic acid (Neu5Gc), a preferred Sia-ligand of ancestral CD33. Mutation analysis and MD simulations indicate that the consistent change in amino acid 21 of the hominin V group domain and His45-related conformational changes corrected for Neu5Gc loss by switching to nAcetylneuraminic acid (Neu5Ac) – identification.
We show that human pathogens Neisseria gonorrhoeae and group b Streptococcus selectively bind huCD33 as part of the SAMPs host immune molecular mimicry and that this binding is significantly influenced by 21 amino acid modification.
In addition to protective LOAD CD33 Alleles, humans harbor derived, population-wide and protective variants of cognition at several other loci. Interestingly, 11 out of 13 polymorphisms in these human genes (including CD33) are not shared by the genomes of ancient hominins: Neanderthals and Denisovans.
We present a plausible evolutionary scenario to synthesize, relate and understand current knowledge about the evolution of huCD33 and suggest that the novelty emerged in humans.
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