Did gonorrhea give us grandparents?
Summary: Researchers have identified a set of genetic mutations that protect against cognitive decline in older people. A new study suggests that selective pressure from infectious pathogens like gonorrhea may have favored the emergence of this genetic variance in Homo sapiens.
Researchers at the University of California, San Diego School of Medicine have previously discovered a set of human genetic mutations that protect older adults against cognitive decline and dementia.
In a new study, published on July 9, 2022 in Molecular biology and evolutionthey focus on one of these mutated genes and attempt to trace its evolution — when and why it appeared in the human genome.
The results suggest that selective pressure from infectious pathogens like gonorrhea may have favored the emergence of this genetic variant in Homo sapiensand inadvertently 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 lifespan. In fact, humans are one of the only species known to live well past menopause.
According to the “grandmother hypothesis”, this is because older females provide important support in raising human infants and children, who require more care than young of other species. . Scientists are now trying to understand what features of human biology make this longer-term health possible.
When 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 that all human cells are coated with. When the immune cell detects sialic acid via 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 clearing damaged brain cells and amyloid plaques associated with Alzheimer’s disease. By binding to sialic acids on these cells and plaques, regular CD33 receptors actually suppress this important microglial function and increase the risk of dementia.
This is where the new gene variant 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 on damaged cells and plaques, allowing microglia to break them down. Indeed, higher levels of this CD33 variant have been shown to be independently protective against late-onset Alzheimer’s disease.
In trying to figure out when this genetic variant first emerged, co-lead author Ajit Varki, MD, professor emeritus of medicine and cellular and molecular medicine at UC San Diego School of Medicine, and colleagues found evidence of strong positive selection, suggesting that something was driving the gene to evolve faster than expected.
They also discovered that this particular version of CD33 was not present in the genomes of Neanderthals or Denisovans, our closest evolutionary relatives.
“For most of the genes that are different in humans and chimpanzees, Neanderthals usually have the same version as humans, so that was really surprising to us,” Varki said. “These findings suggest that the wisdom and care of healthy grandparents may have been an important evolutionary advantage we had over other ancient hominin species.”
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 in support of the grandmother hypothesis.
Yet the theory of evolution asserts that reproductive success is the primary 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 like gonorrhea, which can impair reproductive health, could have impacted human evolution. Gonorrhea bacteria coat themselves with the same sugars that CD33 receptors bind to. Like a wolf in sheep’s clothing, the bacteria is able to trick human immune cells into not identifying them as outside invaders.
The researchers suggest that the mutated version of CD33 without a sugar-binding site emerged as a human adaptation against such “molecular mimicry” by gonorrhea and other pathogens. Indeed, they confirmed that one of the human-specific mutations was able to completely abolish the interaction between the bacterium and CD33, which would allow immune cells to attack the bacterium again.
Altogether, the authors believe that humans initially inherited the mutated form of CD33 to protect against gonorrhea during childbearing age, and this variant of the gene was later co-opted by the brain for its benefits against dementia.
“It is possible that CD33 is one of many genes selected for their survival advantages against infectious pathogens in early life, but which are then selected secondarily for their protective effects against dementia and other diseases related to dementia. aging,” Gagneux said.
Co-authors include: Sudeshna Saha, Naazneen Khan, Andrea Verhagen, Aniruddha Sasmal, and Sandra Diaz at UC San Diego, Troy Comi and Joshua M. Akey at Princeton University, Hai Yu and Xi Chen at UC Davis, and Martin Frank at Biognos AB .
Funding: This work was funded by the National Institutes of Health (grant R01GM32373) and the Cure Alzheimer’s Fund.
About this genetics and evolutionary neuroscience research news
Author: Scott the Fairy
Contact: Scott La Fee – UCSD
Image: Image is credited to the NIH
Original research: Free access.
“Evolution of male-specific alleles protecting cognitive function in grandmothers” by Ajit Varki et al. Molecular biology and evolution
Evolution of human-specific alleles protecting cognitive function in grandmothers
The myelomonocyte receptor CD33 (Siglec-3) inhibits innate immune reactivity through extracellular recognition of the V-set domain of “self-associated molecular patterns” (SAMPs) containing sialic acid (SIA). We have shown previously that V-set domain-deficient CD33– the variant allele, protective against late Alzheimer’s disease (LOAD), is derived and specific to the hominin line.
We now report several hominin-specific CD33 V-set domain mutations. Due to a hominin-specific fixed-function loss mutation in the CMAH gene, humans lack NOT– glycolylneuraminic acid (Neu5Gc), the preferred Sia-ligand of ancestral CD33. Mutational analysis and MD simulations indicate that the hominin V-set domain amino acid 21 fixed change and His45-related conformational changes corrected the loss of Neu5Gc to NOT-recognition of acetylneuraminic acid (Neu5Ac).
We show that human-specific pathogens Neisseria gonorrhoeae and Group B Streptococcus selectively bind to huCD33 as part of immune evasion molecular mimicry of host SAMPs and that this binding is significantly affected by modification of amino acid 21.
In addition to LOAD protection CD33 alleles, humans harbor derived, population-universal, cognition-protective variants at several other loci. Interestingly, 11 of the 13 SNPs of these human genes (including CD33) are not shared by the genomes of archaic hominins: Neanderthals and Denisovans.
We present a plausible evolutionary scenario to compile, correlate, and understand existing knowledge about the evolution of huCD33 and suggest that the grandmother originated in humans.