At a recent conference held on the evolution of infectious
diseases, pathologist Nissi Varki,
University of California, San Diego (UCSD),
observed that humans suffer from a long list of fatal diseases — including
typhoid fever, cholera, mumps, whooping cough, measles, smallpox, polio, and
gonorrhea — that don't bother chimpanzees and most other mammals.
Both these bacteria follow the same mechanism to get into
our cells: they target sugar molecules called sialic acids. Hundreds of
millions of these sugars study the outer surface of any cell in the human body
— and human sialic acids differ from apes.
Varki and an international research team have now studied
how nature could have struggled to develop new defenses after molecular
instability appeared in our distant ancestors. Through studying current human
genomes and ancient DNA from our extinct ancestors, Neanderthals and
Denisovans, the researchers found an evolutionary explosion of our immune cells
that happened at least 600,000 years ago in an ancestor of all three human
forms.
As researchers write in Genome Biology and Evolution's current problem, these genetic modifications may have sharpened the body's
defenses against the pathogens emerging to target sialic acids — but produced
new vulnerabilities. In an additional irony, they say, the characteristic
sialic acids of humans were once a defense against disease.
Evolutionary saga is a dramatic example of human-microbe
rivalry, says microbiologist Christine
Szymanski of Georgia University, Athens,
who is not a co-author. "This gives a human perspective on how to keep
changing to keep pace."
The domain for this biological arms race is glycocalyx, a
sugar-coating that covers the cells' outer membrane. It consists of a bacterial
forest from the cell membrane. Sialic acids are at the tip of the strongest
roots, sugar chains or glycans, embedded lower in the membrane of fats and
proteins.
Despite their importance and number, sialic acids are
typically the first molecules to meet invading pathogens. One form of sialic acid,
N-acetylneuraminic acid (Neu5Ac), coats human cells. Yet apes and other humans
also bear another, N-glycolylneuraminic acid (Neu5Gc).
According to multiple molecular clock methods, a mutation in
the CMAH gene on chromosome six made it impossible for human ancestors to
produce Neu5Gc anymore; instead, they made more of another sialic acid, Neu5Ac.
"We now learn we have an ancient full structure of the surface of human
cells," says UCSD evolutionary biologist Pascal Gagneux, co-author of the
new article. Birds, rats, ferrets, and New World monkeys made the same genetic
transition independently.
The move likely emerged as a defense against malaria, says
UCSD physicist-scientist Ajit Varki, paper's senior author and Nissi Varki 's
husband. Malarial parasites that infect chimpanzees will no longer bind our red
blood cells with altered sialic acids.
Yet it became a vulnerability over the next million years or
so, as Neu5Ac became a preferred gateway for a flurry of other pathogens. At
the symposium on infectious disease organized by UCSD's Anthropogeny Academic
Research and Training Center, researchers described how multiple diseases
evolved to use Neu5Ac to enter cells or evade immune cells.
Coronaviruses are no different. "Many coronaviruses
infect cells in two stages — first, by establishing abundant sialic acids as
binding sites to obtain
A foothold, and then higher-affinity protein receptors like
ACE2, "says Ajit Varki. "Think of it as an initial handshake or the presentation needed before a date can be demanded." Two preprints say the
novel coronavirus, SARS-CoV-2, also docks with sialic acids before binding to
human cells with the ACE2 receptor.
In previous research, Ajit Varki and Gagneux proposed cell
structure and the lack of Neu5Gc may have led to the emergence of a new
species in our Homo genus. When a woman with only Neu5Ac sialic acids matted
with a man who also expressed Neu5Gc, she may have denied the man's sperm or
the fetus resulted from it.
More than 2 million years ago, researchers hypothesized,
this reproductive barrier may have helped split homo populations into separate
groups.
But the change in sialic acid also sparked a new arms race
between pathogens and our ancestors. Researchers scanned DNA for immune genes
in six Neanderthals, two Denisovans, and 1000 humans in the latest research and
even looked at hundreds of chimps, bonobos, gorillas, and orangutans. We found
evolutionary modifications that "markedly changed" one family of
proteins—sialic acid-binding immunoglobulin-type lectins, or Siglecs—usually
sitting on human immune cells' surface and detecting sialic acids.
Siglecs are molecular sentries: they check sialic acids to
see if they are common body components or alien invaders. When Siglecs find
damaged or absent sialic acids, they signal immune cells to activate, rousing
an aggressive force to strike foreign invaders or clean damaged cells. When,
then, sialic acids tend to be natural components of our own bodies, other,
inhibitory Siglecs turn down immune responses to prevent targeting our own tissues
(see graph above).
Researchers reported functional variations in eight out of
13 Siglecs genomic DNA expressed in a CD33 gene cluster on chromosome 19 in
humans, Neanderthals, and Denisovans. This hot spot in evolution happened only
invariants in Siglec genes, not in adjacent chromosome genes, indicating that
natural selection favored these changes, possibly because they helped combat
pathogens attacking Neu5Ac.
Apes didn't show these changes, says first
author Naazneen Khan, an evolutionary biologist at Kentucky University.
Considering the prevalence of mutations in ancient hominins, this explosion in
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