evolution reached a mysterious bottleneck roughly 100,000 years ago. At
that time our ancestors had been reduced to perhaps five to ten
thousand individuals living in Africa. 'Behaviorally modern' humans
would emerge from this population, expanding dramatically in both number
and range, and replacing all other co-existing evolutionary cousins,
such as the Neanderthals in time.
The cause of the bottleneck remains unsolved, with proposed answers
ranging from gene mutations to cultural developments like language to
climate-altering events, among them a massive volcanic eruption.
Add another possible factor: infectious disease.
In a paper published in the June 4, 2012 online Early Edition of
The Proceedings of the National Academy of Sciences
an international team of researchers, led by scientists at the
University of California, San Diego School of Medicine, suggest that
inactivation of two specific genes related to the immune system may have
conferred selected ancestors of modern humans with improved protection
from some pathogenic bacterial strains, such as Escherichia
and Group B Streptococci
leading causes of sepsis and meningitis in human fetuses, newborns and
"In a small, restricted population, a single mutation can have a big
effect, a rare allele can get to high frequency," said senior author
Ajit Varki, MD, professor of medicine and cellular and molecular
medicine and co-director of the Center for Academic Research and
Training in Anthropogeny at UC San Diego. "We''ve found two genes that
are non-functional in humans, but not in related primates, which could
have been targets for bacterial pathogens particularly lethal to
newborns and infants. Killing the very young can have a major impact
upon reproductive fitness. Species survival can then depend upon either
resisting the pathogen or on eliminating the target proteins it uses to
gain the upper hand."
In this case, Varki, who is also director of the UC San Diego
Glycobiology Research and Training Center, and colleagues in the United
States, Japan and Italy, propose that the latter occurred. Specifically,
they point to inactivation of two sialic acid-recognized signaling
receptors (siglecs) that modulate immune responses and are part of a
larger family of genes believed to have been very active in human
Working with Victor Nizet, MD, professor of pediatrics and pharmacy,
Varki''s group had previously shown that some pathogens can exploit
siglecs to alter the host immune responses in favor of the microbe. In
the latest study, the scientists found that the gene for Siglec-13 was
no longer part of the modern human genome, though it remains intact and
functional in chimpanzees, our closest evolutionary cousins. The other
siglec gene - for Siglec-17 - was still expressed in humans, but it had
been slightly tweaked to make a short, inactive protein of no use to
"Genome sequencing can provide powerful insights into how organisms
evolve, including humans," said co-author Eric D. Green, MD, PhD,
director of the National Human Genome Research Institute at the National
Institutes of Health.
In a novel experiment, the scientists "resurrected" these "molecular
fossils" and found that the proteins were recognized by current
pathogenic strains of E. coli
and Group B
. "The modern bugs can still bind and could
potentially have altered immune reactions," Varki said.
Though it is impossible to discern exactly what happened during
evolution, the investigators studied molecular signatures surrounding
these genes to hypothesize that predecessors of modern humans grappled
with a massive pathogenic menace between 100,000 and 200,000 years ago.
This presumed "selective sweep" would have devastated their numbers.
Only individuals with certain gene mutations survived - the tiny,
emergent population of anatomically modern humans that would result in
everyone alive today possessing a non-functional Siglec-17 gene and a
missing Siglec-13 gene.
Varki said it''s probable that humanity''s evolutionary bottleneck was
the complex result of multiple, interacting factors. "Speciation (the
process of evolving new species from existing ones) is driven by many
things," he said. "We think infectious agents are one of them."
Co-authors of the paper include Xiaoxia Wang, Ismael Secundino, Nivedita
Mitra, Kalyan Banda, Vered Padler-Karavani, Andrea Verhagen and Chris
Reid, Victor Nizet and Jack D. Bui, Departments of Medicine, Cellular
and Molecular Medicine, Pathology and Pediatrics, UC San Diego and the
UC San Diego Glycobiology Research and Training Center; the Skaggs
School of Pharmacy and Pharmaceutical Sciences and UC San Diego /Salk
Center for Academic Research and Training in Anthropogeny; Marti