the Third Reich
Kidney disease could be the price of resistance
to a virulent parasite. Researchers describe
two Jekyll-and-Hyde genetic variations online
in Science this week ( www.sciencemag.org/
cgi/content/abstract/1193032) that can lead
to kidney shutdown but may also fend off a
microorganism that causes sleeping sickness
in thousands of people in Africa.
“This is perhaps the best example, except
for sickle cell anemia, of a common disease
being caused by genetic variants that also
play a role in resistance to infectious disease,” says human geneticist Sarah Tishkoff
of the University of Pennsylvania. Similar
findings may soon follow, researchers predict. The study “offers a lot of encouragement that we are going to find more cases
where there are genetic bases for human
adaptations,” says evolutionary biologist
Gregory Wray of Duke University in
Durham, North Carolina.
For a long time, the prime example of how natural selection can favor
“harmful” mutations if they also confer
pathogen protection has been sickle cell
disease. A mutation in the gene for hemoglobin produces deformed red blood cells and
can lead to an early death in severe cases. But
it also enhances resistance to the most serious
variety of malaria. The sickle cell mutation
is so prevalent where this type of malaria is
rife—particularly sub-Saharan Africa—that
researchers have concluded that, despite its
lethal downside, the mutated gene evolved to
higher frequencies in these areas because of
its malaria-stopping benefits.
Africa’s parasites may also explain the
new kidney disease–promoting gene variants. Martin Pollak, a nephrologist and
human geneticist at Harvard Medical School
in Boston, and colleagues were searching
for genetic risk factors for two renal conditions—focal segmental glomerulosclerosis
and hypertension-attributed end-stage kidney
disease—that are four to five times more common among African Americans than among
people of European ancestry. Previous studies had homed in on a stretch of chromosome
22 but couldn’t pinpoint the culprits.
Pollak and colleagues expanded the
search to nearby DNA, including the APOL1
gene, which codes for the blood protein apoli-
poprotein L-1 (ApoL1). The researchers used
data from the 1000 Genomes Project—which
is sequencing DNA of people from around
the world—and scoured this chromosome
region for mutations that were much more
common in Africans than in Europeans.
Then by statistically analyzing the gene variants in African Americans who had either of
the kidney diseases, the team identified two
alterations in the APOL1 gene that correlated with illness. The G1 variant, for example, turned up in 52% of glomerulosclerosis
patients, versus 18% of controls. And the
G2 variant was about 50% more common
in patients with either kidney disease than it
was in healthy people.
The power of these gene alterations sur-
prised the team, Pollak says. The researchers
calculated that if both of a person’s APOL1
genes have one of the illness-causing mutations (no gene carries both), the risk of
developing hypertension-attributed end-stage kidney disease shoots up more than
Given this impact, it is surprising how
common G1 and G2 are in Africa. Among
the Yoruba people of Nigeria, G2’s frequency
was 8%, and G1’s was a whopping 38%.
What’s more, when the researchers applied
a statistical technique that can discern the
effects of natural selection, they found that
G1’s prevalence in Africa had surged within
the past 10,000 years. “The variants must
have positive effects in order to balance out
kidney disease,” Pollak says.
He and his colleagues hypothesized that
the G1 and G2 versions of ApoL1 better pro-
tect against Trypanosoma brucei, a micro-
scopic parasite spread in Africa by tsetse flies.
The standard version of ApoL1 slays one subspecies of the parasite, T. brucei brucei, but
not another subspecies, T. brucei
rhodesiense, which makes a protein called SRA that neutralizes
the blood defender.
But G1 and G2 reconfigure
ApoL1, restoring its potency.
Blood plasma from people who
carried G1 or G2 killed the
rhodesiense version of the parasite,
as did lab-made copies of the
altered proteins. “The effect was
really dramatic,” Pollak says.
Parasitologist Jayne Raper
of New York University says
the new study illustrates the
ongoing “molecular arms race
between host and pathogen.”
However, the study isn’t conclusive, the authors and outside experts agree.
The Yoruba people hail from West Africa,
whereas the altered ApoL1 proteins were
effective against the subspecies of T. brucei
that lives in East Africa. The G1 and G2 vari-
ants didn’t kill T. brucei gambiense, which
causes sleeping sickness in West Africa.
“That discrepancy needs to be resolved,”
Pollak and his colleagues plan to determine if the variants are common elsewhere
in Africa, including East Africa. They also
suggest that synthetic versions of the more
effective ApoL1 proteins, or even plasma
from people who carry G1 or G2, could provide a new treatment for African sleeping
sickness. The work doesn’t yet offer such
clear direction for helping people who get
kidney disease because of the mutations.
But discovering that APOL1 has a role in
renal illness is valuable, Pollak says: “Now
we know the biological pathways we should
be trying to understand.”
Kidney Disease Is Parasite-Slaying Protein’s Downside
Good gene, bad gene. The same gene variants that promote destruction of the kidney’s
filtration units (above) also combat
Trypanosoma brucei rhodesiense parasites (left).