Variations in DNA at a specific location (or 'locus') on the
genome that protect African children from developing severe
malaria, in some cases nearly halving a child's chance of
developing the life-threatening disease, have been identified in
the largest genetic association study of malaria to date.
The findings detail a new gene locus that can explain why, in
communities where everyone is constantly exposed to malaria, some
children develop severe malaria and others don't. Now, researchers
can be sure that this particular stretch of our DNA plays a crucial
role in the progression of the disease.
The research was conducted by MalariaGEN, an international
network of scientists and clinicians spread across Africa, Asia and
other malaria-endemic regions of the world, largely funded by the
Wellcome Trust. In this study they analysed data from eight
different African countries: Burkina Faso, Cameroon, Ghana, Kenya,
Malawi, Mali, The Gambia and Tanzania.
To identify the new locus, researchers performed a genome-wide
association study (GWAS) that compared the DNA of 5,633 children
with severe malaria with the DNA of 5,919 children without severe
malaria. They then replicated their key findings in a further
14,000 children.
The new locus they have identified is near a cluster of genes
which code for proteins called 'glycophorins' that are involved in
the malaria parasite's invasion of red blood cells. Although many
different malaria resistance loci have been postulated over the
years, this is one of very few that have stood up to stringent
testing in a large multi-centre study; the others include the genes
for sickle cell and the O blood group.
A particularly strongly-protective variant, known in genetics as
an 'allele', was found most commonly among children in Kenya in
East Africa. Having this allele reduces the risk of severe malaria
by about 40% in Kenyan children, with a slightly smaller effect
across all the other populations studied. The authors speculate
that this difference between populations could be due to the
genetic features of the local malaria parasite in East Africa.
Researchers have known for decades that the glycophorin cluster
of genes is highly variable, but it was not possible to show that
this genetic variation was responsible for protecting people
against severe malaria. Now, with improved GWAS methodology, and
the ability to collect samples from across different African
countries, researchers are better able to understand the complexity
in the patterns of DNA and, crucially, accurately measure their
effects on an individual's level of resistance to the disease.
Intriguingly, the new genetic resistance locus lies within a
region of the genome where humans and chimpanzees have been known
to share particular combinations of DNA variants, known as
haplotypes. This indicates that some of the variation seen in
contemporary humans has been present for millions of years. The
finding also suggests that this region of the genome is the subject
of 'balancing selection'.
Balancing selection happens when a particular genetic variant
evolves because it confers health benefits, but it is carried by
only a proportion of the population because it also has damaging
consequences. The classic example is the sickle cell gene - people
with one copy of the gene are strongly protected against malaria
but those with two copies of the gene develop a life-threatening
condition known as sickle-cell disease.
Professor Dominic Kwiatkowski, of the Wellcome Trust Sanger
Institute and the Wellcome Trust Centre for Human Genetics, said:
"We can now say, unequivocally, that genetic variations in this
region of the human genome provide strong protection against severe
malaria in real-world settings, making a difference to whether a
child lives or dies.
"These findings indicate that balancing selection and resistance
to malaria are deeply intertwined themes in our ancient
evolutionary history.
"This new resistance locus is particularly interesting because
it lies so close to genes that are gatekeepers for the malaria
parasite's invasion machinery. We now need to drill down at this
locus to characterise these complex patterns of genetic variation
more precisely and to understand the molecular mechanisms by which
they act."
Professor Ogobara K. Doumbo of the Malaria Research and Training
Center at the University of Bamako in Mali, said: "This type of
discovery is made possible by a strong collaboration between
malaria investigators in the field and northern collaborators who
have the technology platform and the capacity to analyse big
data.
"These findings provide new insights into the human and
plasmodium genetic interaction that are determined by their
co-evolution. How these findings could be used in public health
settings, as a marker of individual and population risk of malaria
infection, is the next step. Applying the findings in this way will
only be possible by training a critical mass of African scientists
in genomics and big data management and analysis. Both are
addressed by the MalariaGEN Consortium and the next Wellcome Trust
DELTAS Africa programmes."
The paper, A novel locus of resistance to severe malaria in a region of
ancient balancing selection, is published inNature.