Malaria is shaping the human genome

Researchers from the Malaria Genomic Epidemiology Network (MalariaGEN) have found that malaria has been a major force of evolutionary selection on the human genome. Small genetic changes have resulted in improved survival against malaria, and children carrying these genes have a better chance of passing them on.

Many genetic variants, or polymorphisms, have been reported as associated with susceptibility or protection from severe malaria, but most of these have shown discordant results or haven’t been replicated elsewhere. The study set out to replicate these findings, integrating data from almost 30,000 participants across multiple locations in Africa, Asia and Oceania. Dr Kirk Rockett, a founding member of MalariaGEN, said this was “a massive collective effort spanning nearly a decade”.

The findings, published in the journal Nature Genetics, highlight the complexity in the way the human genome may have been shaped by malaria and other infectious diseases. The researchers have found a biological trade-off through different forms of the same disease; that is, genetic variants become balanced in the population if there is a downside to carrying the gene.

For example, children carrying one copy of the gene for sickle cell haemoglobin (HbS) have a 10-fold reduction in their risk of cerebral malaria - a very severe form of malaria that has a mortality of around one in five children affected - which accounts for the high frequency of this mutation. However, if a child has two copies of the genetic variant - eg, they inherit it from both parents - they develop sickle cell disease and usually die before adulthood.

The study confirmed these findings to a very high level of confidence, across all the locations in the study. Meanwhile, more than 20 previously reported associations could not be confirmed, while others appeared to have some influence at some locations but not others. MalariaGEN leader Professor Dominic Kwiatkowski said the study therefore enabled the researchers to evaluate previous studies and to “distinguish genuine differences from differences due to different methodology or experimental error”.

The study also revealed a new finding regarding the gene variant which causes G6PD deficiency. Carriers of a single copy of the variant had been thought to be protected from malaria in a similar fashion to sickle cell carriers; however, the study found that although G6PD carriers were protected against cerebral malaria, they were more likely to suffer from anaemia as a complication of malaria. Thus, said Professor Kwiatkowski, “G6PD is not providing strong protection”.

It is not obvious how a mutation with such contrasting effects might have emerged during human evolution. One possibility is that it became common as a result of ‘balancing selection’ by a different malaria parasite, Plasmodium vivax, which no longer exists in much of Africa. The mutation would then persist there merely as an evolutionary throwback. Whatever the case, Professor Kwiatkowski concludes that “life has got more interesting”.

“In different places, the evolutionary battle between host and parasite has played out in different ways,” he said. “And it’s clear that in order to understand resistance, you need to amalgamate data from many places. Our study has provided a platform for the discovery of new loci associated with resistance to malaria.”