The current epidemic of artemisinin resistant Plasmodium falciparum in Southeast Asia is the result of a soft selective sweep involving at least 20 independent kelch13 mutations. In a large global survey, we find that kelch13 mutations which cause resistance in Southeast Asia are present at low frequency in Africa. We show that African kelch13 mutations have originated locally, and that kelch13 shows a normal variation pattern relative to other genes in Africa, whereas in Southeast Asia there is a great excess of non-synonymous mutations, many of which cause radical amino-acid changes. Thus, kelch13 is not currently undergoing strong selection in Africa, despite a deep reservoir of variations that could potentially allow resistance to emerge rapidly. The practical implications are that public health surveillance for artemisinin resistance should not rely on kelch13 data alone, and interventions to prevent resistance must account for local evolutionary conditions, shown by genomic epidemiology to differ greatly between geographical regions. DOI: http://dx.doi.org/10.7554/eLife.08714.001 eLife digest Malaria is an infectious disease caused by a microscopic parasite called Plasmodium , which is transferred between humans by mosquitos. One species of malaria parasite called Plasmodium falciparum can cause particularly severe and life-threatening forms of the disease. Currently, the most widely used treatment for P. falciparum infections is artemisinin combination therapy, a treatment that combines the drug artemisinin (or a closely related molecule) with another antimalarial drug. However, resistance to artemisinin has started to spread throughout Southeast Asia. Artemisinin resistance is caused by mutations in a parasite gene called kelch13 , and researchers have identified over 20 different mutations in P. falciparum that confer artemisinin resistance. The diversity of mutations involved, and the fact that the same mutation can arise independently in different locations, make it difficult to track the spread of resistance using conventional molecular marker approaches. Here, Amato, Miotto et al. sequenced the entire genomes of more than 3,000 clinical samples of P. falciparum from Southeast Asia and Africa, collected as part of a global network of research groups called the MalariaGEN Plasmodium falciparum Community Project. Amato, Miotto et al. found that African parasites had independently acquired many of the same kelch13 mutations that are known to cause resistance to artemisinin in Southeast Asia. However the kelch13 mutations seen in Africa remained at low levels in the parasite population, and appeared to be under much less pressure for evolutionary selection than those found in Southeast Asia. These findings demonstrate that the emergence and spread of resistance to antimalarial drugs does not depend solely on the mutational process, but also on other factors that influence whether the mutations will spread in the population. Understanding how this is affected by different patterns of drug treatments and other environmental conditions will be important in developing more effective strategies for combating malaria. DOI: http://dx.doi.org/10.7554/eLife.08714.002
【저자키워드】 Artemisinin, malaria, drug resistance, Other, Plasmodium falciparum, Kelch13,