Hemoglobin E, malaria and natural selection

It is known that there has been positive natural selection for hemoglobin S and C in humans despite negative health effects, due to its role in malaria resistance. However, it is not well understood, if there has been natural selection for hemoglobin E (HbE), which is a common variant in Southeast Asia. Therefore, we reviewed previous studies and discussed the potential role of natural selection in the prevalence of HbE. Our review shows that in vitro studies, evolutionary genetics studies and epidemiologic studies largely support an involvement of natural selection in the evolution of HbE and a protective role of HbE against malaria infection. However, the evidence is inconsistent, provided from different regions, and insufficient to perform an aggregated analysis such as a meta-analysis. In addition, few candidate gene, genome-wide association or epistasis studies, which have been made possible with the use of big data in the post-genomic era, have investigated HbE. The biological pathways linking HbE and malaria infection have not yet been fully elucidated. Therefore, further research is necessary before it can be concluded that there was positive natural selection for HbE due to protection against malaria. Lay summary: Our review shows that evidence largely supports an involvement of natural selection in the evolution of HbE and a protective role of HbE against malaria. However, the evidence is not consistent. Further research is necessary before it is concluded.