page_title: Human genetic resistance to malaria
section_title: Validating the malaria hypothesis
hierarchical_section_title: Human genetic resistance to malaria / Validating the malaria hypothesis
caption_attribution_description: English: Survival curves of Luo children in an area of Kenya where malaria transmission is intense. HbAS: Heterozygous sickle-cell hemoglobin; HbAA: normal hemoglobin; HbSS: homozygous sickle-cell hemoglobin. Based on data published in Aidoo et.al. Lancet, 2002 , 359, 1311)
context_page_description: Human genetic resistance to malaria refers to inherited changes in the DNA of humans which increase resistance to malaria and result in increased survival of individuals with those genetic changes. The existence of these genotypes is likely due to evolutionary pressure exerted by parasites of the genus Plasmodium which cause malaria. Since malaria infects red blood cells, these genetic changes are most commonly alterations to molecules essential for red blood cell function, such as hemoglobin or other cellular proteins or enzymes of red blood cells. These alterations generally protect red blood cells from invasion by Plasmodium parasites or replication of parasites within the red blood cell.
  These inherited changes to hemoglobin or other characteristic proteins, which are critical and rather invariant features of mammalian biochemistry, usually cause some kind of inherited disease. Therefore, they are commonly referred to by the names of the blood disorders associated with them, including sickle-cell disease, thalassemia, glucose-6-phosphate dehydrogenase deficiency, and others.
context_section_description: Evolutionary biologist J.B.S. Haldane was the first to give a hypothesis on the relationship between malaria and the genetic disease. He first delivered his hypothesis at the Eighth International Congress of Genetics held in 1948 at Stockholm on a topic "The Rate of Mutation of Human Genes". He formalised in a technical paper published in 1949 in which he made a prophetic statement: "The corpuscles of the anaemic heterozygotes are smaller than normal, and more resistant to hypotonic solutions. It is at least conceivable that they are also more resistant to attacks by the sporozoa which cause malaria." This became known as 'Haldane's malaria hypothesis', or concisely, the 'malaria hypothesis'.
  Detailed study of a cohort of 1022 Kenyan children living near Lake Victoria, published in 2002, confirmed this prediction. Many SS children still died before they attained one year of age. Between 2 and 16 months the mortality in AS children was found to be significantly lower than that in AA children. This well-controlled investigation shows the ongoing action of natural selection through disease in a human population.
  Analysis of genome wide association (GWA) and fine-resolution association mapping is a powerful method for establishing the inheritance of resistance to infections and other diseases. Two independent preliminary analyses of GWA association with severe falciparum malaria in Africans have been carried out, one by the Malariagen Consortium in a Gambian population and the other by Rolf Horstmann (Bernhard Nocht Institute for Tropical Medicine, Hamburg) and his colleagues on a Ghanaian population. In both cases the only signal of association reaching genome-wide significance was with the HBB locus encoding the β-chain of hemoglobin, which is abnormal in HbS. This does not imply that HbS is the only gene conferring innate resistance to falciparum malaria; there could be many such genes exerting more modest effects that are challenging to detect by GWA because of the low levels of linkage disequilibrium in African populations. However the same GWA association in two populations is powerful evidence that the single gene conferring strongest innate resistance to falciparum malaria is that encoding HbS.
caption: Survival curves of Luo children in an area of Kenya where malaria transmission is intense. HbAS: Heterozygous sickle-cell hemoglobin; HbAA: normal hemoglobin; HbSS: homozygous sickle-cell hemoglobin. [65]
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