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We determined almost a million mutations in each of 1,400 children affected by severe malaria and 800 unaffected children, and then deduced an additional roughly five million mutations by imputation (see p.67). Besides the expected unequal distribution of the sickle-cell trait and blood group O, significant differences between diseased and healthy children were newly identified in two regions of the genome and these were confirmed in 3,500 additional children.
One of them was located in a large intron of the ATP2B4 gene, i.e. in a DNA sequence lying between two parts of the gene. ATP2B4 codes for a calcium pump that lies in the wall of, among others, red blood cells and influences the calcium concentration inside cells. The second region is located about 6,000 base pairs in front of the MARVELD3 gene. MARVELD3 codes for a protein that seals off spaces between cells lining our blood vessels. One can well imagine that the calcium concentration of the host cells of malaria parasites as well as the seals in our vessel walls could influence the course of the malaria. What is not clear, however, is how mutations can have an effect if they are located between two parts of a gene or relatively far from a gene. It is conceivable indeed therefore that the mutations discovered affect as yet unknown regulatory functions (see p.73).
Christian Timmann, Thorsten Thye, Jennifer Evans, Jürgen May, Christa Ehmen, Jürgen Sievertsen, Birgit Muntau, Gerd Ruge, Wibke Loag, Michael Brendel, Kathrin Schuldt, Christian G. Meyer, Rolf Horstmann, and cooperation partners (see publication)