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According to the initial sequencing completed in 2000, only two to three per cent of our genome contain identifiable genes and thus are considered as functionally active.
We have compared the entire genomes of several thousand patients and healthy controls in our search for mechanisms that make many people resistant to tuberculosis and life threatening malaria, and have discovered statistically significant differences. These kinds of comparisons have meanwhile been performed in more than 1300 instances for many diseases. In total, 88 per cent of all significant differences found between patients and healthy persons were found located in areas of the human genome to which no specific function can be attributed at present.
In the past years, laborious methods had been developed by the international Encyclopedia of DNA Elements (ENCODE) consortium to unravel as yet unknown genetic regulatory processes. Several of the complex interactions between RNA molecules that do not code for proteins, genomic DNA and regulatory proteins have already been identified. Apparently, every gene is controlled by numerous regulatory events, which determine at what point in time during development (embryonic stage, foetal stage, etc.) the gene is read, “expressed” as a protein, in which tissue, in what state of activation, how this is coordinated with other genes and so on. Minor variations in this highly complex genetic regulation appear to be of critical importance for the development of most common diseases as for susceptibility and resistance to infections.
The same mutations (genetic variants) may occur in a number of individuals, “linked” to each other, if they are located near one another on the same chromosome and have not been separated by the mixing between our chromosome pairs – we have two sets of chromosomes – in the generation of egg and sperm cells. The closer to one another that two mutations are located and the fewer generations have ensued since their random formation, the lower the probability, as a rule, that they have been separated from one another. As a result, the chromosomes in a population consist of a chain of blocks of different lengths which contain mutations that belong together, referred to as linkage groups. The more recent a mutation has occured, the larger is its linkage group – which in the case of a new ("de novo") mutation is the entire chromosome. If the genomes of many individuals in a given population have been sequenced, one can determine the linkage groups in this population quite reliably, and, for individuals for whom the genome sequence is unknown, the linkage group around any mutation can be deduced, allowing the other mutations in the vicinity to be “imputed”.
Being protected against Malaria by the sickle-cell trait is a perfect example how human mutations affect resistances against infections. 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 Info-Box). 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.
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)
Using imputation (see Info-Box), we have found an additional region in the human genome in which a mutation is located that protects against tuberculosis (TB). Unfortunately, the mutation is located quite distant from any known genes, so that we cannot deduce how it might influence protection against TB and how the information can be used to develop means for prophylaxis or treatment. A noteworthy aspect of the study is that it was the first time that twelve research groups from seven countries participated and mounted a total sample of 8,821 cases and 13,859 control persons. These kinds of cooperations are likely to be the model of the future.
Thorsten Thye, Ellis Owusu-Dabo, Christa Ehmen, Birgit Muntau, Gerd Ruge, Jürgen Sievertsen, Rolf Horstmann, Christian Meyer, and external cooperation partners (see publication an Fig. on the right)