G6PD deficiency is very frequent in Africa, Middle East, and Southeast Asia, but rare in Northern Europe (including Germany) or Northern America (except African Americans). This raises the question, whether differences in population genetics might account for this phenomenon. Rather than genetic or biological borders among human populations and tribes, the geographical distribution contributes to the cumulative occurrence of different forms of G6PD deficiency. The Mediterranean variants are not or rarely found in Asia or America. The fact that Japan is an island may explain the restricted occurrence of the G6PD Japan variant to this geographical area [12]. In the present investigation, we describe the three-dimensional localization of the structural modification in six G6PD class 1 variants of German origin. It is intriguing that none of the common Mediterranean variants are found in Germany as of yet. As can be seen in Table 2 and 3, some G6PD variants are restricted to certain areas and regions, while others are more widely spread. G6PD variants with locally restricted occurrence speak for an independent development during evolution. On the other side, a number of G6PD variants were found in Mediterranean and Middle-Eastern European populations as well as in the Near and Middle East suggesting a significant gene flow from Near East both to South-Eastern Europe and via sub-Saharan Africa to the South Mediterranean [13], [14]. An enhanced distribution of G6PD deficiency may have taken place by Greek settlers, who established many colonies throughout the Mediterranean world in ancient times [15]. In spite of this distribution of G6PD deficiency over Europe the question arises, why the common Mediterranean mutations were not found in German populations suffering from G6PD deficiency. | Table 2 Ubiquitous G6PD variants in Europe, Near East, and Africa |
| Table 3 Endemic G6PD variants in Europe, Near East, and Africa |
Different hypotheses can be entertained to explain the differing occurrence of G6PD deficiency in various areas and populations. One point of view is that G6PD deficiency has independently developed with comparable frequencies in different areas. This is true for G6PD class 1 variants, which are found as sporadic cases worldwide and which cause chronic hemolytic anemia. Class 2 or class 3 G6PD deficiency is different from class 1. These forms are better tolerated except in case of oxidative stress leading to a hemolytic crisis. Class 2 and 3 variants have been selected by malaria. Diminished concentrations of reduced glutathione may represent a permissive environment for protozoal parasites such as Plasmodium falciparum. Hence, G6PD mutations are protective against malaria [16]. A comparable convergent evolution between protecting G6PD mutations and thalassemia or sickle cell anemia has been proposed [17], [18]. Malaria, thalassemia, and sickle cell anemia may, therefore, exert a positive selection pressure for carriers of G6PD mutations. As malaria is not endemic in Germany, but was present in certain Mediterranean (i.e. Sardinia), African and Arabian regions in former times, it is reasonable to speculate that for this reason G6PD deficiency class 3 is not as frequent as in areas plagued with malaria. Indeed, G6PD variants class 3 from Germany are rarely described. Except of G6PD Frankfurt, no other form appeared in the medical literature during the past six decades ( Table 3). This is in contrast to the occurrence of G6PD variants on other populations, where class 3 mutants appear with a much higher frequency [19]It could also be argued that the Limes Germanicus (Latin for German frontier) of the ancient Roman Empire, which separated the roman empire from un-subdued German tribes and had its maximum extent in the second century A.D., had a barrier function further restricting the distribution of G6PD deficiency in Middle European areas (if not distributed before the Roman Empire and the Limes were established). Class 1 variants are sporadic by definition, and apparently do not provide any advantage against malaria. Falciparum malaria, the selective force responsible for the expansion of class 2 G6PD variants (typically, G6PD Mediterranean), was never present in Northern Europe. The prevalence of falciparum (malignant) malaria was low during the Roman Empire period. After the fall of the Empire, falciparum malaria exploded and became endemic in some Southern region due to the collapse of the irrigation system and expansion of marshes. The Roman citizens (cives romani) were a minority in the Northern provinces and largely outnumbered by the Romanized local populations. Finally, the Limes was not an efficient barrier against the inflowing large Germanic populations (barbari) that came in during the following centuries. Very extensive admixture of different German populations occurred later on, i.e., during the Thirty Years' War (1618–1648) and recently after the huge population shifts in Germany after World War II. Hence, the hypothesis of a barrier function of the Roman limes is not convincing. The fact that G6PD-deficiency is rare in Germany but relatively common in the Mediterranean region and Northern Africa gave rise to speculations in the past that G6PD-deficiency was spread into German populations, as the Roman Empire had occupied the countries beyond the Alps. Offspring of Roman soldiers of Mediterranean or Northern African origin and German inhabitants might have carried G6PD mutations leading to G6PD-deficiency in German populations nowadays. This opinion, which might have its roots in fascistic mindsets, seemed reasonable at superficial consideration in ages when solely clinical or biochemical data of G6PD deficiency were available. As of now, all G6PD mutations of German ancestries are different at the DNA level from the known Mediterranean and Northern African forms of G6PD-deficiency. This clearly disproves the ambiguous idea that G6PD deficiency appeared in Germany by mating of Roman soldiers and German women. In areas where malaria does not represent a challenge for human populations, other weak influences may affect the manifestation of G6PD deficiency. A negative selection pressure has been discussed for non-lethal disorders or rare inherited syndromes. Decreased amounts of reduced glutathione may favour disorders such as manic depression, red/green colour vision, multiple sclerosis, diabetes mellitus, cataract, fragile X-syndrome and others. A relationship between lethal diseases such as cancer and G6PD deficiency has also been proposed. However, all these associations are weak. If any, these factors may have a weak influence on the manifestation of G6PD deficiency and may lead to a reduction of the frequency of G6PD deficiency in German populations. The most likely possibility is that the sporadic variants that are observed in Germany really represent the effect of random mutations. The mutations that are seen, then, represent the balance between the rate at which these mutations occur and the rate at which they are lost from the population. Except for the class 1 variants, which are probably lost very rapidly, most G6PD deficiency has very little effect on fitness and is therefore relatively slowly lost from the population. |
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