An evolutionary approach to the high frequency of the Delta F508 CFTR mutation in European populations

Abstract

The diffusion of the cattle pastoralism across Europe during the Neolithic period was probably accompanied by the emergence and spread of diverse contagious diseases that were unknown in the Paleolithic and that would have affected the frequency of genes directly or indirectly associated with differential susceptibility and/or resistance to infectious pathogens. We therefore propose that the high frequency of the CFTR gene, and in particular, the common Delta F508 allele mutation in current European and European-derived populations might be a consequence of the impact of selective pressures generated by the transmission of pathogenic agents from domesticated animals, mainly bovine cattle, to the man. Intestinal infectious diseases were probably a major health problem for Neolithic peoples. In such a context, a gene mutation that conferred an increased resistance to the diseases caused by pathogens transmitted by dairy cattle would have constituted a definite selective advantage, particularly in those human groups where cow's milk became an essential component of the diet. This selective advantage would be determined by an increased resistance to Cl(-)-secreting diarrheas of those individuals carrying a single copy of the Delta F508 CFTR mutation (heterozygote resistance). This hypothesis is supported by the strong association between the geography of the diffusion of cattle pastoralism (assessed indirectly by the lactase persistence distribution), the geographic distribution of a sizeable number of HLA alleles (as indicative of potential selective pressures generated by epidemic mortality) and the geographic distribution of the most common mutation causing cystic fibrosis (Delta F508). The systematic interaction of humans with infectious pathogens would have begun in northern Europe, among the carriers of the Funnel Beaker Culture, the first farmers of the North European plain, moving progressively to the south with the dissemination of the cattle pastoralism. This gradual exposure to epidemic mortality among populations located further and further south in Europe as cattle pastoralism expanded could have generated differences in CFTR gene frequencies, thereby shaping the latitudinal frequency gradients observed in present-day European populations.