WS17.1 The ancient origin of F508del-CF: When and where the mutation arose

Objective To determine when and where the F508del mutation arose and how it may have diffused in Europe. Methods A total of 182 CF patients and their parents from 7 countries were studied. They were genotyped for 10 microsatellite markers, and haplotypes were reconstructed using the Beagle program (Browning et al. Am J Hum Genet 2007; 81: 1084–97) on both the trios and the pairs with 100 imputations. Only the haplotypes that were the same over the 100 imputations were kept for the analysis, resulting in 219 such non-ambiguous haplotypes coming from 130 independent trios. The age of the most recent common ancestor of F508del was estimated in each population from the length of the haplotypes shared by the mutation carriers using the Estiage program (Genin et al. J Med Genet 2004; 41: 445–49) under a stepwise mutation model at the different markers, assuming a mutation rate of 10−3 per meiosis and 20 years/generation). Results The estimated “age” of F508del in the various populations is shown in the table. Country Number of generations Number of years ago Calendar year a Fiance 259 5180 3166 BCE Denmark 243 4860 2846 BCE Ireland 241 4820 2806 BCE Austria 220 4400 2386 BCE Czech Republic 137 1780 626 BCE Greece 79 1580 434 Albania 61 1220 794 a BCE, before the common era. Conclusions The data reveal an early Bronze Age origin with relatively swift diffusion in Western Europe and a west-to-east dissemination.