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• The high frequencies of CFTR variants can be explained by a selective advantage for healthy carriers (4–6 % per generation). • Spreading of disease-causing allele carriers was accelerated towards the end of the 18th century. • The most widespread variant (F508del) is estimated to have appeared approximately 190 generations ago. The French region of Brittany presents one of the highest cystic fibrosis (CF)-causing allele frequency in Europe. Here, we tested two hypotheses: i) CF-causing allele carriers arrived by sea in the middle of the 1st millennium AD, and ii) a selective advantage for healthy carriers explains this high rate. From the census of cystic fibrosis patients, frequency maps of the most widespread alleles were established. A mathematical model was developed, based on birth date and place of the ancestors of these patients over 5 centuries, to determine the distribution of local migrations and their parameters for inter-generational intervals of 32 years. This model was applied to simulate the spread of CF-causing variant carriers, according to different scenarios that corresponded to the immigration of a given number of variant carriers at different times (year) and places, and to compare their results to current frequency maps. Migrants carrying a CFTR variant settled in several locations, around which they spread, notably in Central Brittany (F508del variant), Léon (G551D variant) and Cornouaille (1078delT variant). Until the end of the 18th century, the spreading of disease-causing allele carriers was relatively slow, and allele frequencies progressively increased. Then, the mean migration distances increased rapidly, leading to a decline in local frequencies. The main CFTR variants could only have reached their current frequencies through a selective advantage for healthy carriers of the order of 4–6 % at each generation. For the most widespread variant (F508del), the model supports the hypothesis that it appeared around 190 generations ago. [ABSTRACT FROM AUTHOR]