The high incidence of cystic fibrosis (CF) is due to the frequency of the c.1521_1523delCTT variant in the cystic fibrosis transmembrane conductance regulator (CFTR), but its age and origin are uncertain. This gap limits attempts to shed light on the presumed heterozygote selective advantage that accounts for the variant's high prevalence among Caucasian Europeans and Europe-derived populations. In addition, explaining the nature of heterozygosity to screened individuals with one c.1521_1523delCTT variant is challenging when families raise questions about these issues. To address this gap, we obtained DNA samples from 190 patients bearing c.1521_1523delCTT and their parents residing in geographically distinct European populations plus a Germany-derived population in the USA. We identified microsatellites spanning CFTR and reconstructed haplotypes at 10 loci to estimate the time/age of the most recent common ancestor (tMRCA) with the Estiage program. We found that the age estimates differ between northwestern populations, where the mean tMRCA values vary between 4600 and 4725 years, and the southeastern populations where c.1521_1523delCTT seems to have been introduced only about 1000 years ago. The tMRCA values of Central Europeans were intermediate. Thus, our data resolve a controversy by establishing an early Bronze Age origin of the c.1521_1523delCTT allele and demonstrating its likely spread from northwest to southeast during ancient migrations. Moreover, taking the archeological record into account, our results introduce a novel concept by suggesting that Bell Beaker folk were the probable migrating population responsible for the early dissemination of c.1521_1523delCTT in prehistoric Europe.

Department of Biology and Medical Genetics Charles University 2nd Faculty of Medicine and Motol University Hospital Prague Czech Republic

Department of Clinical Genetics Our Lady's Children's Hospital Dublin Ireland

Department of Clinical Genetics University Hospital Copenhagen Copenhagen Denmark

Department of Medical Genetics School of Medicine National and Kapodistrian University of Athens Athens Greece

Fondation Jean Dausset CEPH Paris France

Laboratoire de Génétique CHU Brest Brest France

Meyer Children Hospital Cystic Fibrosis Center Florence University Florence Italy

Northwestern University Feinberg School of Medicine and the Ann and Robert H Lurie Children's Hospital Chicago IL USA

Paediatrics and Adolescent Medicine Medical University Vienna Vienna Austria

Pediatrics and Population Health Sciences University of Wisconsin Madison WI USA

School of Medicine University College Dublin Dublin Ireland

UMR 1078 Génétique Génomique fonctionnelle et Biotechnologies Inserm Université de Brest EFS CHU Brest Brest France

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