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.
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We thank three archeologists who contributed to this study with encouragement, project design, and/or interpretation of results coupled to manuscript revisions: Sir Barry Cunliffe (Oxford University), William Aylward (University of Wisconsin-Madison), and T. Douglas Price (University of Wisconsin-Madison and the University of Aarhus). In addition, Patrick Sosnay (Johns Hopkins University) and Mark Louden (University of Wisconsin-Madison) contributed significantly to the manuscript. We are also grateful to Anita Laxova for her important efforts during the organization phase and for securing approvals from the Human Subjects IRB at the University of Wisconsin-Madison. The haplotype and Estiage analyses were performed with support from Inserm UMR 1078 under the leadership of Drs. Férec and Génin, while Dr. Farrell was funded by NIH grant DK 34108 and Dr. Macek by IP00064203/6003, CZ.02.1.01/0.0/0.0/16_013/0001634, LM2015091.
PF, as the overall project leader for investigation of “The Ancient Origin of Cystic Fibrosis,” proposed an assessment of the “age” of the p.Phe508del variant across Europe, obtained IRB approval, requested and secured the specimens as well as coordinating shipments with the Laboratoire de Génétique in Brest, and completed the initial manuscript draft and final version, while participating in data interpretations and consulting with archeologists. CF has been responsible for the design, genetics laboratory leadership, selection of European regions for evaluation, haplotype determinations, data interpretations, manuscript drafting, and revising. MM reviewed/approved the expanded design, provided appropriate DNA specimens from Czech CF patients and their parents, participated in data interpretation, and then during the final manuscript preparation process contributed an important comparison of the geographic, genetic, and archaeologic interpretations with insights that added significantly to our conclusions. TF and SR, with the assistance of KR, after reviewing and approving the design, obtained ethics committee approval in Vienna, selected carefully the native Austrian patient/parent trios, obtained the blood specimens, harvested the leukocyte fractions, and then reviewed and approved the manuscript. DB, with the assistance of MR, reviewed/approved the design, provided appropriate DNA specimens from Irish CF patients and their parents, participated in data interpretation, and then reviewed and revised the manuscript. TR reviewed/approved the design, provided appropriate specimens from native Albanian CF patients and their parents who attend the CF clinic in Florence, and lastly reviewed and revised the manuscript. MT reviewed/approved the design, provided DNA specimens from Greek and Albanian CF patients and their parents, then participated in data interpretation, and lastly reviewed and revised the manuscript. KG performed the lab work and the genetic analysis. and approved the manuscript. MD reviewed/approved the design, provided appropriate DNA specimens from Danish CF patients and their parents, participated in data interpretation, and reviewed and revised the manuscript. HL provided appropriate DNA specimens from Wisconsin-based, CF patients and their parents with known ancestry, participated in data interpretation, and reviewed and revised the manuscript. MS contributed to the data management and prepared the data for the statistical analyses and approved the manuscript. YF designed the haplotype experiments, supervised the essential lab work to generate data for Estiage analyses, and approved the manuscript. CLM designed the genetics experiments, supervised the lab work, reviewed/revised and approved the manuscript, and has provided important advice for the overall project. EG developed the essential Estiage method, led the design efforts, was responsible for the strategy employed for haplotype data analyses via Estiage, performed the analyses and interpretations of results, created most of the tables, wrote the initial Methods and Results sections of the manuscript, and assumed responsibility for the manuscript revisions and the final version.