Estimating the age of p.(Phe508del) with family studies of geographically distinct European populations and the early spread of cystic fibrosis

Abstract

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.

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

“…Archeological estimates indicate that the most prevalent CFcausing mutation, the deletion of a phenylalanine at position 508 (F508del), originated in Western Europe during the Early Bronze Age (Farrell et al, 2018). Although there are some archaic references regarding "children whose brow had salty taste when kissed and prematurely died" , CF remained uncharacterized until the 1930s.…”

How can we relieve gastrointestinal symptoms in people with cystic fibrosis? An international qualitative survey

“…Cystic fibrosis (CF) is the most common autosomal recessive inherited disease in people of European descent. 1 It was once considered a disease of childhood as survival was rarely beyond the childhood years. With the advent of new treatments and novel drugs, people with CF (pwCF) are now living longer and often well into adulthood.…”

Regulation of CFTR Biogenesis by the Proteostatic Network and Pharmacological Modulators

“…Mutations in CFTR are thought to have been selected for amongst Bronze Age peoples of Western Europe as an adaptation against secretory diarrheal diseases, such as cholera [41,42]. Notably, individuals carrying one defective allele are less prone to severe dehydration.…”