Cystic fibrosis transmembrane conductance regulator (CFTR)’s evolution revealed that its mutation causes cystic fibrosis

Abstract

Cystic fibrosis ( CF ) is a hereditary disease that can lead to death, mainly caused by mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR ). These mutations exhibit varying mechanisms and severity levels, posing a challenge for understanding their impact. Here, we hypothesized that mutations occurring in functionally important, conserved regions of the CFTR protein might lead to more severe CF phenotypes, while mutations in other domains may be less harmful. To identify these crucial regions, we conducted a survey of amino acid substitutions in CFTR across primates and non-primate mammals. Intriguingly, we found that most naturally occurring substitutions clustered within two CFTR domains, which paradoxically lacked CF-causing mutations. In contrast, CF mutations in humans are mainly located in the relatively conserved regions of CFTR, namely transmembrane domain 1 ( TMD1) and nucleotide binding domain 1 ( NBD1 ). This study presents the distribution of naturally occurring substitutions, and our findings provides a unique perspective for inferring and predicting disease-causing genetic variations by analyzing evolutionary trends.