Mathematical sequence analyses of cystic fibrosis transmembrane conductance regulator (CFTR): Cross-species skeletal frameworks in cystic fibrosis
Year: 2026
Type: article
Abstract: Background Rare diseases, though individually uncommon, collectively represent a major global health challenge. Cystic fibrosis (CF), a multisystem autosomal recessive disorder caused by pathogenic variants in the Cystic Fibrosis Transmembrane Conductance Regulator ( CFTR ) gene, exemplifies this burden. While diverse mutational spectra complicate diagnosis and therapy, comparative molecular insights into CFTR biology are essential to complement clinical research. Methods We performed integrative cross-species analyses of CFTR sequences across 42 vertebrate species representing 40 unique homologs. Analyses encompassed amino acid composition, sequence homology, frequency-dominant residue patterns, hydropathy-based n-gram distributions, hydropathy profile continuity, and intrinsic disorder architectures. Results Across 42 vertebrate CFTR sequences, we identified 530 invariant residues (37.6%), consistent leucine enrichment and cystine scarcity, and reproducible clustering patterns under multiple quantitative feature-descriptors. Disorder-promoting residues were enriched, supporting CFTR’s intrinsic disorder architecture, while polar to non-polar non-synonymous substitutions were predominantly CF-causing, when cross-referenced with the Clinical and Functional TRanslation of CFTR (CFTR2) database. These quantitative descriptors revealed a skeletal framework of CFTR sequences, showing how each species imprints its own self-organized pattern within the primary sequence while retaining conserved evolutionary signatures. Conclusions Comparative CFTR protein analysis bridges evolutionary biology with clinical investigation, establishing an evolutionary framework for functional studies in cystic fibrosis. However, this study has limitations, as analyses were restricted to vertebrate sequences available in public databases, and functional validation of predicted motifs was not performed. Thus, while evolutionary signatures are informative, experimental confirmation remains essential.
Source: Current Genomics
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W7212377077