Conservation of CFTR codon frequency through primates suggests synonymous mutations could have a functional effect

Area of Science:

• Genetics
• Molecular Biology
• Human Physiology

Background:

• Cystic fibrosis (CF) is a genetic disorder affecting ~1:3000 people, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
• Over 1900 CFTR mutations are known, but the functional impact of many, especially synonymous mutations, remains unclear.
• Synonymous mutations, which do not alter the amino acid sequence, were historically considered neutral but recent evidence suggests otherwise.

Purpose of the Study:

• To investigate the potential functional effects of synonymous mutations in the CFTR gene.
• To analyze codon usage and divergence patterns in human and primate CFTR to identify functionally relevant regions.

Main Methods:

• Analysis of codon usage patterns in human and primate CFTR genes.
• Examination of sequence conservation and divergence patterns.
• Identification of regions with biased codon frequencies.

Main Results:

• Identified regions within the CFTR gene enriched in both rare and frequent codons.
• Observed conservation of these codon usage patterns across primates, beyond simple sequence conservation.
• Evidence suggests these patterns are maintained by purifying selection.

Conclusions:

• The findings indicate that specific codon usage patterns in CFTR may have functional implications.
• Synonymous mutations within these regions could play a role in cystic fibrosis pathogenesis.
• This challenges the long-held view of synonymous mutations as functionally neutral.