A large-scale study of the random variability of a coding sequence: a study on the CFTR gene

Area of Science:

• Human Genetics
• Population Genetics
• Molecular Biology

Background:

• Coding single nucleotide substitutions (cSNSs) are typically studied in small gene samples.
• The CFTR gene, crucial for Cystic Fibrosis, is a key focus in genetic variation studies.

Purpose of the Study:

• To investigate the variability of nonsynonymous (NS) and synonymous (S) substitutions in the CFTR gene using a large European population sample.
• To determine the role of genetic drift versus selection in subpolymorphic variability for autosomal genes with potentially harmful recessive alleles.

Main Methods:

• Analysis of a large random European population sample (average n(g) approximately 1500) for CFTR gene variations.
• Comparison of polymorphism (q > 0.005) and subpolymorphism (q < 0.005) rates between NS and S substitutions.

Main Results:

• Nonsynonymous substitutions in CFTR showed a lower probability of being polymorphic compared to synonymous substitutions.
• However, NS and S substitutions exhibited similar rates of subpolymorphic variability.
• Genetic drift appears to dominate selection in the subpolymorphic range for functionally important, non-duplicated autosomal genes.

Conclusions:

• The majority of subpolymorphic nonsynonymous alleles in genes like CFTR are likely selectively disadvantageous or pathogenic.
• Selection is less effective in the subpolymorphic range for these genes, allowing potentially harmful alleles to persist.
• Findings have implications for understanding the evolution of genetic diseases and the interpretation of genetic variation data.