Cystic fibrosis modifier genes: the last refuge of the complex

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Cystic fibrosis is a rare but lethal autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR is responsible for the balance of salt versus water movement in cells, and defects in CFTR lead to thickened secretions, for example in the lungs, which cause recurrent lung infections that eventually become fatal. The most common CFTR mutation is DeltaF508, in which the protein lacks a phenylalanine (F) residue at position 508. However, patients with the DeltaF508 mutation vary considerably in the severity of the clinical manifestation of cystic fibrosis, suggesting that other genetic factors contribute to disease phenotype.

These genetic factors, so called modifier genes, remain for the most part elusive, but the teams of Elizabeth Miller and John Hartman now report in Genome Medicine a high-throughput model that could help find their identity. These investigators developed a yeast-based phenomic model for DeltaF508 CFTR that quantitatively scans the yeast genome for gene interactions with DeltaF670 Yor1, the equivalently-mutated yeast homolog of DeltaF508 CFTR.

Using this phenomic model, the authors found several genes whose human homologs have been implicated in the regulation of CFTR processing, but more importantly, novel genes that can modify DeltaF670 Yor1 processing in evolutionarily conserved pathways. Although caution is needed when extrapolating from studies in model organisms to complex human disease phenotypes, this study identified pathways of potential modifier genes of the cystic fibrosis DeltaF508 CFTR phenotype.

To paraphrase Oscar Wilde, simplicity is the last refuge of the complex, and in an accompanying research highlight, Marc Blondel explains why simple, broad, efficient and unbiased models, such as this one, are an important contribution to the complex genetics of cystic fibrosis. According to the author, disentangling modifier genes in clinical phenotypes is not only a stepping-stone to personalized medicine, but also the major challenge of modern human genetics.