The Paradox of ?F508: How Cystic Fibrosis' Main Mutation Persisted
Cystic fibrosis is the most common autosomal recessive disorder and is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene1. CFTR is an ion channel located at the internal surfaces of lung, pancreas and gut regulating chloride and bicarbonate transport to maintain fluid balance. A loss of function in the CFTR gene leads to abnormally thick mucus, manifesting in chronic endobronchial bacterial infections associated with obstructive airway disease, among other symptoms2. Approximately 70% of cases in European-derived populations involve ?F508, a three-nucleotide deletion in the CFTR gene3. Previous studies disagree on when ?F508 first arose, with estimates ranging from ~52,000 years ago to as recent as ~3,000 years ago. Given that cystic fibrosis is characterized by significant health complications and infertility, ?F508 is expected to be under negative selection4,5. This is in contrast to the unusually high frequency of ?F508, found in approximately one in twenty-five Europeans. To explain this discrepancy, it has been hypothesized that a heterozygous state (wild-type and ?F508) may confer an advantage, such as resistance to gastrointestinal infections, e.g. cholera6,7. Here we screen 27,501 prehistoric and historic West Eurasian individuals, identifying carriers of the deletion as old as 5300-4900 cal BCE. We show that the frequency of ?F508 is stable across time, consistent with balancing selection. We explore explanations for a potential heterozygous advantage with analyses of more than 1.3 million individuals in large modern biobank datasets. These indicate that heterozygous carriers of pathogenic CFTR variants have altered immune-related disease risk, including a reduced lifetime risk of ankylosing spondylitis and other autoimmune conditions. These findings support the hypothesis that partial CFTR loss-of-function may confer immunological benefits, potentially through effects on host-pathogen interactions in the human gut.
Cystic fibrosis is the most common autosomal recessive disorder and is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene1. CFTR is an ion channel located at the internal surfaces of lung, pancreas and gut regulating chloride and bicarbonate transport to maintain fluid balance. A loss of function in the CFTR gene leads to abnormally thick mucus, manifesting in chronic endobronchial bacterial infections associated with obstructive airway disease, among other symptoms2. Approximately 70% of cases in European-derived populations involve ?F508, a three-nucleotide deletion in the CFTR gene3. Previous studies disagree on when ?F508 first arose, with estimates ranging from ~52,000 years ago to as recent as ~3,000 years ago. Given that cystic fibrosis is characterized by significant health complications and infertility, ?F508 is expected to be under negative selection4,5. This is in contrast to the unusually high frequency of ?F508, found in approximately one in twenty-five Europeans. To explain this discrepancy, it has been hypothesized that a heterozygous state (wild-type and ?F508) may confer an advantage, such as resistance to gastrointestinal infections, e.g. cholera6,7. Here we screen 27,501 prehistoric and historic West Eurasian individuals, identifying carriers of the deletion as old as 5300-4900 cal BCE. We show that the frequency of ?F508 is stable across time, consistent with balancing selection. We explore explanations for a potential heterozygous advantage with analyses of more than 1.3 million individuals in large modern biobank datasets. These indicate that heterozygous carriers of pathogenic CFTR variants have altered immune-related disease risk, including a reduced lifetime risk of ankylosing spondylitis and other autoimmune conditions. These findings support the hypothesis that partial CFTR loss-of-function may confer immunological benefits, potentially through effects on host-pathogen interactions in the human gut.
Max Planck Institute for Evolutionary Anthropology