relating the disease mutation spectrum to the evolution of the cystic fibrosis transmembrane conductance regulator (cftr)有关疾病的突变谱的演变囊性纤维化跨膜电导调节cftr(检测).pdfVIP

Relating the Disease Mutation Spectrum to the Evolution of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) 1. 1. 1 1 1,2 Lavanya Rishishwar , Neha Varghese , Eishita Tyagi , Stephen C. Harvey , I. King Jordan , Nael A. McCarty3* 1 School of Biology, Georgia Institute of Technology, Atlanta, Georgia, United States of America, 2 PanAmerican Bioinformatics Institute, Santa Marta, Magdalena, Colombia, 3 Department of Pediatrics, Emory University School of Medicine, Center for Cystic Fibrosis Research, Children’s Healthcare of Atlanta, Atlanta, Georgia, United States of America Abstract Cystic fibrosis (CF) is the most common genetic disease among Caucasians, and accordingly the cystic fibrosis transmembrane conductance regulator (CFTR) protein has perhaps the best characterized disease mutation spectrum with more than 1,500 causative mutations having been identified. In this study, we took advantage of that wealth of mutational information in an effort to relate site-specific evolutionary parameters with the propensity and severity of CFTR disease- causing mutations. To do this, we devised a scoring scheme for known CFTR disease-causing mutations based on the Grantham amino acid chemical difference matrix. CFTR site-specific evolutionary constraint values were then computed for seven different evolutionary metrics across a range of increasing evolutionary depths. The CFTR mutational scores and the various site-specific evolutionary constraint values were compared in order to evaluate which evolutionary measures best reflect the disease-causing mutation spectrum.