Genomic, transcriptomic, and protein landscape profile of CFTR and cystic fibrosis
- 29 July 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Human Genetics
- Vol. 140 (3), 423-439
- https://doi.org/10.1007/s00439-020-02211-w
Abstract
Cystic Fibrosis (CF) is caused most often by removal of amino acid 508 (Phe508del, deltaF508) within CFTR, yet dozens of additional CFTR variants are known to give rise to CF and many variants in the genome are known to contribute to CF pathology. To address CFTR coding variants, we developed a sequence-to-structure-to-dynamic matrix for all amino acids of CFTR using 233 vertebrate species, CFTR structure within a lipid membrane, and 20 ns of molecular dynamic simulation to assess known variants from the CFTR1, CFTR2, ClinVar, TOPmed, gnomAD, and COSMIC databases. Surprisingly, we identify 18 variants of uncertain significance within CFTR from diverse populations that are heritable and a likely cause of CF that have been understudied due to nonexistence in Caucasian populations. In addition, 15 sites within the genome are known to modulate CF pathology, where we have identified one genome region (chr11:34754985-34836401) that contributes to CF through modulation of expression of a noncoding RNA in epithelial cells. These 15 sites are just the beginning of understanding comodifiers of CF, where utilization of eQTLs suggests many additional genomics of CFTR expressing cells that can be influenced by genomic background of CFTR variants. This work highlights that many additional insights of CF genetics are needed, particularly as pharmaceutical interventions increase in the coming years.Keywords
Funding Information
- National Institutes of Health (K01-ES025435)
This publication has 76 references indexed in Scilit:
- STRING v9.1: protein-protein interaction networks, with increased coverage and integrationNucleic Acids Research, 2012
- Annotation of functional variation in personal genomes using RegulomeDBGenome Research, 2012
- An integrated encyclopedia of DNA elements in the human genomeNature, 2012
- Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2Nature Genetics, 2011
- MEGA5: Molecular Evolutionary Genetics Analysis Using Maximum Likelihood, Evolutionary Distance, and Maximum Parsimony MethodsMolecular Biology and Evolution, 2011
- COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in CancerNucleic Acids Research, 2010
- Improving physical realism, stereochemistry, and side‐chain accuracy in homology modeling: Four approaches that performed well in CASP8Proteins-Structure Function and Bioinformatics, 2009
- Clustal W and Clustal X version 2.0Bioinformatics, 2007
- UniProt: the Universal Protein knowledgebaseNucleic Acids Research, 2004
- A point‐charge force field for molecular mechanics simulations of proteins based on condensed‐phase quantum mechanical calculationsJournal of Computational Chemistry, 2003