title: From Single Variants to Protein Cascades: MULTISCALE MODELING OF SINGLE NUCLEOTIDE VARIANT SETS IN GENETIC DISORDERS.
abstract: Understanding the role of genetics in disease has become a central part of medical research. Non-synonymous single nucleotide variants (nsSNVs) in coding regions of human genes frequently lead to pathological phenotypes. Beyond single variations, the individual combination of nsSNVs may add to pathogenic processes. We developed a multiscale pipeline to systematically analyze the existence of quantitative effects of multiple nsSNVs and gene combinations in single individuals on pathogenicity. Based on this pipeline, we detected in a data set of 842 nsSNVs discovered in 76 genes related to cardiomyopathies, associated nsSNV combinations in seven genes present in at least 70% of all 639 patient samples, but not in a control cohort of healthy humans. Structural analyses of these revealed primarily an influence on the protein stability. For amino acid substitutions located at the protein surface, we generally observed a proximity to putative binding pockets. To computationally analyze cumulative effects and their impact, pathogenicity methods are currently being developed. Our approach supports this process, as shown on the example of a cardiac phenotype but can be likewise applied to other diseases such as cancer.
authors.affiliation: From the Chair for Clinical Bioinformatics, Saarland University, 66123 Saarbrücken, Germany,; Department of Human Genetics, Saarland University, 66421 Homburg, Germany,. Electronic address: sabine.mueller@uniklinikum-saarland.de.
authors.forename: Sabine C
authors.initials: SC
authors.lastname: Mueller
authors.affiliation: the Bio-/Medical Informatics Department, Faculty of Technology, Bielefeld University, 33501 Bielefeld, Germany,; Clayton School of Information Technology, Faculty of Information Technology, Monash University, Melbourne 3800, Australia.
authors.forename: Björn
authors.initials: B
authors.lastname: Sommer
authors.affiliation: From the Chair for Clinical Bioinformatics, Saarland University, 66123 Saarbrücken, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Backes
authors.affiliation: the Department of Internal Medicine III, Heidelberg University, 69120 Heidelberg, Germany, and; the DZHK (German Centre for Cardiovascular Research), 69120 Heidelberg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Haas
authors.affiliation: the Department of Internal Medicine III, Heidelberg University, 69120 Heidelberg, Germany, and; the DZHK (German Centre for Cardiovascular Research), 69120 Heidelberg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Meder
authors.affiliation: Department of Human Genetics, Saarland University, 66421 Homburg, Germany.
authors.forename: Eckart
authors.initials: E
authors.lastname: Meese
authors.affiliation: From the Chair for Clinical Bioinformatics, Saarland University, 66123 Saarbrücken, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Keller
mesh_terms: D019943:Amino Acid Substitution; D009202:Cardiomyopathies / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D019295:Computational Biology; D053263:Gene Regulatory Networks; D030342:Genetic Diseases, Inborn / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D011506:Proteins
keywords: bioinformatics; cardiomyopathy; computational biology; genetic polymorphism; molecular genetics