From Single Variants to Protein Cascades: MULTISCALE MODELING OF SINGLE NUCLEOTIDE VARIANT SETS IN GENETIC DISORDERS. Mueller, S. C, Sommer, B., Backes, C., Haas, J., Meder, B., Meese, E., & Keller, A. The Journal of biological chemistry, 291:1582–1590, January, 2016.
doi  abstract   bibtex   
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.
@Article{Mueller2016,
  author          = {Mueller, Sabine C and Sommer, Björn and Backes, Christina and Haas, Jan and Meder, Benjamin and Meese, Eckart and Keller, Andreas},
  title           = {From Single Variants to Protein Cascades: MULTISCALE MODELING OF SINGLE NUCLEOTIDE VARIANT SETS IN GENETIC DISORDERS.},
  journal         = {The Journal of biological chemistry},
  year            = {2016},
  volume          = {291},
  pages           = {1582--1590},
  month           = jan,
  issn            = {1083-351X},
  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. },
  chemicals       = {Proteins},
  citation-subset = {IM},
  completed       = {2016-08-22},
  country         = {United States},
  doi             = {10.1074/jbc.M115.695247},
  issn-linking    = {0021-9258},
  issue           = {4},
  keywords        = {Amino Acid Substitution; Cardiomyopathies, genetics, metabolism; Cohort Studies; Computational Biology; Gene Regulatory Networks; Genetic Diseases, Inborn, genetics, metabolism; Humans; Polymorphism, Single Nucleotide; Proteins, genetics, metabolism; bioinformatics; cardiomyopathy; computational biology; genetic polymorphism; molecular genetics},
  nlm-id          = {2985121R},
  owner           = {NLM},
  pii             = {M115.695247},
  pmc             = {PMC4722441},
  pmid            = {26601959},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2017-02-20},
}
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