Assessing Protein Surface-Based Scoring for Interpreting Genomic Variants
Clinical genomics sequencing is rapidly expanding the number of variants that need to be functionally elucidated. Interpreting genetic variants (i.e., mutations) usually begins by identifying how they affect protein-coding sequences. Still, the three-dimensional (3D) protein molecule is rarely consi...
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| Veröffentlicht in: | International journal of molecular sciences Jg. 25; H. 22; S. 12018 |
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| Abstract | Clinical genomics sequencing is rapidly expanding the number of variants that need to be functionally elucidated. Interpreting genetic variants (i.e., mutations) usually begins by identifying how they affect protein-coding sequences. Still, the three-dimensional (3D) protein molecule is rarely considered for large-scale variant analysis, nor in analyses of how proteins interact with each other and their environment. We propose a standardized approach to scoring protein surface property changes as a new dimension for functionally and mechanistically interpreting genomic variants. Further, it directs hypothesis generation for functional genomics research to learn more about the encoded protein’s function. We developed a novel method leveraging 3D structures and time-dependent simulations to score and statistically evaluate protein surface property changes. We evaluated positive controls composed of eight thermophilic versus mesophilic orthologs and variants that experimentally change the protein’s solubility, which all showed large and statistically significant differences in charge distribution (p < 0.01). We scored static 3D structures and dynamic ensembles for 43 independent variants (23 pathogenic and 20 uninterpreted) across four proteins. Focusing on the potassium ion channel, KCNK9, the average local surface potential shifts were 0.41 kBT/ec with an average p-value of 1 × 10−2. In contrast, dynamic ensemble shifts averaged 1.15 kBT/ec with an average p-value of 1 × 10−5, enabling the identification of changes far from mutated sites. This study demonstrates that an objective assessment of how mutations affect electrostatic distributions of protein surfaces can aid in interpreting genomic variants discovered through clinical genomic sequencing. |
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| AbstractList | Clinical genomics sequencing is rapidly expanding the number of variants that need to be functionally elucidated. Interpreting genetic variants (i.e., mutations) usually begins by identifying how they affect protein-coding sequences. Still, the three-dimensional (3D) protein molecule is rarely considered for large-scale variant analysis, nor in analyses of how proteins interact with each other and their environment. We propose a standardized approach to scoring protein surface property changes as a new dimension for functionally and mechanistically interpreting genomic variants. Further, it directs hypothesis generation for functional genomics research to learn more about the encoded protein’s function. We developed a novel method leveraging 3D structures and time-dependent simulations to score and statistically evaluate protein surface property changes. We evaluated positive controls composed of eight thermophilic versus mesophilic orthologs and variants that experimentally change the protein’s solubility, which all showed large and statistically significant differences in charge distribution (p < 0.01). We scored static 3D structures and dynamic ensembles for 43 independent variants (23 pathogenic and 20 uninterpreted) across four proteins. Focusing on the potassium ion channel, KCNK9, the average local surface potential shifts were 0.41 kBT/ec with an average p-value of 1 × 10−2. In contrast, dynamic ensemble shifts averaged 1.15 kBT/ec with an average p-value of 1 × 10−5, enabling the identification of changes far from mutated sites. This study demonstrates that an objective assessment of how mutations affect electrostatic distributions of protein surfaces can aid in interpreting genomic variants discovered through clinical genomic sequencing. Clinical genomics sequencing is rapidly expanding the number of variants that need to be functionally elucidated. Interpreting genetic variants (i.e., mutations) usually begins by identifying how they affect protein-coding sequences. Still, the three-dimensional (3D) protein molecule is rarely considered for large-scale variant analysis, nor in analyses of how proteins interact with each other and their environment. We propose a standardized approach to scoring protein surface property changes as a new dimension for functionally and mechanistically interpreting genomic variants. Further, it directs hypothesis generation for functional genomics research to learn more about the encoded protein's function. We developed a novel method leveraging 3D structures and time-dependent simulations to score and statistically evaluate protein surface property changes. We evaluated positive controls composed of eight thermophilic versus mesophilic orthologs and variants that experimentally change the protein's solubility, which all showed large and statistically significant differences in charge distribution ( < 0.01). We scored static 3D structures and dynamic ensembles for 43 independent variants (23 pathogenic and 20 uninterpreted) across four proteins. Focusing on the potassium ion channel, KCNK9, the average local surface potential shifts were 0.41 k T/ec with an average -value of 1 × 10 . In contrast, dynamic ensemble shifts averaged 1.15 k T/ec with an average -value of 1 × 10 , enabling the identification of changes far from mutated sites. This study demonstrates that an objective assessment of how mutations affect electrostatic distributions of protein surfaces can aid in interpreting genomic variants discovered through clinical genomic sequencing. Clinical genomics sequencing is rapidly expanding the number of variants that need to be functionally elucidated. Interpreting genetic variants (i.e., mutations) usually begins by identifying how they affect protein-coding sequences. Still, the three-dimensional (3D) protein molecule is rarely considered for large-scale variant analysis, nor in analyses of how proteins interact with each other and their environment. We propose a standardized approach to scoring protein surface property changes as a new dimension for functionally and mechanistically interpreting genomic variants. Further, it directs hypothesis generation for functional genomics research to learn more about the encoded protein's function. We developed a novel method leveraging 3D structures and time-dependent simulations to score and statistically evaluate protein surface property changes. We evaluated positive controls composed of eight thermophilic versus mesophilic orthologs and variants that experimentally change the protein's solubility, which all showed large and statistically significant differences in charge distribution (p < 0.01). We scored static 3D structures and dynamic ensembles for 43 independent variants (23 pathogenic and 20 uninterpreted) across four proteins. Focusing on the potassium ion channel, KCNK9, the average local surface potential shifts were 0.41 kBT/ec with an average p-value of 1 × 10-2. In contrast, dynamic ensemble shifts averaged 1.15 kBT/ec with an average p-value of 1 × 10-5, enabling the identification of changes far from mutated sites. This study demonstrates that an objective assessment of how mutations affect electrostatic distributions of protein surfaces can aid in interpreting genomic variants discovered through clinical genomic sequencing.Clinical genomics sequencing is rapidly expanding the number of variants that need to be functionally elucidated. Interpreting genetic variants (i.e., mutations) usually begins by identifying how they affect protein-coding sequences. Still, the three-dimensional (3D) protein molecule is rarely considered for large-scale variant analysis, nor in analyses of how proteins interact with each other and their environment. We propose a standardized approach to scoring protein surface property changes as a new dimension for functionally and mechanistically interpreting genomic variants. Further, it directs hypothesis generation for functional genomics research to learn more about the encoded protein's function. We developed a novel method leveraging 3D structures and time-dependent simulations to score and statistically evaluate protein surface property changes. We evaluated positive controls composed of eight thermophilic versus mesophilic orthologs and variants that experimentally change the protein's solubility, which all showed large and statistically significant differences in charge distribution (p < 0.01). We scored static 3D structures and dynamic ensembles for 43 independent variants (23 pathogenic and 20 uninterpreted) across four proteins. Focusing on the potassium ion channel, KCNK9, the average local surface potential shifts were 0.41 kBT/ec with an average p-value of 1 × 10-2. In contrast, dynamic ensemble shifts averaged 1.15 kBT/ec with an average p-value of 1 × 10-5, enabling the identification of changes far from mutated sites. This study demonstrates that an objective assessment of how mutations affect electrostatic distributions of protein surfaces can aid in interpreting genomic variants discovered through clinical genomic sequencing. Clinical genomics sequencing is rapidly expanding the number of variants that need to be functionally elucidated. Interpreting genetic variants (i.e., mutations) usually begins by identifying how they affect protein-coding sequences. Still, the three-dimensional (3D) protein molecule is rarely considered for large-scale variant analysis, nor in analyses of how proteins interact with each other and their environment. We propose a standardized approach to scoring protein surface property changes as a new dimension for functionally and mechanistically interpreting genomic variants. Further, it directs hypothesis generation for functional genomics research to learn more about the encoded protein’s function. We developed a novel method leveraging 3D structures and time-dependent simulations to score and statistically evaluate protein surface property changes. We evaluated positive controls composed of eight thermophilic versus mesophilic orthologs and variants that experimentally change the protein’s solubility, which all showed large and statistically significant differences in charge distribution (p < 0.01). We scored static 3D structures and dynamic ensembles for 43 independent variants (23 pathogenic and 20 uninterpreted) across four proteins. Focusing on the potassium ion channel, KCNK9, the average local surface potential shifts were 0.41 k[sub.B] T/ec with an average p -value of 1 × 10[sup.−2] . In contrast, dynamic ensemble shifts averaged 1.15 k[sub.B] T/ec with an average p -value of 1 × 10[sup.−5] , enabling the identification of changes far from mutated sites. This study demonstrates that an objective assessment of how mutations affect electrostatic distributions of protein surfaces can aid in interpreting genomic variants discovered through clinical genomic sequencing. |
| Audience | Academic |
| Author | Haque, Neshatul Dsouza, Nikita R. Zimmermann, Michael T. Tripathi, Swarnendu |
| AuthorAffiliation | 2 Data Science Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA 3 Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA 1 Computational Structural Genomics Unit, Linda T. and John A. Mellowes Center for Genomics Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA; nikitadsouza30@gmail.com (N.R.D.); nehaque@mcw.edu (N.H.); swarnendu.tripathi@gmail.com (S.T.) |
| AuthorAffiliation_xml | – name: 1 Computational Structural Genomics Unit, Linda T. and John A. Mellowes Center for Genomics Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA; nikitadsouza30@gmail.com (N.R.D.); nehaque@mcw.edu (N.H.); swarnendu.tripathi@gmail.com (S.T.) – name: 2 Data Science Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA – name: 3 Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA |
| Author_xml | – sequence: 1 givenname: Nikita R. surname: Dsouza fullname: Dsouza, Nikita R. – sequence: 2 givenname: Neshatul surname: Haque fullname: Haque, Neshatul – sequence: 3 givenname: Swarnendu surname: Tripathi fullname: Tripathi, Swarnendu – sequence: 4 givenname: Michael T. orcidid: 0000-0001-7073-0525 surname: Zimmermann fullname: Zimmermann, Michael T. |
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| Keywords | molecular genetics protein surface protein science genomic data interpretation |
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| SubjectTerms | Amino acids Analysis Dehydrogenases Enzymes Genetic research Genetic Variation Genomics Genomics - methods Humans Kinases Models, Molecular Mutation Phosphatase Physiological aspects Protein Conformation Proteins Proteins - chemistry Proteins - genetics Proteins - metabolism Structure Surface Properties Whole genome sequencing |
| Title | Assessing Protein Surface-Based Scoring for Interpreting Genomic Variants |
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