The Extent of Edgetic Perturbations in the Human Interactome Caused by Population-Specific Mutations
Until recently, efforts in population genetics have been focused primarily on people of European ancestry. To attenuate this bias, global population studies, such as the 1000 Genomes Project, have revealed differences in genetic variation across ethnic groups. How many of these differences can be at...
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| Format: | Article |
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MDPI AG
2023-12-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/14/1/40 |
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| author | Hongzhu Cui Suhas Srinivasan Ziyang Gao Dmitry Korkin |
| author_facet | Hongzhu Cui Suhas Srinivasan Ziyang Gao Dmitry Korkin |
| author_sort | Hongzhu Cui |
| collection | DOAJ |
| description | Until recently, efforts in population genetics have been focused primarily on people of European ancestry. To attenuate this bias, global population studies, such as the 1000 Genomes Project, have revealed differences in genetic variation across ethnic groups. How many of these differences can be attributed to population-specific traits? To answer this question, the mutation data must be linked with functional outcomes. A new “edgotype” concept has been proposed, which emphasizes the interaction-specific, “edgetic”, perturbations caused by mutations in the interacting proteins. In this work, we performed systematic in silico edgetic profiling of ~50,000 non-synonymous SNVs (nsSNVs) from the 1000 Genomes Project by leveraging our semi-supervised learning approach SNP-IN tool on a comprehensive set of over 10,000 protein interaction complexes. We interrogated the functional roles of the variants and their impact on the human interactome and compared the results with the pathogenic variants disrupting PPIs in the same interactome. Our results demonstrated that a considerable number of nsSNVs from healthy populations could rewire the interactome. We also showed that the proteins enriched with interaction-disrupting mutations were associated with diverse functions and had implications in a broad spectrum of diseases. Further analysis indicated that distinct gene edgetic profiles among major populations could shed light on the molecular mechanisms behind the population phenotypic variances. Finally, the network analysis revealed that the disease-associated modules surprisingly harbored a higher density of interaction-disrupting mutations from healthy populations. The variation in the cumulative network damage within these modules could potentially account for the observed disparities in disease susceptibility, which are distinctly specific to certain populations. Our work demonstrates the feasibility of a large-scale in silico edgetic study, and reveals insights into the orchestrated play of population-specific mutations in the human interactome. |
| first_indexed | 2024-03-08T11:03:54Z |
| format | Article |
| id | doaj.art-0d45de0c4bc1482fb462c6869b9ff18f |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-08T11:03:54Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-0d45de0c4bc1482fb462c6869b9ff18f2024-01-26T15:18:30ZengMDPI AGBiomolecules2218-273X2023-12-011414010.3390/biom14010040The Extent of Edgetic Perturbations in the Human Interactome Caused by Population-Specific MutationsHongzhu Cui0Suhas Srinivasan1Ziyang Gao2Dmitry Korkin3Bioinformatics and Computational Biology Program, Worcester Polytechnic Institute, Worcester, MA 01609, USAData Science Program, Worcester Polytechnic Institute, Worcester, MA 01609, USABioinformatics and Computational Biology Program, Worcester Polytechnic Institute, Worcester, MA 01609, USABioinformatics and Computational Biology Program, Worcester Polytechnic Institute, Worcester, MA 01609, USAUntil recently, efforts in population genetics have been focused primarily on people of European ancestry. To attenuate this bias, global population studies, such as the 1000 Genomes Project, have revealed differences in genetic variation across ethnic groups. How many of these differences can be attributed to population-specific traits? To answer this question, the mutation data must be linked with functional outcomes. A new “edgotype” concept has been proposed, which emphasizes the interaction-specific, “edgetic”, perturbations caused by mutations in the interacting proteins. In this work, we performed systematic in silico edgetic profiling of ~50,000 non-synonymous SNVs (nsSNVs) from the 1000 Genomes Project by leveraging our semi-supervised learning approach SNP-IN tool on a comprehensive set of over 10,000 protein interaction complexes. We interrogated the functional roles of the variants and their impact on the human interactome and compared the results with the pathogenic variants disrupting PPIs in the same interactome. Our results demonstrated that a considerable number of nsSNVs from healthy populations could rewire the interactome. We also showed that the proteins enriched with interaction-disrupting mutations were associated with diverse functions and had implications in a broad spectrum of diseases. Further analysis indicated that distinct gene edgetic profiles among major populations could shed light on the molecular mechanisms behind the population phenotypic variances. Finally, the network analysis revealed that the disease-associated modules surprisingly harbored a higher density of interaction-disrupting mutations from healthy populations. The variation in the cumulative network damage within these modules could potentially account for the observed disparities in disease susceptibility, which are distinctly specific to certain populations. Our work demonstrates the feasibility of a large-scale in silico edgetic study, and reveals insights into the orchestrated play of population-specific mutations in the human interactome.https://www.mdpi.com/2218-273X/14/1/40population geneticsfunctional nsSNVsprotein-protein interactioninteractomeedgeticnon-synonymous mutations |
| spellingShingle | Hongzhu Cui Suhas Srinivasan Ziyang Gao Dmitry Korkin The Extent of Edgetic Perturbations in the Human Interactome Caused by Population-Specific Mutations Biomolecules population genetics functional nsSNVs protein-protein interaction interactome edgetic non-synonymous mutations |
| title | The Extent of Edgetic Perturbations in the Human Interactome Caused by Population-Specific Mutations |
| title_full | The Extent of Edgetic Perturbations in the Human Interactome Caused by Population-Specific Mutations |
| title_fullStr | The Extent of Edgetic Perturbations in the Human Interactome Caused by Population-Specific Mutations |
| title_full_unstemmed | The Extent of Edgetic Perturbations in the Human Interactome Caused by Population-Specific Mutations |
| title_short | The Extent of Edgetic Perturbations in the Human Interactome Caused by Population-Specific Mutations |
| title_sort | extent of edgetic perturbations in the human interactome caused by population specific mutations |
| topic | population genetics functional nsSNVs protein-protein interaction interactome edgetic non-synonymous mutations |
| url | https://www.mdpi.com/2218-273X/14/1/40 |
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