Parallel functional annotation of cancer-associated missense mutations in histone methyltransferases
Abstract Using exome sequencing for biomarker discovery and precision medicine requires connecting nucleotide-level variation with functional changes in encoded proteins. However, for functionally annotating the thousands of cancer-associated missense mutations, or variants of uncertain significance...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2022-11-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-23229-2 |
| _version_ | 1811223636193837056 |
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| author | Ashley J. Canning Susan Viggiano Martin E. Fernandez-Zapico Michael S. Cosgrove |
| author_facet | Ashley J. Canning Susan Viggiano Martin E. Fernandez-Zapico Michael S. Cosgrove |
| author_sort | Ashley J. Canning |
| collection | DOAJ |
| description | Abstract Using exome sequencing for biomarker discovery and precision medicine requires connecting nucleotide-level variation with functional changes in encoded proteins. However, for functionally annotating the thousands of cancer-associated missense mutations, or variants of uncertain significance (VUS), purifying variant proteins for biochemical and functional analysis is cost-prohibitive and inefficient. We describe parallel functional annotation (PFA) of large numbers of VUS using small cultures and crude extracts in 96-well plates. Using members of a histone methyltransferase family, we demonstrate high-throughput structural and functional annotation of cancer-associated mutations. By combining functional annotation of paralogs, we discovered two phylogenetic and clustering parameters that improve the accuracy of sequence-based functional predictions to over 90%. Our results demonstrate the value of PFA for defining oncogenic/tumor suppressor functions of histone methyltransferases as well as enhancing the accuracy of sequence-based algorithms in predicting the effects of cancer-associated mutations. |
| first_indexed | 2024-04-12T08:36:11Z |
| format | Article |
| id | doaj.art-4e8bfe39794b477585dcf9d054f04673 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-12T08:36:11Z |
| publishDate | 2022-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-4e8bfe39794b477585dcf9d054f046732022-12-22T03:40:00ZengNature PortfolioScientific Reports2045-23222022-11-0112111310.1038/s41598-022-23229-2Parallel functional annotation of cancer-associated missense mutations in histone methyltransferasesAshley J. Canning0Susan Viggiano1Martin E. Fernandez-Zapico2Michael S. Cosgrove3Department of Biochemistry and Molecular Biology, State University of New York (SUNY) Upstate Medical UniversityDepartment of Biochemistry and Molecular Biology, State University of New York (SUNY) Upstate Medical UniversitySchulze Center for Novel Therapeutics, Division of Oncology Research, Mayo ClinicDepartment of Biochemistry and Molecular Biology, State University of New York (SUNY) Upstate Medical UniversityAbstract Using exome sequencing for biomarker discovery and precision medicine requires connecting nucleotide-level variation with functional changes in encoded proteins. However, for functionally annotating the thousands of cancer-associated missense mutations, or variants of uncertain significance (VUS), purifying variant proteins for biochemical and functional analysis is cost-prohibitive and inefficient. We describe parallel functional annotation (PFA) of large numbers of VUS using small cultures and crude extracts in 96-well plates. Using members of a histone methyltransferase family, we demonstrate high-throughput structural and functional annotation of cancer-associated mutations. By combining functional annotation of paralogs, we discovered two phylogenetic and clustering parameters that improve the accuracy of sequence-based functional predictions to over 90%. Our results demonstrate the value of PFA for defining oncogenic/tumor suppressor functions of histone methyltransferases as well as enhancing the accuracy of sequence-based algorithms in predicting the effects of cancer-associated mutations.https://doi.org/10.1038/s41598-022-23229-2 |
| spellingShingle | Ashley J. Canning Susan Viggiano Martin E. Fernandez-Zapico Michael S. Cosgrove Parallel functional annotation of cancer-associated missense mutations in histone methyltransferases Scientific Reports |
| title | Parallel functional annotation of cancer-associated missense mutations in histone methyltransferases |
| title_full | Parallel functional annotation of cancer-associated missense mutations in histone methyltransferases |
| title_fullStr | Parallel functional annotation of cancer-associated missense mutations in histone methyltransferases |
| title_full_unstemmed | Parallel functional annotation of cancer-associated missense mutations in histone methyltransferases |
| title_short | Parallel functional annotation of cancer-associated missense mutations in histone methyltransferases |
| title_sort | parallel functional annotation of cancer associated missense mutations in histone methyltransferases |
| url | https://doi.org/10.1038/s41598-022-23229-2 |
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