Understanding genetic variants in context
Over the last three decades, human genetics has gone from dissecting high-penetrance Mendelian diseases to discovering the vast and complex genetic etiology of common human diseases. In tackling this complexity, scientists have discovered the importance of numerous genetic processes – most notably f...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2024-12-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/88231 |
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| author | Nasa Sinnott-Armstrong Stanley Fields Frederick Roth Lea M Starita Cole Trapnell Judit Villen Douglas M Fowler Christine Queitsch |
| author_facet | Nasa Sinnott-Armstrong Stanley Fields Frederick Roth Lea M Starita Cole Trapnell Judit Villen Douglas M Fowler Christine Queitsch |
| author_sort | Nasa Sinnott-Armstrong |
| collection | DOAJ |
| description | Over the last three decades, human genetics has gone from dissecting high-penetrance Mendelian diseases to discovering the vast and complex genetic etiology of common human diseases. In tackling this complexity, scientists have discovered the importance of numerous genetic processes – most notably functional regulatory elements – in the development and progression of these diseases. Simultaneously, scientists have increasingly used multiplex assays of variant effect to systematically phenotype the cellular consequences of millions of genetic variants. In this article, we argue that the context of genetic variants – at all scales, from other genetic variants and gene regulation to cell biology to organismal environment – are critical components of how we can employ genomics to interpret these variants, and ultimately treat these diseases. We describe approaches to extend existing experimental assays and computational approaches to examine and quantify the importance of this context, including through causal analytic approaches. Having a unified understanding of the molecular, physiological, and environmental processes governing the interpretation of genetic variants is sorely needed for the field, and this perspective argues for feasible approaches by which the combined interpretation of cellular, animal, and epidemiological data can yield that knowledge. |
| format | Article |
| id | doaj-art-69da816b45074542be41e4914ffd3473 |
| institution | DOAJ |
| issn | 2050-084X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-69da816b45074542be41e4914ffd34732025-08-20T02:52:42ZengeLife Sciences Publications LtdeLife2050-084X2024-12-011310.7554/eLife.88231Understanding genetic variants in contextNasa Sinnott-Armstrong0https://orcid.org/0000-0003-4490-0601Stanley Fields1https://orcid.org/0000-0001-5504-5925Frederick Roth2Lea M Starita3Cole Trapnell4https://orcid.org/0000-0002-8105-4347Judit Villen5Douglas M Fowler6https://orcid.org/0000-0001-7614-1713Christine Queitsch7https://orcid.org/0000-0002-0905-4705Herbold Computational Biology Program, Fred Hutchinson Cancer Center, Seattle, United States; Department of Genome Sciences, University of Washington, Seattle, United States; Brotman Baty Institute for Precision Medicine, Seattle, United StatesDepartment of Genome Sciences, University of Washington, Seattle, United States; Department of Medicine, University of Washington, Seattle, United StatesDonnelly Centre and Departments of Molecular Genetics and Computer Science, University of Toronto, Toronto, Canada; Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Canada; Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, United StatesDepartment of Genome Sciences, University of Washington, Seattle, United States; Brotman Baty Institute for Precision Medicine, Seattle, United StatesDepartment of Genome Sciences, University of Washington, Seattle, United States; Brotman Baty Institute for Precision Medicine, Seattle, United StatesDepartment of Genome Sciences, University of Washington, Seattle, United States; Brotman Baty Institute for Precision Medicine, Seattle, United StatesDepartment of Genome Sciences, University of Washington, Seattle, United States; Brotman Baty Institute for Precision Medicine, Seattle, United States; Department of Bioengineering, University of Washington, Seattle, United StatesDepartment of Genome Sciences, University of Washington, Seattle, United States; Brotman Baty Institute for Precision Medicine, Seattle, United StatesOver the last three decades, human genetics has gone from dissecting high-penetrance Mendelian diseases to discovering the vast and complex genetic etiology of common human diseases. In tackling this complexity, scientists have discovered the importance of numerous genetic processes – most notably functional regulatory elements – in the development and progression of these diseases. Simultaneously, scientists have increasingly used multiplex assays of variant effect to systematically phenotype the cellular consequences of millions of genetic variants. In this article, we argue that the context of genetic variants – at all scales, from other genetic variants and gene regulation to cell biology to organismal environment – are critical components of how we can employ genomics to interpret these variants, and ultimately treat these diseases. We describe approaches to extend existing experimental assays and computational approaches to examine and quantify the importance of this context, including through causal analytic approaches. Having a unified understanding of the molecular, physiological, and environmental processes governing the interpretation of genetic variants is sorely needed for the field, and this perspective argues for feasible approaches by which the combined interpretation of cellular, animal, and epidemiological data can yield that knowledge.https://elifesciences.org/articles/88231gene–environment interactionsmultiplexed assays of variant effectepistasis |
| spellingShingle | Nasa Sinnott-Armstrong Stanley Fields Frederick Roth Lea M Starita Cole Trapnell Judit Villen Douglas M Fowler Christine Queitsch Understanding genetic variants in context eLife gene–environment interactions multiplexed assays of variant effect epistasis |
| title | Understanding genetic variants in context |
| title_full | Understanding genetic variants in context |
| title_fullStr | Understanding genetic variants in context |
| title_full_unstemmed | Understanding genetic variants in context |
| title_short | Understanding genetic variants in context |
| title_sort | understanding genetic variants in context |
| topic | gene–environment interactions multiplexed assays of variant effect epistasis |
| url | https://elifesciences.org/articles/88231 |
| work_keys_str_mv | AT nasasinnottarmstrong understandinggeneticvariantsincontext AT stanleyfields understandinggeneticvariantsincontext AT frederickroth understandinggeneticvariantsincontext AT leamstarita understandinggeneticvariantsincontext AT coletrapnell understandinggeneticvariantsincontext AT juditvillen understandinggeneticvariantsincontext AT douglasmfowler understandinggeneticvariantsincontext AT christinequeitsch understandinggeneticvariantsincontext |