Leveraging base-pair mammalian constraint to understand genetic variation and human disease
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- dc.contributor.author Sullivan, Patrick F.
- dc.contributor.author Zoonomia Consortium
- dc.contributor.author Lindblad-Toh, Kerstin
- dc.date.accessioned 2024-03-25T07:10:04Z
- dc.date.available 2024-03-25T07:10:04Z
- dc.date.issued 2023
- dc.description.abstract Thousands of genomic regions have been associated with heritable human diseases, but attempts to elucidate biological mechanisms are impeded by an inability to discern which genomic positions are functionally important. Evolutionary constraint is a powerful predictor of function, agnostic to cell type or disease mechanism. Single-base phyloP scores from 240 mammals identified 3.3% of the human genome as significantly constrained and likely functional. We compared phyloP scores to genome annotation, association studies, copy-number variation, clinical genetics findings, and cancer data. Constrained positions are enriched for variants that explain common disease heritability more than other functional annotations. Our results improve variant annotation but also highlight that the regulatory landscape of the human genome still needs to be further explored and linked to disease.
- dc.format.mimetype application/pdf
- dc.identifier.citation Sullivan PF, Meadows JRS, Gazal S, Phan BN, Li X, Genereux DP, et al. Leveraging base-pair mammalian constraint to understand genetic variation and human disease. Science. 2023 Apr 28;380(6643):eabn2937. DOI: 10.1126/science.abn2937
- dc.identifier.doi http://dx.doi.org/10.1126/science.abn2937
- dc.identifier.issn 0036-8075
- dc.identifier.uri http://hdl.handle.net/10230/59549
- dc.language.iso eng
- dc.publisher American Association for the Advancement of Science (AAAS)
- dc.relation.ispartof Science. 2023 Apr 28;380(6643):eabn2937
- dc.rights This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science on 2023 Apr 28;380(6643):eabn2937, DOI: 10.1126/science.abn2937.
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.subject.other Malalties congènites
- dc.subject.other Genètica mèdica
- dc.title Leveraging base-pair mammalian constraint to understand genetic variation and human disease
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/acceptedVersion