ArticleScience (New York, N.Y.)2023
Leveraging base-pair mammalian constraint to understand genetic variation and human disease.
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Article in Science (New York, N.Y.), 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 88 papers.
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88citing papers in PubMed
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Who cites it
88 citing papers in PubMed.
- Accelerated Evolution of Context-Dependent Gene Expression in Primate Immune Cells.bioRxiv : the preprint server for biology · 2026Article
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- Comparative Genomic Screening Identifies Developmental Constraint Loci Underscoring the Phenotypic Evolution of Syngnathids.Integrative zoology · 2026Article
- Advances in genomics-driven genetic decoding and genomic design breeding in tomato.Horticulture research · 2026Article
- Base-pair resolution conservation data improves cell type specific sequence-to-expression prediction.Bioinformatics (Oxford, England) · 2026Article
- Bridging precision agriculture and human medicine through comparative genetics.Nature reviews. Genetics · 2026Review
- Genetic Analysis of Genomic and Methylomic Variation and Identification of Multi-Trait Mutants in Rice Carried on Chang'e-5.Plants (Basel, Switzerland) · 2026Article
- Determinants of functional burden pleiotropy and gene dosage responses across human traits.Nature communications · 2026Article
- Massive Genetic Diversity Loss Within Asian Elephant Subspecies: New Insights for Determining Conservation Priorities.Genome biology and evolution · 2026Article
- Atypical energy-related symptoms define biologically distinct subtypes of major depressive disorder.medRxiv : the preprint server for health sciences · 2026Article
- Phylogenomic blind spots: the limits of UCE and BUSCO loci in the presence of gene flow.Molecular biology and evolution · 2026Article
- The Vertebrate Genomes Project Phase I: A global reference genome resource.bioRxiv : the preprint server for biology · 2026Article
- Going wild: prioritizing experimental models of rodent-borne viruses to decode zoonotic spillover and pandemic risk.Journal of virology · 2026Review
- Fine-mapping candidate neuropsychiatric regulatory variants using cell type-aware comparative genomics.bioRxiv : the preprint server for biology · 2026Article
- In Vitro Massively Parallel Screening of Human Regulatory Elements Involved in Postcranial Skeletal Development for Differential Activity Compared to Chimpanzee.Genome biology and evolution · 2026Article
- Cross-species prediction reveals chromatin regions with increased accessibility in humans.Science advances · 2026Article
- Article
- Beyond Exons: Linking Noncoding Heritability and Polygenicity across Complex Human Traits and Disorders.bioRxiv : the preprint server for biology · 2026Article
- Article
- Farm animal evolution demonstrates hidden molecular basis of human traits.bioRxiv : the preprint server for biology · 2026Article
28 more citing papers are in PubMed but not listed here.
Corrections and comments
- Update of
Authors and funding
40 authors.
Patrick F Sullivan *Department of Genetics, University of North Carolina Medical School, Chapel Hill, NC 27599, USA.ORCID 0000-0002-6619-873X
Jennifer R S Meadows *Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, 75132 Uppsala, Sweden.ORCID 0000-0002-0850-230X
Steven Gazal *Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.ORCID 0000-0003-4510-5730
BaDoi N PhanDepartment of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA.ORCID 0000-0001-6331-5980
Xue LiProgram in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.ORCID 0000-0002-9126-2692
Diane P GenereuxProgram in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.ORCID 0000-0001-5770-0989
Michael X DongDepartment of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, 75132 Uppsala, Sweden.ORCID 0000-0003-4084-3099
Matteo BianchiDepartment of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, 75132 Uppsala, Sweden.ORCID 0000-0003-3394-6495
Gregory AndrewsProgram in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.ORCID 0000-0002-9880-3965
Sharadha SakthikumarDepartment of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, 75132 Uppsala, Sweden.ORCID 0000-0002-7746-8264
Jessika NordinDepartment of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, 75132 Uppsala, Sweden.ORCID 0000-0002-8414-2190
Ananya RoyDepartment of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 75185 Uppsala, Sweden.
Matthew J ChristmasDepartment of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, 75132 Uppsala, Sweden.ORCID 0000-0002-6355-7581
Voichita D MarinescuDepartment of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, 75132 Uppsala, Sweden.ORCID 0000-0002-4803-4707
Chao WangDepartment of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, 75132 Uppsala, Sweden.ORCID 0000-0003-3936-4023
Ola WallermanDepartment of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, 75132 Uppsala, Sweden.ORCID 0000-0003-1037-7904
James XueBroad Institute of MIT and Harvard, Cambridge, MA 02139, USA.ORCID 0000-0002-3332-5747
Shuyang YaoDepartment of Medical Epidemiology and Biostatistics, Karolinska Institute, 17177 Stockholm, Sweden.ORCID 0000-0001-9669-4470
Quan SunDepartment of Genetics, University of North Carolina Medical School, Chapel Hill, NC 27599, USA.ORCID 0000-0001-8324-2803
Jin SzatkiewiczDepartment of Genetics, University of North Carolina Medical School, Chapel Hill, NC 27599, USA.ORCID 0000-0002-4898-7401
Jia WenDepartment of Genetics, University of North Carolina Medical School, Chapel Hill, NC 27599, USA.
Laura M HuckinsDepartment of Genetic and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.ORCID 0000-0002-5369-6502
Alyssa LawlerNeuroscience Institute, Carnegie Mellon University, Pittsburgh, PA 15213, USA.ORCID 0000-0002-2151-5164
Kathleen C KeoughGladstone Institutes, San Francisco, CA 94158, USA.ORCID 0000-0002-7481-0511
Zhili ZhengInstitute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia.ORCID 0000-0003-2102-221X
Jian ZengInstitute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia.ORCID 0000-0001-8801-5220
Naomi R WrayInstitute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia.ORCID 0000-0001-7421-3357
Yun LiDepartment of Genetics, University of North Carolina Medical School, Chapel Hill, NC 27599, USA.ORCID 0000-0002-9275-4189
Jessica JohnsonDepartment of Genetic and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.ORCID 0000-0002-4519-3120
Jiawen ChenDepartment of Biostatistics, University of North Carolina Medical School, Chapel Hill, NC 27599, USA.ORCID 0000-0002-6193-534X
Zoonomia Consortium§
Benedict PatenUC Santa Cruz Genomics Institute, Santa Cruz, CA 95064, USA.ORCID 0000-0001-8863-3539
Steven K ReillyDepartment of Genetics, Yale School of Medicine, New Haven, CT 06510, USA.ORCID 0000-0003-3140-1483
Graham M HughesSchool of Biology and Environmental Science, University College Dublin, Belfield, Dublin 4, Ireland.ORCID 0000-0003-3088-345X
Zhiping WengProgram in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.ORCID 0000-0002-3032-7966
Katherine S PollardGladstone Institutes, San Francisco, CA 94158, USA.ORCID 0000-0002-9870-6196
Andreas R PfenningDepartment of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA.ORCID 0000-0002-3447-9801
Karin Forsberg-NilssonDepartment of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 75185 Uppsala, Sweden.ORCID 0000-0003-0692-6245
Elinor K Karlsson *Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.ORCID 0000-0002-4343-3776
Kerstin Lindblad-Toh *Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, 75132 Uppsala, Sweden.ORCID 0000-0001-8338-0253
Funding
The UCSC Genome BrowserU41HG002371 · NHGRI · UNIVERSITY OF CALIFORNIA SANTA CRUZ · PI KENT, WILLIAM JAMES · 2012 to 2021
$36.6MGENCODE: comprehensive reference genome annotation for human and mouseU24HG007234 · NHGRI · EUROPEAN MOLECULAR BIOLOGY LABORATORY · PI Fergal James Martin · 2021 to 2026
$16.1MPolygenic risk scores for cardiometabolic disorders: the role of blood cells immune response and evolutionary adaptationU01HG011720 · NHGRI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Yun Li, ALEXANDER P REINER · 2021 to 2026
$5.4MModeling the interaction of physiological and environmental stressors on common variants to psychiatric traitsR01ES033630 · NIEHS · YALE UNIVERSITY · PI Kristen Jennifer Brennand · 2022 to 2026
$4.6MPredicting the multi-omic impact of psychiatric GWAS associationsR01MH118278 · NIMH · YALE UNIVERSITY · PI HUCKINS, LAURA MARIANNE · 2019 to 2023
$3.6MTransforming family dogs into a powerful and accessible model for human cancerR37CA218570 · NCI · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI KARLSSON, ELINOR · 2018 to 2022
$3.2MThe 200 mammals project: sequencing genomes by a novel cost-effective method, yielding a high resolution annotation of the human genome.R01HG008742 · NHGRI · BROAD INSTITUTE, INC. · PI BIRREN, BRUCE W., KARLSSON, ELINOR · 2016 to 2020
$2.8MMassively parallel characterization of psychiatric disease associated regulatory elements in defined cell typesU01MH116438 · NIMH · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI AHITUV, NADAV, POLLARD, KATHERINE S. · 2018 to 2021
$2.7MEnabling Comparative PangenomicsR01HG010485 · NHGRI · UNIVERSITY OF CALIFORNIA SANTA CRUZ · PI HAUSSLER, DAVID H, MARTIN, FERGAL JAMES · 2020 to 2023
$2.6MInterpreting the regulatory mechanisms underlying the predisposition to substance use disordersDP1DA046585 · NIDA · CARNEGIE-MELLON UNIVERSITY · PI PFENNING, ANDREAS ROBERT · 2018 to 2022
$2.4MCharacterizing genetic signatures of natural selection to understand human diseasesR35GM147789 · NIGMS · UNIVERSITY OF SOUTHERN CALIFORNIA · PI Steven Gazal · 2022 to 2026
$2.0M3/7 Psychiatric Genomics Consortium: Advancing Discovery and ImpactR01MH124839 · NIMH · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI ANDREASSEN, OLE A, HUCKINS, LAURA MARIANNE · 2021 to 2025
$2.0MNCI NIH HHS R37 CA218570NHGRI NIH HHS R00 HG010160NHGRI NIH HHS R01 HG008742NHGRI NIH HHS R01 HG010485NHGRI NIH HHS U01 HG011720NHGRI NIH HHS U24 HG007234NHGRI NIH HHS U41 HG002371NIDA NIH HHS DP1 DA046585NIDA NIH HHS F30 DA053020NIEHS NIH HHS R01 ES033630NIGMS NIH HHS R35 GM147789NIMH NIH HHS R01 MH118278NIMH NIH HHS R01 MH124839NIMH NIH HHS U01 MH116438
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.
Indexed as
DiseaseGenetic VariationAnimalsBiological EvolutionGenome, HumanGenome-Wide Association StudyGenomicsHumansMolecular Sequence AnnotationPolymorphism, Single Nucleotide
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