11
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Identification of constrained sequence elements across 239 primate genomes

      research-article
      1 , 1 , 1 , 1 , 1 , 2 , 1 , 1 , 1 , 1 , 3 , 2 , 2 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 8 , 12 , 8 , 13 , 14 , 15 , 15 , 15 , 4 , 4 , 16 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 11 , 24 , 1 , 25 , 26 , 27 , 28 , 26 , 29 , 30 , 31 , 32 , 33 , 10 , 34 , 26 , 35 , 36 , 36 , 36 , 37 , 38 , 39 , 39 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 44 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 11 , 53 , 54 , 11 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 60 , 62 , 63 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 15 , 70 , 71 , 72 , 17 , 73 , 8 , 4 , 74 , 75 , 76 , 77 , 78 , 9 , 10 , 79 , 4 , 80 , 81 , 82 , 2 , 3 , 83 , 16 , , 11 , 15 , 53 , 55 , 58 , , 1 ,
      Nature
      Nature Publishing Group UK
      Comparative genomics, Evolutionary genetics, Genetic variation, Transcriptional regulatory elements, Genome evolution

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Noncoding DNA is central to our understanding of human gene regulation and complex diseases 1, 2 , and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome 39 . Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA 10 , the relatively short timescales separating primate species 11 , and the previously limited availability of whole-genome sequences 12 . Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals.

          Abstract

          Whole-genome alignment of 239 primate species reveals noncoding regulatory elements that are under selective constraint in primates but not in other placental mammals, that are enriched for variants that affect human gene expression and complex traits in diseases.

          Related collections

          Most cited references74

          • Record: found
          • Abstract: found
          • Article: found
          Is Open Access

          The mutational constraint spectrum quantified from variation in 141,456 humans

          Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes 1 . Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            An Integrated Encyclopedia of DNA Elements in the Human Genome

            Summary The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure, and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall the project provides new insights into the organization and regulation of our genes and genome, and an expansive resource of functional annotations for biomedical research.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              The UK Biobank resource with deep phenotyping and genomic data

              The UK Biobank project is a prospective cohort study with deep genetic and phenotypic data collected on approximately 500,000 individuals from across the United Kingdom, aged between 40 and 69 at recruitment. The open resource is unique in its size and scope. A rich variety of phenotypic and health-related information is available on each participant, including biological measurements, lifestyle indicators, biomarkers in blood and urine, and imaging of the body and brain. Follow-up information is provided by linking health and medical records. Genome-wide genotype data have been collected on all participants, providing many opportunities for the discovery of new genetic associations and the genetic bases of complex traits. Here we describe the centralized analysis of the genetic data, including genotype quality, properties of population structure and relatedness of the genetic data, and efficient phasing and genotype imputation that increases the number of testable variants to around 96 million. Classical allelic variation at 11 human leukocyte antigen genes was imputed, resulting in the recovery of signals with known associations between human leukocyte antigen alleles and many diseases.
                Bookmark

                Author and article information

                Contributors
                jr13@bcm.edu
                tomas.marques@upf.edu
                kfarh@illumina.com
                Journal
                Nature
                Nature
                Nature
                Nature Publishing Group UK (London )
                0028-0836
                1476-4687
                29 November 2023
                29 November 2023
                2024
                : 625
                : 7996
                : 735-742
                Affiliations
                [1 ]Illumina Artificial Intelligence Laboratory, Illumina, ( https://ror.org/05k34t975) San Diego, CA USA
                [2 ]GRID grid.205975.c, ISNI 0000 0001 0740 6917, UC Santa Cruz Genomics Institute, , University of California, ; Santa Cruz, CA USA
                [3 ]GRID grid.8993.b, ISNI 0000 0004 1936 9457, Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, , Uppsala University, ; Uppsala, Sweden
                [4 ]School of Science, Engineering and Environment, University of Salford, ( https://ror.org/01tmqtf75) Salford, UK
                [5 ]Department of Evolutionary Anthropology, University of Vienna, ( https://ror.org/03prydq77) Vienna, Austria
                [6 ]Human Evolution and Archaeological Sciences (HEAS), University of Vienna, ( https://ror.org/03prydq77) Vienna, Austria
                [7 ]Département d’Anthropologie, Université de Montréal, ( https://ror.org/0161xgx34) Montréal, Quebec Canada
                [8 ]Bioinformatics Research Centre, Aarhus University, ( https://ror.org/01aj84f44) Aarhus, Denmark
                [9 ]Academy of Scientific and Innovative Research (AcSIR), ( https://ror.org/053rcsq61) Ghaziabad, India
                [10 ]Laboratory for the Conservation of Endangered Species, CSIR-Centre for Cellular and Molecular Biology, ( https://ror.org/05shq4n12) Hyderabad, India
                [11 ]IBE, Institute of Evolutionary Biology (UPF-CSIC), Department of Medicine and Life Sciences, Universitat Pompeu Fabra, ( https://ror.org/04n0g0b29) Barcelona, Spain
                [12 ]Section for Ecoinformatics and Biodiversity, Department of Biology, Aarhus University, ( https://ror.org/01aj84f44) Aarhus, Denmark
                [13 ]Research Group on Primate Biology and Conservation, Mamirauá Institute for Sustainable Development, Tefé, Brazil
                [14 ]Evolutionary Biology and Ecology (EBE), Département de Biologie des Organismes, Université libre de Bruxelles (ULB), ( https://ror.org/01r9htc13) Brussels, Belgium
                [15 ]Centro Nacional de Analisis Genomico (CNAG), ( https://ror.org/03mynna02) Barcelona, Spain
                [16 ]Human Genome Sequencing Center and Department of Molecular and Human Genetics, Baylor College of Medicine, ( https://ror.org/02pttbw34) Houston, TX USA
                [17 ]Department of Ecology and Genetics, Animal Ecology, Uppsala University, ( https://ror.org/048a87296) Uppsala, Sweden
                [18 ]Tanzania National Parks, ( https://ror.org/028prp877) Arusha, Tanzania
                [19 ]North Carolina Museum of Natural Sciences, ( https://ror.org/01bqnjh41) Raleigh, NC USA
                [20 ]Department of Biological and Biomedical Sciences, North Carolina Central University, ( https://ror.org/051r3tx83) Durham, NC USA
                [21 ]Department of Biological Sciences, North Carolina State University, ( https://ror.org/04tj63d06) Raleigh, NC USA
                [22 ]Department of Evolutionary Anthropology, Duke University, ( https://ror.org/00py81415) Durham, NC USA
                [23 ]GRID grid.10698.36, ISNI 0000000122483208, Renaissance Computing Institute, , University of North Carolina at Chapel Hill, ; Chapel Hill, NC USA
                [24 ]Copenhagen Zoo, ( https://ror.org/019950a73) Frederiksberg, Denmark
                [25 ]Universidade Federal de Viçosa, ( https://ror.org/0409dgb37) Viçosa, Brazil
                [26 ]Universidade Federal do Amazonas, Departamento de Genética, Laboratório de Evolução e Genética Animal (LEGAL), ( https://ror.org/02263ky35) Manaus, Brazil
                [27 ]Department of Anthropology, University of Utah, ( https://ror.org/03r0ha626) Salt Lake City, UT USA
                [28 ]Universidade Federal do Para, ( https://ror.org/03q9sr818) Bragança, Brazil
                [29 ]Research Group on Terrestrial Vertebrate Ecology, Mamirauá Institute for Sustainable Development, Tefé, Brazil
                [30 ]Rede de Pesquisa em Diversidade, Conservação e Uso da Fauna da Amazônia – RedeFauna, Manaus, Brazil
                [31 ]Comunidad de Manejo de Fauna Silvestre en la Amazonía y en Latinoamérica—ComFauna, Iquitos, Peru
                [32 ]Universidade Federal de Rondônia, ( https://ror.org/02842cb31) Porto Velho, Brazil
                [33 ]Instituto Nacional de Pesquisas da Amazônia, ( https://ror.org/01xe86309) Manaus, Brazil
                [34 ]Instituto de Biociências, Universidade Federal do Mato Grosso, ( https://ror.org/01mqvjv41) Cuiabá, Brazil
                [35 ]Department of Biology, Trinity University, ( https://ror.org/00t8gz605) San Antonio, TX USA
                [36 ]Life Sciences and Environment, Technology and Environment of Mahajanga, University of Mahajanga, Mahajanga, Madagascar
                [37 ]Department of Anthropology, New York University, ( https://ror.org/0190ak572) New York, NY USA
                [38 ]GRID grid.4367.6, ISNI 0000 0001 2355 7002, Department of Neuroscience, , Washington University School of Medicine in St Louis, ; St Louis, MO USA
                [39 ]GRID grid.240145.6, ISNI 0000 0001 2291 4776, Keeling Center for Comparative Medicine and Research, , MD Anderson Cancer Center, ; Bastrop, TX USA
                [40 ]Department of Anthropology, Yale University, ( https://ror.org/03v76x132) New Haven, CT USA
                [41 ]School of Interdisciplinary Forensics, Arizona State University, ( https://ror.org/03efmqc40) Phoenix, AZ USA
                [42 ]GRID grid.27860.3b, ISNI 0000 0004 1936 9684, California National Primate Research Center, , University of California, ; Davis, CA USA
                [43 ]GRID grid.512758.c, Guinea Worm Eradication Program, The Carter Center Ethiopia, ; Addis Ababa, Ethiopia
                [44 ]GRID grid.9227.e, ISNI 0000000119573309, State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, , Chinese Academy of Sciences, ; Kunming, China
                [45 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, Center for Evolutionary and Organismal Biology, , Zhejiang University School of Medicine, ; Hangzhou, China
                [46 ]Villum Centre for Biodiversity Genomics, Section for Ecology and Evolution, Department of Biology, University of Copenhagen, ( https://ror.org/035b05819) Copenhagen, Denmark
                [47 ]Liangzhu Laboratory, Zhejiang University Medical Center, ( https://ror.org/00a2xv884) Hangzhou, China
                [48 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, Women’s Hospital, School of Medicine, , Zhejiang University, ; Hangzhou, China
                [49 ]Tanzania Wildlife Research Institute (TAWIRI), ( https://ror.org/04sv7km52) Arusha, Tanzania
                [50 ]Institute of International Animal Health/One Health, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, ( https://ror.org/025fw7a54) Greifswald–Insel Riems, Germany
                [51 ]GRID grid.8664.c, ISNI 0000 0001 2165 8627, Professorship for International Animal Health/One Health, Faculty of Veterinary Medicine, , Justus Liebig University, ; Giessen, Germany
                [52 ]GRID grid.267852.c, ISNI 0000 0004 0637 2083, Department of Environmental Ecology, Faculty of Environmental Sciences, , University of Science and Central Institute for Natural Resources and Environmental Studies, Vietnam National University, ; Hanoi, Vietnam
                [53 ]GRID grid.7080.f, ISNI 0000 0001 2296 0625, Institut Català de Paleontologia Miquel Crusafont, , Universitat Autònoma de Barcelona, ; Barcelona, Spain
                [54 ]Department of Zoology, State Museum of Natural History Stuttgart, ( https://ror.org/05k35b119) Stuttgart, Germany
                [55 ]Institució Catalana de Recerca i Estudis Avançats (ICREA), ( https://ror.org/0371hy230) Barcelona, Spain
                [56 ]Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, ( https://ror.org/03wyzt892) Barcelona, Spain
                [57 ]GRID grid.430077.7, Barcelonaβeta Brain Research Center, , Pasqual Maragall Foundation, ; Barcelona, Spain
                [58 ]Universitat Pompeu Fabra, ( https://ror.org/04n0g0b29) Barcelona, Spain
                [59 ]Cuc Phuong Commune, Nho Quan District, Vietnam
                [60 ]Genome Institute of Singapore, Agency for Science, Technology and Research, ( https://ror.org/05k8wg936) Singapore, Singapore
                [61 ]Mandai Nature, Singapore, Singapore
                [62 ]SingHealth Duke–NUS Institute of Precision Medicine (PRISM), ( https://ror.org/02j1m6098) Singapore, Singapore
                [63 ]Cancer and Stem Cell Biology Program, Duke-NUS Medical School, ( https://ror.org/02j1m6098) Singapore, Singapore
                [64 ]SingHealth Duke–NUS Genomic Medicine Centre, ( https://ror.org/02j1m6098) Singapore, Singapore
                [65 ]Department of Natural Sciences, National Museums Scotland, ( https://ror.org/00pxfwe85) Edinburgh, UK
                [66 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, School of Geosciences, ; Edinburgh, UK
                [67 ]Cognitive Ethology Laboratory, Germany Primate Center, Leibniz Institute for Primate Research, ( https://ror.org/02f99v835) Göttingen, Germany
                [68 ]Department of Primate Cognition, Georg-August-Universität Göttingen, ( https://ror.org/01y9bpm73) Göttingen, Germany
                [69 ]Leibniz ScienceCampus Primate Cognition, ( https://ror.org/05ehdmg18) Göttingen, Germany
                [70 ]GRID grid.22072.35, ISNI 0000 0004 1936 7697, Department of Anthropology and Archaeology, , University of Calgary, ; Calgary, Alberta Canada
                [71 ]GRID grid.22072.35, ISNI 0000 0004 1936 7697, Department of Medical Genetics, , University of Calgary, ; Calgary, Alberta Canada
                [72 ]GRID grid.22072.35, ISNI 0000 0004 1936 7697, Alberta Children’s Hospital Research Institute, , University of Calgary, ; Calgary, Alberta Canada
                [73 ]Institute of Ecology and Evolution, School of Biological Sciences, University of Edinburgh, ( https://ror.org/01nrxwf90) Edinburgh, UK
                [74 ]Cardiovascular Institute, Stanford University, ( https://ror.org/00f54p054) Stanford, CA USA
                [75 ]Department of Cardiothoracic Surgery, Stanford University, ( https://ror.org/00f54p054) Stanford, CA USA
                [76 ]Department of Cancer Biology, Stanford University, ( https://ror.org/00f54p054) Stanford, CA USA
                [77 ]GRID grid.168010.e, ISNI 0000000419368956, Department of Dermatology, , Stanford University School of Medicine, ; Stanford, CA USA
                [78 ]GRID grid.280747.e, ISNI 0000 0004 0419 2556, Veterans Affairs Palo Alto Healthcare System, ; Palo Alto, CA USA
                [79 ]Gene Bank of Primates and Primate Genetics Laboratory, German Primate Center, Leibniz Institute for Primate Research, ( https://ror.org/02f99v835) Göttingen, Germany
                [80 ]Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, ( https://ror.org/02qz8b764) Cold Spring Harbor, NY USA
                [81 ]Department of Computer Science, Stanford University, ( https://ror.org/00f54p054) Stanford, CA USA
                [82 ]Department of Genetics, Stanford University, ( https://ror.org/00f54p054) Stanford, CA USA
                [83 ]Broad Institute of MIT and Harvard, ( https://ror.org/05a0ya142) Cambridge, MA USA
                Author information
                http://orcid.org/0000-0002-9992-9295
                http://orcid.org/0000-0002-2280-9404
                http://orcid.org/0000-0001-6274-4513
                http://orcid.org/0000-0001-9414-300X
                http://orcid.org/0000-0002-7759-2556
                http://orcid.org/0000-0002-0115-1797
                http://orcid.org/0000-0002-9114-8793
                http://orcid.org/0000-0002-2252-3887
                http://orcid.org/0000-0002-9415-2747
                http://orcid.org/0000-0003-3930-0732
                http://orcid.org/0000-0003-3358-2759
                http://orcid.org/0000-0002-5367-0628
                http://orcid.org/0000-0002-4063-7159
                http://orcid.org/0000-0002-6809-0052
                http://orcid.org/0000-0002-3110-9442
                http://orcid.org/0000-0001-6185-4059
                http://orcid.org/0000-0003-1912-9667
                http://orcid.org/0000-0001-6431-6950
                http://orcid.org/0000-0002-1416-4351
                http://orcid.org/0000-0002-9138-0381
                http://orcid.org/0000-0003-3239-7068
                http://orcid.org/0000-0002-3773-1064
                http://orcid.org/0000-0003-1815-6831
                http://orcid.org/0000-0002-3993-7912
                http://orcid.org/0000-0001-7101-7297
                http://orcid.org/0000-0001-7596-2691
                http://orcid.org/0000-0003-1704-8425
                http://orcid.org/0000-0001-5744-4946
                http://orcid.org/0000-0003-3304-9807
                http://orcid.org/0000-0003-3142-7720
                http://orcid.org/0000-0003-2162-8246
                http://orcid.org/0000-0002-1128-4729
                http://orcid.org/0000-0003-0757-4237
                http://orcid.org/0000-0002-0179-8048
                http://orcid.org/0000-0003-4391-1130
                http://orcid.org/0000-0003-2594-0827
                http://orcid.org/0000-0003-3967-8014
                http://orcid.org/0000-0001-7219-632X
                http://orcid.org/0000-0002-0612-2514
                http://orcid.org/0000-0002-8493-5457
                http://orcid.org/0000-0002-5028-1790
                http://orcid.org/0000-0002-7050-7072
                http://orcid.org/0000-0003-4086-7445
                http://orcid.org/0000-0003-0190-4266
                http://orcid.org/0000-0002-5833-9264
                http://orcid.org/0000-0002-3557-7219
                http://orcid.org/0000-0001-8863-3539
                http://orcid.org/0000-0001-8338-0253
                http://orcid.org/0000-0002-7374-6490
                http://orcid.org/0000-0002-5597-3075
                http://orcid.org/0000-0001-6947-8537
                Article
                6798
                10.1038/s41586-023-06798-8
                10808062
                38030727
                21d0f37e-82b2-4e0a-ab92-26c6038bf7a2
                © The Author(s) 2023

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 9 February 2023
                : 30 October 2023
                Categories
                Article
                Custom metadata
                © Springer Nature Limited 2024

                Uncategorized
                comparative genomics,evolutionary genetics,genetic variation,transcriptional regulatory elements,genome evolution

                Comments

                Comment on this article