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A high-resolution map of human evolutionary constraint using 29 mammals

Author

Listed:
  • Kerstin Lindblad-Toh

    (Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center
    Science for Life Laboratory, Uppsala University, Box 582)

  • Manuel Garber

    (Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center)

  • Or Zuk

    (Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center)

  • Michael F. Lin

    (Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center
    MIT Computer Science and Artificial Intelligence Laboratory)

  • Brian J. Parker

    (The Bioinformatics Centre, University of Copenhagen)

  • Stefan Washietl

    (MIT Computer Science and Artificial Intelligence Laboratory)

  • Pouya Kheradpour

    (Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center
    MIT Computer Science and Artificial Intelligence Laboratory)

  • Jason Ernst

    (Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center
    MIT Computer Science and Artificial Intelligence Laboratory)

  • Gregory Jordan

    (EMBL-EBI, Wellcome Trust Genome Campus)

  • Evan Mauceli

    (Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center)

  • Lucas D. Ward

    (Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center
    MIT Computer Science and Artificial Intelligence Laboratory)

  • Craig B. Lowe

    (Center for Biomolecular Science and Engineering, University of California
    Stanford University
    Howard Hughes Medical Institute, 4000 Jones Bridge Road)

  • Alisha K. Holloway

    (Gladstone Institutes, University of California)

  • Michele Clamp

    (Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center
    BioTeam Inc, 7 Derosier Drive)

  • Sante Gnerre

    (Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center)

  • Jessica Alföldi

    (Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center)

  • Kathryn Beal

    (EMBL-EBI, Wellcome Trust Genome Campus)

  • Jean Chang

    (Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center)

  • Hiram Clawson

    (Center for Biomolecular Science and Engineering, University of California)

  • James Cuff

    (Research Computing, Faculty of Arts and Sciences, Harvard University)

  • Federica Di Palma

    (Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center)

  • Stephen Fitzgerald

    (EMBL-EBI, Wellcome Trust Genome Campus)

  • Paul Flicek

    (EMBL-EBI, Wellcome Trust Genome Campus)

  • Mitchell Guttman

    (Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center)

  • Melissa J. Hubisz

    (Cornell University)

  • David B. Jaffe

    (Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center)

  • Irwin Jungreis

    (MIT Computer Science and Artificial Intelligence Laboratory)

  • W. James Kent

    (Gladstone Institutes, University of California)

  • Dennis Kostka

    (Gladstone Institutes, University of California)

  • Marcia Lara

    (Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center)

  • Andre L. Martins

    (Cornell University)

  • Tim Massingham

    (EMBL-EBI, Wellcome Trust Genome Campus)

  • Ida Moltke

    (The Bioinformatics Centre, University of Copenhagen)

  • Brian J. Raney

    (Center for Biomolecular Science and Engineering, University of California)

  • Matthew D. Rasmussen

    (MIT Computer Science and Artificial Intelligence Laboratory)

  • Jim Robinson

    (Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center)

  • Alexander Stark

    (Research Institute of Molecular Pathology (IMP))

  • Albert J. Vilella

    (EMBL-EBI, Wellcome Trust Genome Campus)

  • Jiayu Wen

    (The Bioinformatics Centre, University of Copenhagen)

  • Xiaohui Xie

    (Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center)

  • Michael C. Zody

    (Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center)

  • Kim C. Worley

    (Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza)

  • Christie L. Kovar

    (Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza)

  • Donna M. Muzny

    (Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza)

  • Richard A. Gibbs

    (Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza)

  • Wesley C. Warren

    (Genome Institute at Washington University, Washington University School of Medicine)

  • Elaine R. Mardis

    (Genome Institute at Washington University, Washington University School of Medicine)

  • George M. Weinstock

    (Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza
    Genome Institute at Washington University, Washington University School of Medicine)

  • Richard K. Wilson

    (Genome Institute at Washington University, Washington University School of Medicine)

  • Ewan Birney

    (EMBL-EBI, Wellcome Trust Genome Campus)

  • Elliott H. Margulies

    (Genome Informatics Section, Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health)

  • Javier Herrero

    (EMBL-EBI, Wellcome Trust Genome Campus)

  • Eric D. Green

    (NISC Comparative Sequencing Program, Genome Technology Branch and NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health)

  • David Haussler

    (Center for Biomolecular Science and Engineering, University of California
    Howard Hughes Medical Institute, 4000 Jones Bridge Road)

  • Adam Siepel

    (Cornell University)

  • Nick Goldman

    (EMBL-EBI, Wellcome Trust Genome Campus)

  • Katherine S. Pollard

    (Gladstone Institutes, University of California
    Institute for Human Genetics, University of California)

  • Jakob S. Pedersen

    (The Bioinformatics Centre, University of Copenhagen
    Aarhus University Hospital, Skejby)

  • Eric S. Lander

    (Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center)

  • Manolis Kellis

    (Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center
    MIT Computer Science and Artificial Intelligence Laboratory)

Abstract

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease.

Suggested Citation

  • Kerstin Lindblad-Toh & Manuel Garber & Or Zuk & Michael F. Lin & Brian J. Parker & Stefan Washietl & Pouya Kheradpour & Jason Ernst & Gregory Jordan & Evan Mauceli & Lucas D. Ward & Craig B. Lowe & Al, 2011. "A high-resolution map of human evolutionary constraint using 29 mammals," Nature, Nature, vol. 478(7370), pages 476-482, October.
    • Handle: RePEc:nat:nature:v:478:y:2011:i:7370:d:10.1038_nature10530
    DOI: 10.1038/nature10530
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    Cited by:

    1. Lijing Tang & Benjamin Swedlund & Sébastien Dupont & Chad Harland & Gabriel Costa Monteiro Moreira & Keith Durkin & Maria Artesi & Eric Mullaart & Arnaud Sartelet & Latifa Karim & Wouter Coppieters & , 2024. "GWAS reveals determinants of mobilization rate and dynamics of an active endogenous retrovirus of cattle," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Adriana Arneson & Amin Haghani & Michael J. Thompson & Matteo Pellegrini & Soo Bin Kwon & Ha Vu & Emily Maciejewski & Mingjia Yao & Caesar Z. Li & Ake T. Lu & Marco Morselli & Liudmilla Rubbi & Bret B, 2022. "A mammalian methylation array for profiling methylation levels at conserved sequences," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Xinru Zhang & Bohao Fang & Yi-Fei Huang, 2023. "Transcription factor binding sites are frequently under accelerated evolution in primates," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    4. Scott D. Findlay & Lindsay Romo & Christopher B. Burge, 2024. "Quantifying negative selection in human 3ʹ UTRs uncovers constrained targets of RNA-binding proteins," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    5. Maria Niarchou & Daniel E. Gustavson & J. Fah Sathirapongsasuti & Manuel Anglada-Tort & Else Eising & Eamonn Bell & Evonne McArthur & Peter Straub & J. Devin McAuley & John A. Capra & Fredrik Ullén & , 2022. "Genome-wide association study of musical beat synchronization demonstrates high polygenicity," Nature Human Behaviour, Nature, vol. 6(9), pages 1292-1309, September.
    6. Alan Selewa & Kaixuan Luo & Michael Wasney & Linsin Smith & Xiaotong Sun & Chenwei Tang & Heather Eckart & Ivan P. Moskowitz & Anindita Basu & Xin He & Sebastian Pott, 2023. "Single-cell genomics improves the discovery of risk variants and genes of atrial fibrillation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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