A high-resolution map of human evolutionary constraint using 29 mammals
Open accessAbstract
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. This comparative genomics study, comparing the complete human genome sequence with those of 29 placental mammals, including chimpanzees, mice and dogs, identifies 4.2% of the human genome as constrained by evolutionary selection, and ascribes a potential function to about 60% of these constrained bases. A series of evolutionary signatures emerges, providing insights into coding and non-coding functional genomic elements, candidate RNA structural families and aspects of genome organization and evolution. Overlap with disease-associated variants indicates that the findings will be relevant for studies of human disease.
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Not all distal conserved elements are detectably enhancers, and far more of the gene-distal non-coding genome is annotated as a regulatory element than is conserved.
“Not all distal conserved elements are detectably enhancers39 and far more of the gene-distal non-coding genome is annotated as a regulatory element than is conserved60,104.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [104]
The Detection of constrained sequence section reports that constrained elements span 4.2% of the genome. The Chromatin signatures section reports regulatory-associated chromatin states among noncoding constrained elements, but does not directly establish that far more of the gene-distal noncoding genome is annotated as regulatory than conserved. The first clause is attached to a different citation and is not assessed here; page numbers are unavailable in our copy. (LLM, conf=0.74)
Experimental — accuracy not yet measuredThe finding is consistent with the theory that selection keeps fitness-reducing alleles at low frequency at a large proportion of genes.
“However, the finding is consistent with the theory that selection keeps fitness-reducing alleles at a large proportion of genes at low frequency35.”
From Rare and common variants: twenty arguments (2012) · cites this paper as [35]
Using WW data, INRICH enrichment analysis observed enrichment at empirical P ≤ .05 for the synaptic co-expression network M13, Mendelian disease genes, and human and primate-accelerated regions; none exceeded experiment-wise corrected P ≤ .05.
“Using the WW data, we observe enrichment at an empirical P ≤ .05 for the synaptic co-expression network M13 [48], Mendelian disease genes [11], and both human (HARs) and primate-accelerated regions (PARs) [49]. None of these enrichments exceeded the experiment-wise corrected P ≤ .05.”
Many conserved noncoding elements were derived from transposable elements, and the number of conserved noncoding elements is sharply increased in the genome of placental mammals.
“Many conserved noncoding elements were derived from transposable elements. Comparison of placental and marsupial genomes demonstrates that the number of conserved noncoding elements is sharply increased in the genome of placental mammals (Lindblad-Toh et al., 2011; Mikkelsen et al., 2007).”
From Genetic Changes Shaping the Human Brain (2015) · cites this paper as Lindblad-Toh et al., 2011
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Self-citation
- Authors
- Broad Institute Sequencing Platform and Whole Genome Assembly Team, Lindblad-Toh, K., Baylor College of Medicine Human Genome Sequencing Center Sequencing Team, Genome Institute at Washington University, Garber, M., Zuk, O., Lin, M. F., Parker, B. J., Washietl, S., Kheradpour, P., Ernst, J., Jordan, G., Mauceli, E., Ward, L. D., Lowe, C. B., Holloway, A. K., Clamp, M., Gnerre, S., Alföldi, J., Beal, K., Chang, J., Clawson, H., Cuff, J., Di Palma, F., Fitzgerald, S., Flicek, P., Guttman, M., Hubisz, M. J., Jaffe, D. B., Jungreis, I., Kent, W. J., Kostka, D., Lara, M., Martins, A. L., Massingham, T., Moltke, I., Raney, B. J., Rasmussen, M. D., Robinson, J., Stark, A., Vilella, A. J., Wen, J., Xie, X., Zody, M. C., Worley, K. C., Kovar, C. L., Muzny, D. M., Gibbs, R. A., Warren, W. C., Mardis, E. R., Weinstock, G. M., Wilson, R. K., Birney, E., Margulies, E. H., Herrero, J., Green, E. D., Haussler, D., Siepel, A., Goldman, N., Pollard, K. S., Pedersen, J. S., Lander, E. S., & Kellis, M.
- Affiliations
- Broad Institute (US)
- University of Copenhagen (DK)
- European Bioinformatics Institute (GB)
- Howard Hughes Medical Institute (US)
- Gladstone Institutes (US)
- University of California, Santa Cruz (US)
- Harvard University (US)
- Cornell University (US)
- MIT Computer Science and Artificial Intelligence Laboratory (US)
- Research Institute of Molecular Pathology (AT)
- Baylor College of Medicine (US)
- Washington University in St. Louis (US)
- National Institutes of Health (US)
- Corresponding author
- Lander, Eric S.
- Kellis, Manolis
- ORCID
- Garber, Manuel
- Zuk, Or
- Lin, Michael F.
- Parker, Brian J.
- Ernst, Jason
- Jordan, Gregory
- Ward, Lucas D.
- Lowe, Craig B.
- Holloway, Alisha K.
- Alföldi, Jessica
- Beal, Kathryn
- Clawson, Hiram
- Cuff, James
- Fitzgerald, Stephen
- Flicek, Paul
- Guttman, Mitchell
- Hubisz, Melissa J.
- Jaffe, David B.
- Jungreis, Irwin
- Kostka, Dennis
- Moltke, Ida
- Raney, Brian J.
- Stark, Alexander
- Vilella, Albert J.
- Wen, Jiayu
- Xie, Xiaohui
- Zody, Michael C.
- Worley, Kim C.
- Muzny, Donna M.
- Gibbs, Richard A.
- Warren, Wesley C.
- Mardis, Elaine R.
- Weinstock, George M.
- Birney, Ewan
- Herrero, Javier
- Green, Eric D.
- Haussler, David
- Siepel, Adam
- Goldman, Nick
- Pollard, Katherine S.
- Pedersen, Jakob S.
- Lander, Eric S.
- Kellis, Manolis
- Venue
- Nature
- Published
- 2011-10
- Volume
- 478
- Issue
- 7370
- Pages
- 476-482
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3207357
- OpenAlex
- W2024439539
- Cited by
- 1,108
- References
- 51
- Citations by year
- 2026: 28 · 2025: 36 · 2024: 46 · 2023: 49 · 2022: 61 · 2021: 72 · 2020: 77 · 2019: 77 · 2018: 85 · 2017: 78 · 2016: 78 · 2015: 122 · 2014: 99 · 2013: 109 · 2012: 79
- FWCI
- 38.32
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion, cc-by-nc-sa)
- RePEc: Research Papers in Economics (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- National Science Foundation (0644282, 0905968)
- Howard Hughes Medical Institute
- Alfred P. Sloan Foundation
- Harvard University
- Gladstone Institutes
- Wellcome Trust (095908)
- European Bioinformatics Institute
- European Science Foundation
- Cambridge Trust
- Lundbeckfonden (R5-2006-123)
- Novo Nordisk
- Danmarks Frie Forskningsfond
- Gates Cambridge Trust
- Uppsala Universitet
- H. Lundbeck A/S
- National Institutes of Health
- Faculty of Arts and Sciences
- Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology
- National Human Genome Research Institute (U54HG003067, U54HG003273, R01HG003474, R01HG004037)
- National Institute of General Medical Sciences (R01GM082901, #GM82901)
- Division of Mathematical Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Keywords
- human genome evolution, purifying selection, evolutionary constraints, comparative genomics, positive selection, RNA secondary structure, enhancers, promoter, insulators, stop codon readthrough, disease-associated variants
- MeSH terms
- Animals, Disease, Exons, Health, Humans, Mammals, Phylogeny, RNA, Selection, Genetic, Genome, Human, Sequence Alignment, Genome, Sequence Analysis, DNA, Evolution, Molecular, Genomics, Molecular Sequence Annotation
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