Journal
NATURE
Volume 478, Issue 7370, Pages 476-482Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature10530
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Funding
- National Human Genome Research Institute (NHGRI) [U54 HG003273]
- National Institute for General Medicine (NIGMS) [GM82901]
- European Science Foundation
- NSF National Science Foundation (NSF) [0905968, 0644282]
- NIH [R01 HG004037]
- Sloan Foundation
- Austrian Fonds zur Forderung der Wissenschaftlichen Forschung
- Gates Cambridge Trust
- Novo Nordisk Foundation
- Department of Mathematical Sciences, University of Copenhagen
- David and Lucile Packard Foundation
- Danish Council for Independent Research Medical Sciences
- Lundbeck Foundation
- Lundbeck Foundation [R5-2006-123] Funding Source: researchfish
- Div Of Biological Infrastructure
- Direct For Biological Sciences [0644282] Funding Source: National Science Foundation
- Div Of Biological Infrastructure
- Direct For Biological Sciences [846218, 0905968] Funding Source: National Science Foundation
- Austrian Science Fund (FWF) [W1207] Funding Source: Austrian Science Fund (FWF)
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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 similar to 4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for similar to 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.
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