title: A high-resolution map of human evolutionary constraint using 29 mammals.
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.
authors: Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA. kersli@broadinstitute.org
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mesh_terms: D000818:Animals; D004194:Disease; D019143:Evolution, Molecular; D005091:Exons / Q000235:genetics; D016678:Genome / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D006262:Health; D006801:Humans; D008322:Mammals / Q000235:genetics*; D058977:Molecular Sequence Annotation; D010802:Phylogeny; D012313:RNA / Q000145:classification / Q000235:genetics; D012641:Selection, Genetic / Q000235:genetics; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA
chemical_list: D012313:RNA