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

Lindblad-Toh, K., 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., Alfoldi, 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., Baldwin, J., Bloom, T., Chin, C. W., Heiman, D., Nicol, R., Nusbaum, C., Young, S., Wilkinson, J., Worley, K. C., Kovar, C. L., Muzny, D. M., Gibbs, R. A., Cree, A., Dihn, H. H., Fowler, G., Jhangiani, S., Joshi, V., Lee, S., Lewis, L. R., Nazareth, L. V., Okwuonu, G., Santibanez, J., Warren, W. C., Mardis, E. R., Weinstock, G. M., Wilson, R. K., Delehaunty, K., Dooling, D., Fronik, C., Fulton, L., Fulton, B., Graves, T., Minx, P., Sodergren, E., 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. (2011) A high-resolution map of human evolutionary constraint using 29 mammals. Nature, 478 (7370). pp. 476-82. ISSN 0028-0836

URL: http://www.ncbi.nlm.nih.gov/pubmed/21993624
DOI: 10.1038/nature10530

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 approximately 4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for approximately 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.

Item Type: Paper
Uncontrolled Keywords: Animals Disease *Evolution, Molecular Exons/genetics Genome/*genetics Genome, Human/*genetics Genomics Health Humans Mammals/*genetics Molecular Sequence Annotation Phylogeny RNA/classification/genetics Selection, Genetic/genetics Sequence Alignment Sequence Analysis, DNA
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
evolution
CSHL Authors:
Communities: CSHL labs > Siepel lab
Depositing User: Matt Covey
Date Deposited: 14 Jan 2015 14:52
Last Modified: 14 Jan 2015 14:52
PMCID: PMC3207357
Related URLs:
URI: http://repository.cshl.edu/id/eprint/31078

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