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Genome Res DOI:10.1101/gr.6034307

Analyses of deep mammalian sequence alignments and constraint predictions for 1% of the human genome.

Publication TypeJournal Article
Year of Publication2007
AuthorsMargulies, EH, Cooper, GM, Asimenos, G, Thomas, DJ, Dewey, CN, Siepel, A, Birney, E, Keefe, D, Schwartz, AS, Hou, M, Taylor, J, Nikolaev, S, Montoya-Burgos, JI, Löytynoja, A, Whelan, S, Pardi, F, Massingham, T, Brown, JB, Bickel, P, Holmes, I, Mullikin, JC, Ureta-Vidal, A, Paten, B, Stone, EA, Rosenbloom, KR, W Kent, J, Bouffard, GG, Guan, X, Hansen, NF, Idol, JR, Maduro, VVB, Maskeri, B, McDowell, JC, Park, M, Thomas, PJ, Young, AC, Blakesley, RW, Muzny, DM, Sodergren, E, Wheeler, DA, Worley, KC, Jiang, H, Weinstock, GM, Gibbs, RA, Graves, T, Fulton, R, Mardis, ER, Wilson, RK, Clamp, M, Cuff, J, Gnerre, S, Jaffe, DB, Chang, JL, Lindblad-Toh, K, Lander, ES, Hinrichs, A, Trumbower, H, Clawson, H, Zweig, A, Kuhn, RM, Barber, G, Harte, R, Karolchik, D, Field, MA, Moore, RA, Matthewson, CA, Schein, JE, Marra, MA, Antonarakis, SE, Batzoglou, S, Goldman, N, Hardison, R, Haussler, D, Miller, W, Pachter, L, Green, ED, Sidow, A
JournalGenome Res
Date Published2007 Jun
KeywordsAnimals, Evolution, Molecular, Genome, Human, Human Genome Project, Humans, Mammals, Open Reading Frames, Phylogeny, Sequence Alignment

A key component of the ongoing ENCODE project involves rigorous comparative sequence analyses for the initially targeted 1% of the human genome. Here, we present orthologous sequence generation, alignment, and evolutionary constraint analyses of 23 mammalian species for all ENCODE targets. Alignments were generated using four different methods; comparisons of these methods reveal large-scale consistency but substantial differences in terms of small genomic rearrangements, sensitivity (sequence coverage), and specificity (alignment accuracy). We describe the quantitative and qualitative trade-offs concomitant with alignment method choice and the levels of technical error that need to be accounted for in applications that require multisequence alignments. Using the generated alignments, we identified constrained regions using three different methods. While the different constraint-detecting methods are in general agreement, there are important discrepancies relating to both the underlying alignments and the specific algorithms. However, by integrating the results across the alignments and constraint-detecting methods, we produced constraint annotations that were found to be robust based on multiple independent measures. Analyses of these annotations illustrate that most classes of experimentally annotated functional elements are enriched for constrained sequences; however, large portions of each class (with the exception of protein-coding sequences) do not overlap constrained regions. The latter elements might not be under primary sequence constraint, might not be constrained across all mammals, or might have expendable molecular functions. Conversely, 40% of the constrained sequences do not overlap any of the functional elements that have been experimentally identified. Together, these findings demonstrate and quantify how many genomic functional elements await basic molecular characterization.


Alternate JournalGenome Res.
PubMed ID17567995
PubMed Central IDPMC1891336
Grant ListP41 HG002371 / HG / NHGRI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
R01 GM076705 / GM / NIGMS NIH HHS / United States
/ / Intramural NIH HHS / United States
R43 HG002632 / HG / NHGRI NIH HHS / United States
U01 HG003150 / HG / NHGRI NIH HHS / United States
R01 HG002238 / HG / NHGRI NIH HHS / United States