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

Margulies, Elliott H. and Pachter, Lior (2007) Analyses of deep mammalian sequence alignments and constraint predictions for 1% of the human genome. Genome Research, 17 (6). pp. 760-774. ISSN 1088-9051. PMCID PMC1891336. doi:10.1101/gr.6034307.

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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.

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URLURL TypeDescription CentralArticle Research Data
Pachter, Lior0000-0002-9164-6231
Additional Information:© 2007, Cold Spring Harbor Laboratory Press. Freely available online through the Genome Research Open Access option. The Authors acknowledge that six months after the full-issue publication date, the Article will be distributed under a Creative Commons CC-BY-NC License (Attribution-NonCommercial 4.0 International License, Received October 12, 2006. Accepted February 15, 2007. We thank F. Collins for critical review of the manuscript; all other ENCODE analysis subgroups for their camaraderie and collaboration; P. Good, E. Feingold, and L. Liefer for ENCODE Consortium guidance and administrative assistance; the Wellcome Trust Sanger Institute, the Max Planck Institute for Developmental Biology, and The Netherlands Institute for Developmental Biology for providing a draft zebrafish genome sequence prior to publication; the DOE Joint Genome Institute for providing a draft Xenopus sequence prior to publication; G. Schuler for making ENCODE comparative sequence data available at NCBI; D. Church for coordinating the identification of finished mouse sequence orthologous to ENCODE regions; and the anonymous reviewers of this manuscript for their constructive comments on previous drafts. This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (E.H.M., J.C.M., and E.D.G.). G.M.C. was a Howard Hughes Medical Institute pre-doctoral Fellow. G.A. is a Bio-X Graduate Student Fellow. D.J.T. is supported by NIH 1 P41 HG02371-05. C.N.D. is supported in part by NIH HG003150. M.H., J.T., and W.M. are supported in part by R01:HG002238. T.M. was supported by BBSRC grant 721/BEP17055. I.H. was funded in part by NIH/NHGRI grant 1R01GM076705-01. S.E.A., S.N., and J.I.M. thank the “Vital IT” computational platform and are supported by grants from NIH ENCODE, Swiss National Science Foundation, European Union, and the ChildCare Foundation. L.P. is supported in part by R01:HG02632 and U01:HG003150. N.G. was supported in part by the Wellcome Trust. D.H. and A. Sidow are supported by funds from NHGRI. A. Siepel was supported by the UCBREP GREAT fellowship (University of California Biotechnology Research and Education Program Graduate Research and Education in Adaptive Biotechnology).
Funding AgencyGrant Number
National Human Genome Research InstituteUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
NIH1 P41 HG02371-05
NIHR01 HG002238
Biotechnology and Biological Sciences Research Council (BBSRC)721/BEP17055
Swiss National Science Foundation (SNSF)UNSPECIFIED
ChildCare FoundationUNSPECIFIED
NIHR01 HG02632
NIHU01 HG003150
University of CaliforniaUNSPECIFIED
Issue or Number:6
PubMed Central ID:PMC1891336
Record Number:CaltechAUTHORS:20170307-125526948
Persistent URL:
Official Citation:Analyses of deep mammalian sequence alignments and constraint predictions for 1% of the human genome Elliott H. Margulies, Gregory M. Cooper, George Asimenos, Daryl J. Thomas, Colin N. Dewey, Adam Siepel, Ewan Birney, Damian Keefe, Ariel S. Schwartz, Minmei Hou, James Taylor, Sergey Nikolaev, Juan I. Montoya-Burgos, Ari Löytynoja, Simon Whelan, Fabio Pardi, Tim Massingham, James B. Brown, Peter Bickel, Ian Holmes, James C. Mullikin, Abel Ureta-Vidal, Benedict Paten, Eric A. Stone, Kate R. Rosenbloom, W. James Kent, Gerard G. Bouffard, Xiaobin Guan, Nancy F. Hansen, Jacquelyn R. Idol, Valerie V.B. Maduro, Baishali Maskeri, Jennifer C. McDowell, Morgan Park, Pamela J. Thomas, Alice C. Young, Robert W. Blakesley, Donna M. Muzny, Erica Sodergren, David A. Wheeler, Kim C. Worley, Huaiyang Jiang, George M. Weinstock, Richard A. Gibbs, Tina Graves, Robert Fulton, Elaine R. Mardis, Richard K. Wilson, Michele Clamp, James Cuff, Sante Gnerre, David B. Jaffe, Jean L. Chang, Kerstin Lindblad-Toh, Eric S. Lander, Angie Hinrichs, Heather Trumbower, Hiram Clawson, Ann Zweig, Robert M. Kuhn, Galt Barber, Rachel Harte, Donna Karolchik, Matthew A. Field, Richard A. Moore, Carrie A. Matthewson, Jacqueline E. Schein, Marco A. Marra, Stylianos E. Antonarakis, Serafim Batzoglou, Nick Goldman, Ross Hardison, David Haussler, Webb Miller, Lior Pachter, Eric D. Green, and Arend Sidow Genome Res. June 2007 17: 760-774; doi:10.1101/gr.6034307
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ID Code:74856
Deposited By: George Porter
Deposited On:07 Mar 2017 21:22
Last Modified:15 Nov 2021 16:28

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