Scientific Publications

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

Publication TypeJournal Article
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, Kent WJ, Bouffard GG, Guan X., Hansen NF, Idol JR, Maduro VV, 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 E. S., 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, and Sidow A.
AbstractA 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.
Year of Publication2007
JournalGenome research
Volume17
Issue6
Pages760-74
Date Published (YYYY/MM/DD)2007/06/01
ISSN Number1088-9051
DOI10.1101/gr.6034307
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/17567995?dopt=Abstract