RT Journal
A1 Margulies, Elliott H.
A1 Cooper, Gregory M.
A1 Asimenos, George
A1 Thomas, Daryl J.
A1 Dewey, Colin N.
A1 Siepel, Adam
A1 Birney, Ewan
A1 Keefe, Damian
A1 Schwartz, Ariel S.
A1 Hou, Minmei
A1 Taylor, James
A1 Nikolaev, Sergey
A1 Montoya-Burgos, Juan I.
A1 Löytynoja, Ari
A1 Whelan, Simon
A1 Pardi, Fabio
A1 Massingham, Tim
A1 Brown, James B.
A1 Bickel, Peter
A1 Holmes, Ian
A1 Mullikin, James C.
A1 Ureta-Vidal, Abel
A1 Paten, Benedict
A1 Stone, Eric A.
A1 Rosenbloom, Kate R.
A1 Kent, W. James
A1 Bouffard, Gerard G.
A1 Guan, Xiaobin
A1 Hansen, Nancy F.
A1 Idol, Jacquelyn R.
A1 Maduro, Valerie V.B.
A1 Maskeri, Baishali
A1 McDowell, Jennifer C.
A1 Park, Morgan
A1 Thomas, Pamela J.
A1 Young, Alice C.
A1 Blakesley, Robert W.
A1 Muzny, Donna M.
A1 Sodergren, Erica
A1 Wheeler, David A.
A1 Worley, Kim C.
A1 Jiang, Huaiyang
A1 Weinstock, George M.
A1 Gibbs, Richard A.
A1 Graves, Tina
A1 Fulton, Robert
A1 Mardis, Elaine R.
A1 Wilson, Richard K.
A1 Clamp, Michele
A1 Cuff, James
A1 Gnerre, Sante
A1 Jaffe, David B.
A1 Chang, Jean L.
A1 Lindblad-Toh, Kerstin
A1 Lander, Eric S.
A1 Hinrichs, Angie
A1 Trumbower, Heather
A1 Clawson, Hiram
A1 Zweig, Ann
A1 Kuhn, Robert M.
A1 Barber, Galt
A1 Harte, Rachel
A1 Karolchik, Donna
A1 Field, Matthew A.
A1 Moore, Richard A.
A1 Matthewson, Carrie A.
A1 Schein, Jacqueline E.
A1 Marra, Marco A.
A1 Antonarakis, Stylianos E.
A1 Batzoglou, Serafim
A1 Goldman, Nick
A1 Hardison, Ross
A1 Haussler, David
A1 Miller, Webb
A1 Pachter, Lior
A1 Green, Eric D.
A1 Sidow, Arend
T1 Analyses of deep mammalian sequence alignments and constraint predictions for 1% of the human genome
JF Genome Research 
JO Genome Research 
YR 2007 
FD June 01 
VO 17 
IS 6 
SP 760 
OP 774 
DO 10.1101/gr.6034307 
UL http://genome.cshlp.org/content/17/6/760.abstract 
AB 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.