TY  - JOUR
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
Y1  - 2007/06/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 760 
EP  - 774 
DO  - 10.1101/gr.6034307 
VL  - 17 
IS  - 6 
UR  - http://genome.cshlp.org/content/17/6/760.abstract 
N2  - 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. 
ER  -