%0 Journal Article %J Genome Res %D 2007 %T Analyses of deep mammalian sequence alignments and constraint predictions for 1% of the human genome. %A Margulies, Elliott H %A Cooper, Gregory M %A Asimenos, George %A Thomas, Daryl J %A Dewey, Colin N %A Siepel, Adam %A Birney, Ewan %A Keefe, Damian %A Schwartz, Ariel S %A Hou, Minmei %A Taylor, James %A Nikolaev, Sergey %A Montoya-Burgos, Juan I %A Löytynoja, Ari %A Whelan, Simon %A Pardi, Fabio %A Massingham, Tim %A Brown, James B %A Bickel, Peter %A Holmes, Ian %A Mullikin, James C %A Ureta-Vidal, Abel %A Paten, Benedict %A Stone, Eric A %A Rosenbloom, Kate R %A Kent, W James %A Bouffard, Gerard G %A Guan, Xiaobin %A Hansen, Nancy F %A Idol, Jacquelyn R %A Maduro, Valerie V B %A Maskeri, Baishali %A McDowell, Jennifer C %A Park, Morgan %A Thomas, Pamela J %A Young, Alice C %A Blakesley, Robert W %A Muzny, Donna M %A Sodergren, Erica %A Wheeler, David A %A Worley, Kim C %A Jiang, Huaiyang %A Weinstock, George M %A Gibbs, Richard A %A Graves, Tina %A Fulton, Robert %A Mardis, Elaine R %A Wilson, Richard K %A Clamp, Michele %A Cuff, James %A Gnerre, Sante %A Jaffe, David B %A Chang, Jean L %A Lindblad-Toh, Kerstin %A Lander, Eric S %A Hinrichs, Angie %A Trumbower, Heather %A Clawson, Hiram %A Zweig, Ann %A Kuhn, Robert M %A Barber, Galt %A Harte, Rachel %A Karolchik, Donna %A Field, Matthew A %A Moore, Richard A %A Matthewson, Carrie A %A Schein, Jacqueline E %A Marra, Marco A %A Antonarakis, Stylianos E %A Batzoglou, Serafim %A Goldman, Nick %A Hardison, Ross %A Haussler, David %A Miller, Webb %A Pachter, Lior %A Green, Eric D %A Sidow, Arend %K Animals %K Evolution, Molecular %K Genome, Human %K Human Genome Project %K Humans %K Mammals %K Open Reading Frames %K Phylogeny %K Sequence Alignment %X

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.

%B Genome Res %V 17 %P 760-74 %8 2007 Jun %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/17567995?dopt=Abstract %R 10.1101/gr.6034307 %0 Journal Article %J Nature %D 2007 %T Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. %A Birney, Ewan %A Stamatoyannopoulos, John A %A Dutta, Anindya %A Guigó, Roderic %A Gingeras, Thomas R %A Margulies, Elliott H %A Weng, Zhiping %A Snyder, Michael %A Dermitzakis, Emmanouil T %A Thurman, Robert E %A Kuehn, Michael S %A Taylor, Christopher M %A Neph, Shane %A Koch, Christoph M %A Asthana, Saurabh %A Malhotra, Ankit %A Adzhubei, Ivan %A Greenbaum, Jason A %A Andrews, Robert M %A Flicek, Paul %A Boyle, Patrick J %A Cao, Hua %A Carter, Nigel P %A Clelland, Gayle K %A Davis, Sean %A Day, Nathan %A Dhami, Pawandeep %A Dillon, Shane C %A Dorschner, Michael O %A Fiegler, Heike %A Giresi, Paul G %A Goldy, Jeff %A Hawrylycz, Michael %A Haydock, Andrew %A Humbert, Richard %A James, Keith D %A Johnson, Brett E %A Johnson, Ericka M %A Frum, Tristan T %A Rosenzweig, Elizabeth R %A Karnani, Neerja %A Lee, Kirsten %A Lefebvre, Gregory C %A Navas, Patrick A %A Neri, Fidencio %A Parker, Stephen C J %A Sabo, Peter J %A Sandstrom, Richard %A Shafer, Anthony %A Vetrie, David %A Weaver, Molly %A Wilcox, Sarah %A Yu, Man %A Collins, Francis S %A Dekker, Job %A Lieb, Jason D %A Tullius, Thomas D %A Crawford, Gregory E %A Sunyaev, Shamil %A Noble, William S %A Dunham, Ian %A Denoeud, France %A Reymond, Alexandre %A Kapranov, Philipp %A Rozowsky, Joel %A Zheng, Deyou %A Castelo, Robert %A Frankish, Adam %A Harrow, Jennifer %A Ghosh, Srinka %A Sandelin, Albin %A Hofacker, Ivo L %A Baertsch, Robert %A Keefe, Damian %A Dike, Sujit %A Cheng, Jill %A Hirsch, Heather A %A Sekinger, Edward A %A Lagarde, Julien %A Abril, Josep F %A Shahab, Atif %A Flamm, Christoph %A Fried, Claudia %A Hackermüller, Jörg %A Hertel, Jana %A Lindemeyer, Manja %A Missal, Kristin %A Tanzer, Andrea %A Washietl, Stefan %A Korbel, Jan %A Emanuelsson, Olof %A Pedersen, Jakob S %A Holroyd, Nancy %A Taylor, Ruth %A Swarbreck, David %A Matthews, Nicholas %A Dickson, Mark C %A Thomas, Daryl J %A Weirauch, Matthew T %A Gilbert, James %A Drenkow, Jorg %A Bell, Ian %A Zhao, XiaoDong %A Srinivasan, K G %A Sung, Wing-Kin %A Ooi, Hong Sain %A Chiu, Kuo Ping %A Foissac, Sylvain %A Alioto, Tyler %A Brent, Michael %A Pachter, Lior %A Tress, Michael L %A Valencia, Alfonso %A Choo, Siew Woh %A Choo, Chiou Yu %A Ucla, Catherine %A Manzano, Caroline %A Wyss, Carine %A Cheung, Evelyn %A Clark, Taane G %A Brown, James B %A Ganesh, Madhavan %A Patel, Sandeep %A Tammana, Hari %A Chrast, Jacqueline %A Henrichsen, Charlotte N %A Kai, Chikatoshi %A Kawai, Jun %A Nagalakshmi, Ugrappa %A Wu, Jiaqian %A Lian, Zheng %A Lian, Jin %A Newburger, Peter %A Zhang, Xueqing %A Bickel, Peter %A Mattick, John S %A Carninci, Piero %A Hayashizaki, Yoshihide %A Weissman, Sherman %A Hubbard, Tim %A Myers, Richard M %A Rogers, Jane %A Stadler, Peter F %A Lowe, Todd M %A Wei, Chia-Lin %A Ruan, Yijun %A Struhl, Kevin %A Gerstein, Mark %A Antonarakis, Stylianos E %A Fu, Yutao %A Green, Eric D %A Karaöz, Ulaş %A Siepel, Adam %A Taylor, James %A Liefer, Laura A %A Wetterstrand, Kris A %A Good, Peter J %A Feingold, Elise A %A Guyer, Mark S %A Cooper, Gregory M %A Asimenos, George %A Dewey, Colin N %A Hou, Minmei %A Nikolaev, Sergey %A Montoya-Burgos, Juan I %A Löytynoja, Ari %A Whelan, Simon %A Pardi, Fabio %A Massingham, Tim %A Huang, Haiyan %A Zhang, Nancy R %A Holmes, Ian %A Mullikin, James C %A Ureta-Vidal, Abel %A Paten, Benedict %A Seringhaus, Michael %A Church, Deanna %A Rosenbloom, Kate %A Kent, W James %A Stone, Eric A %A Batzoglou, Serafim %A Goldman, Nick %A Hardison, Ross C %A Haussler, David %A Miller, Webb %A Sidow, Arend %A Trinklein, Nathan D %A Zhang, Zhengdong D %A Barrera, Leah %A Stuart, Rhona %A King, David C %A Ameur, Adam %A Enroth, Stefan %A Bieda, Mark C %A Kim, Jonghwan %A Bhinge, Akshay A %A Jiang, Nan %A Liu, Jun %A Yao, Fei %A Vega, Vinsensius B %A Lee, Charlie W H %A Ng, Patrick %A Shahab, Atif %A Yang, Annie %A Moqtaderi, Zarmik %A Zhu, Zhou %A Xu, Xiaoqin %A Squazzo, Sharon %A Oberley, Matthew J %A Inman, David %A Singer, Michael A %A Richmond, Todd A %A Munn, Kyle J %A Rada-Iglesias, Alvaro %A Wallerman, Ola %A Komorowski, Jan %A Fowler, Joanna C %A Couttet, Phillippe %A Bruce, Alexander W %A Dovey, Oliver M %A Ellis, Peter D %A Langford, Cordelia F %A Nix, David A %A Euskirchen, Ghia %A Hartman, Stephen %A Urban, Alexander E %A Kraus, Peter %A Van Calcar, Sara %A Heintzman, Nate %A Kim, Tae Hoon %A Wang, Kun %A Qu, Chunxu %A Hon, Gary %A Luna, Rosa %A Glass, Christopher K %A Rosenfeld, M Geoff %A Aldred, Shelley Force %A Cooper, Sara J %A Halees, Anason %A Lin, Jane M %A Shulha, Hennady P %A Zhang, Xiaoling %A Xu, Mousheng %A Haidar, Jaafar N S %A Yu, Yong %A Ruan, Yijun %A Iyer, Vishwanath R %A Green, Roland D %A Wadelius, Claes %A Farnham, Peggy J %A Ren, Bing %A Harte, Rachel A %A Hinrichs, Angie S %A Trumbower, Heather %A Clawson, Hiram %A Hillman-Jackson, Jennifer %A Zweig, Ann S %A Smith, Kayla %A Thakkapallayil, Archana %A Barber, Galt %A Kuhn, Robert M %A Karolchik, Donna %A Armengol, Lluis %A Bird, Christine P %A de Bakker, Paul I W %A Kern, Andrew D %A Lopez-Bigas, Nuria %A Martin, Joel D %A Stranger, Barbara E %A Woodroffe, Abigail %A Davydov, Eugene %A Dimas, Antigone %A Eyras, Eduardo %A Hallgrímsdóttir, Ingileif B %A Huppert, Julian %A Zody, Michael C %A Abecasis, Gonçalo R %A Estivill, Xavier %A Bouffard, Gerard G %A Guan, Xiaobin %A Hansen, Nancy F %A Idol, Jacquelyn R %A Maduro, Valerie V B %A Maskeri, Baishali %A McDowell, Jennifer C %A Park, Morgan %A Thomas, Pamela J %A Young, Alice C %A Blakesley, Robert W %A Muzny, Donna M %A Sodergren, Erica %A Wheeler, David A %A Worley, Kim C %A Jiang, Huaiyang %A Weinstock, George M %A Gibbs, Richard A %A Graves, Tina %A Fulton, Robert %A Mardis, Elaine R %A Wilson, Richard K %A Clamp, Michele %A Cuff, James %A Gnerre, Sante %A Jaffe, David B %A Chang, Jean L %A Lindblad-Toh, Kerstin %A Lander, Eric S %A Koriabine, Maxim %A Nefedov, Mikhail %A Osoegawa, Kazutoyo %A Yoshinaga, Yuko %A Zhu, Baoli %A De Jong, Pieter J %K Chromatin %K Chromatin Immunoprecipitation %K Conserved Sequence %K DNA Replication %K Evolution, Molecular %K Exons %K Genetic Variation %K Genome, Human %K Genomics %K Heterozygote %K Histones %K Humans %K Pilot Projects %K Protein Binding %K Regulatory Sequences, Nucleic Acid %K RNA, Messenger %K RNA, Untranslated %K Transcription Factors %K Transcription Initiation Site %K Transcription, Genetic %X

We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.

%B Nature %V 447 %P 799-816 %8 2007 Jun 14 %G eng %N 7146 %1 https://www.ncbi.nlm.nih.gov/pubmed/17571346?dopt=Abstract %R 10.1038/nature05874