%0 Journal Article %J Science %D 2012 %T A systematic survey of loss-of-function variants in human protein-coding genes. %A MacArthur, Daniel G %A Balasubramanian, Suganthi %A Frankish, Adam %A Huang, Ni %A Morris, James %A Walter, Klaudia %A Jostins, Luke %A Habegger, Lukas %A Pickrell, Joseph K %A Montgomery, Stephen B %A Albers, Cornelis A %A Zhang, Zhengdong D %A Conrad, Donald F %A Lunter, Gerton %A Zheng, Hancheng %A Ayub, Qasim %A DePristo, Mark A %A Banks, Eric %A Hu, Min %A Handsaker, Robert E %A Rosenfeld, Jeffrey A %A Fromer, Menachem %A Jin, Mike %A Mu, Xinmeng Jasmine %A Khurana, Ekta %A Ye, Kai %A Kay, Mike %A Saunders, Gary Ian %A Suner, Marie-Marthe %A Hunt, Toby %A Barnes, If H A %A Amid, Clara %A Carvalho-Silva, Denise R %A Bignell, Alexandra H %A Snow, Catherine %A Yngvadottir, Bryndis %A Bumpstead, Suzannah %A Cooper, David N %A Xue, Yali %A Romero, Irene Gallego %A Wang, Jun %A Li, Yingrui %A Gibbs, Richard A %A McCarroll, Steven A %A Dermitzakis, Emmanouil T %A Pritchard, Jonathan K %A Barrett, Jeffrey C %A Harrow, Jennifer %A Hurles, Matthew E %A Gerstein, Mark B %A Tyler-Smith, Chris %K Disease %K Gene Expression %K Gene Frequency %K Genetic Variation %K Genome, Human %K Humans %K Phenotype %K Polymorphism, Single Nucleotide %K Proteins %K Selection, Genetic %X

Genome-sequencing studies indicate that all humans carry many genetic variants predicted to cause loss of function (LoF) of protein-coding genes, suggesting unexpected redundancy in the human genome. Here we apply stringent filters to 2951 putative LoF variants obtained from 185 human genomes to determine their true prevalence and properties. We estimate that human genomes typically contain ~100 genuine LoF variants with ~20 genes completely inactivated. We identify rare and likely deleterious LoF alleles, including 26 known and 21 predicted severe disease-causing variants, as well as common LoF variants in nonessential genes. We describe functional and evolutionary differences between LoF-tolerant and recessive disease genes and a method for using these differences to prioritize candidate genes found in clinical sequencing studies.

%B Science %V 335 %P 823-8 %8 2012 Feb 17 %G eng %N 6070 %1 https://www.ncbi.nlm.nih.gov/pubmed/22344438?dopt=Abstract %R 10.1126/science.1215040 %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 Donna M Muzny %A Sodergren, Erica %A Wheeler, David A %A Worley, Kim C %A Jiang, Huaiyang %A Weinstock, George M %A Richard A Gibbs %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 %0 Journal Article %J Nature %D 2005 %T The DNA sequence of the human X chromosome. %A Ross, Mark T %A Grafham, Darren V %A Coffey, Alison J %A Steven E Scherer %A McLay, Kirsten %A Donna M Muzny %A Platzer, Matthias %A Howell, Gareth R %A Burrows, Christine %A Bird, Christine P %A Frankish, Adam %A Lovell, Frances L %A Howe, Kevin L %A Ashurst, Jennifer L %A Fulton, Robert S %A Sudbrak, Ralf %A Wen, Gaiping %A Jones, Matthew C %A Hurles, Matthew E %A Andrews, T Daniel %A Scott, Carol E %A Searle, Stephen %A Ramser, Juliane %A Whittaker, Adam %A Deadman, Rebecca %A Carter, Nigel P %A Hunt, Sarah E %A Rui Chen %A Cree, Andrew %A Gunaratne, Preethi %A Havlak, Paul %A Hodgson, Anne %A Metzker, Michael L %A Stephen Richards %A Scott, Graham %A Steffen, David %A Sodergren, Erica %A David A Wheeler %A Kim C Worley %A Ainscough, Rachael %A Ambrose, Kerrie D %A Ansari-Lari, M Ali %A Aradhya, Swaroop %A Ashwell, Robert I S %A Babbage, Anne K %A Bagguley, Claire L %A Ballabio, Andrea %A Banerjee, Ruby %A Barker, Gary E %A Barlow, Karen F %A Barrett, Ian P %A Bates, Karen N %A Beare, David M %A Beasley, Helen %A Beasley, Oliver %A Beck, Alfred %A Bethel, Graeme %A Blechschmidt, Karin %A Brady, Nicola %A Bray-Allen, Sarah %A Bridgeman, Anne M %A Brown, Andrew J %A Brown, Mary J %A Bonnin, David %A Bruford, Elspeth A %A Buhay, Christian %A Burch, Paula %A Burford, Deborah %A Burgess, Joanne %A Burrill, Wayne %A Burton, John %A Bye, Jackie M %A Carder, Carol %A Carrel, Laura %A Chako, Joseph %A Chapman, Joanne C %A Chavez, Dean %A Chen, Ellson %A Chen, Guan %A Chen, Yuan %A Chen, Zhijian %A Chinault, Craig %A Ciccodicola, Alfredo %A Clark, Sue Y %A Clarke, Graham %A Clee, Chris M %A Clegg, Sheila %A Clerc-Blankenburg, Kerstin %A Clifford, Karen %A Cobley, Vicky %A Cole, Charlotte G %A Conquer, Jen S %A Corby, Nicole %A Connor, Richard E %A David, Robert %A Davies, Joy %A Davis, Clay %A Davis, John %A Delgado, Oliver %A Deshazo, Denise %A Dhami, Pawandeep %A Ding, Yan %A Dinh, Huyen %A Dodsworth, Steve %A Draper, Heather %A Dugan-Rocha, Shannon %A Dunham, Andrew %A Dunn, Matthew %A Durbin, K James %A Dutta, Ireena %A Eades, Tamsin %A Ellwood, Matthew %A Emery-Cohen, Alexandra %A Errington, Helen %A Evans, Kathryn L %A Faulkner, Louisa %A Francis, Fiona %A Frankland, John %A Fraser, Audrey E %A Galgoczy, Petra %A Gilbert, James %A Gill, Rachel %A Glöckner, Gernot %A Gregory, Simon G %A Gribble, Susan %A Griffiths, Coline %A Grocock, Russell %A Gu, Yanghong %A Gwilliam, Rhian %A Hamilton, Cerissa %A Hart, Elizabeth A %A Hawes, Alicia %A Heath, Paul D %A Heitmann, Katja %A Hennig, Steffen %A Hernandez, Judith %A Hinzmann, Bernd %A Ho, Sarah %A Hoffs, Michael %A Howden, Phillip J %A Huckle, Elizabeth J %A Hume, Jennifer %A Hunt, Paul J %A Hunt, Adrienne R %A Isherwood, Judith %A Jacob, Leni %A Johnson, David %A Jones, Sally %A De Jong, Pieter J %A Joseph, Shirin S %A Keenan, Stephen %A Kelly, Susan %A Kershaw, Joanne K %A Ziad Khan %A Kioschis, Petra %A Klages, Sven %A Knights, Andrew J %A Kosiura, Anna %A Kovar-Smith, Christie %A Laird, Gavin K %A Langford, Cordelia %A Lawlor, Stephanie %A Leversha, Margaret %A Lewis, Lora %A Liu, Wen %A Lloyd, Christine %A Lloyd, David M %A Loulseged, Hermela %A Loveland, Jane E %A Lovell, Jamieson D %A Lozado, Ryan %A Lu, Jing %A Lyne, Rachael %A Ma, Jie %A Maheshwari, Manjula %A Matthews, Lucy H %A McDowall, Jennifer %A McLaren, Stuart %A McMurray, Amanda %A Meidl, Patrick %A Meitinger, Thomas %A Milne, Sarah %A Miner, George %A Mistry, Shailesh L %A Morgan, Margaret %A Morris, Sidney %A Müller, Ines %A Mullikin, James C %A Nguyen, Ngoc %A Nordsiek, Gabriele %A Nyakatura, Gerald %A O'Dell, Christopher N %A Okwuonu, Geoffery %A Palmer, Sophie %A Pandian, Richard %A Parker, David %A Parrish, Julia %A Pasternak, Shiran %A Patel, Dina %A Pearce, Alex V %A Pearson, Danita M %A Pelan, Sarah E %A Perez, Lesette %A Porter, Keith M %A Ramsey, Yvonne %A Reichwald, Kathrin %A Rhodes, Susan %A Ridler, Kerry A %A Schlessinger, David %A Schueler, Mary G %A Sehra, Harminder K %A Shaw-Smith, Charles %A Shen, Hua %A Sheridan, Elizabeth M %A Shownkeen, Ratna %A Skuce, Carl D %A Smith, Michelle L %A Sotheran, Elizabeth C %A Steingruber, Helen E %A Steward, Charles A %A Storey, Roy %A Swann, R Mark %A Swarbreck, David %A Tabor, Paul E %A Taudien, Stefan %A Taylor, Tineace %A Teague, Brian %A Thomas, Karen %A Thorpe, Andrea %A Timms, Kirsten %A Tracey, Alan %A Trevanion, Steve %A Tromans, Anthony C %A d'Urso, Michele %A Verduzco, Daniel %A Villasana, Donna %A Waldron, Lenée %A Wall, Melanie %A Wang, Qiaoyan %A Warren, James %A Warry, Georgina L %A Wei, Xuehong %A West, Anthony %A Whitehead, Siobhan L %A Whiteley, Mathew N %A Wilkinson, Jane E %A Willey, David L %A Williams, Gabrielle %A Williams, Leanne %A Williamson, Angela %A Williamson, Helen %A Wilming, Laurens %A Woodmansey, Rebecca L %A Wray, Paul W %A Yen, Jennifer %A Zhang, Jingkun %A Zhou, Jianling %A Zoghbi, Huda %A Zorilla, Sara %A Buck, David %A Reinhardt, Richard %A Poustka, Annemarie %A Rosenthal, André %A Lehrach, Hans %A Meindl, Alfons %A Minx, Patrick J %A Hillier, LaDeana W %A Willard, Huntington F %A Wilson, Richard K %A Waterston, Robert H %A Rice, Catherine M %A Vaudin, Mark %A Coulson, Alan %A Nelson, David L %A Weinstock, George %A Sulston, John E %A Durbin, Richard %A Hubbard, Tim %A Richard A Gibbs %A Beck, Stephan %A Rogers, Jane %A Bentley, David R %K Animals %K Antigens, Neoplasm %K Centromere %K Chromosomes, Human, X %K Chromosomes, Human, Y %K Contig Mapping %K Crossing Over, Genetic %K Dosage Compensation, Genetic %K Evolution, Molecular %K Female %K Genetic Linkage %K Genetics, Medical %K Genomics %K Humans %K Male %K Polymorphism, Single Nucleotide %K Repetitive Sequences, Nucleic Acid %K RNA %K Sequence Analysis, DNA %K Sequence Homology, Nucleic Acid %K Testis %X

The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence.

%B Nature %V 434 %P 325-37 %8 2005 Mar 17 %G eng %N 7031 %1 https://www.ncbi.nlm.nih.gov/pubmed/15772651?dopt=Abstract %R 10.1038/nature03440