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1. Political Party-Free Representation System: Indonesia’s Possibility for State Philosophy Approach

Author

Al Ghozali Hide, W. Imam, Handayani, I Gusti Ayu Ketut Rahmi, Anom, Djatmiko, Striełkowski, Wadim, Editor-in-Chief, Black, Jessica M., Series Editor, Butterfield, Stephen A., Series Editor, Chang, Chi-Cheng, Series Editor, Cheng, Jiuqing, Series Editor, Dumanig, Francisco Perlas, Series Editor, Al-Mabuk, Radhi, Series Editor, Scheper-Hughes, Nancy, Series Editor, Urban, Mathias, Series Editor, Webb, Stephen, Series Editor, Jaelani, Abdul Kadir, editor, Irwansyah, Irwansyah, editor, Fernhout, Fokke, editor, Raharjo, Agus, editor, Palil, Mohd Rizal, editor, Tegnan, Hilaire, editor, Parama Astirin, Okid, editor, Sutarno, Sutarno, editor, Suryanti, Venty, editor, Pranoto, Pranoto, editor, and Rahim, Robbi, editor

Published
2024
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3. The Transcriptional Landscape of the Mammalian Genome

Author

Carninci, P., Kasukawa, T., Katayama, S., Gough, J., Frith, M. C., Maeda, N., Oyama, R., Ravasi, T., Lenhard, B., Wells, C., Kodzius, R., Shimokawa, K., Bajic, V. B., Brenner, S. E., Batalov, S., Forrest, A. R. R., Zavolan, M., Davis, M. J., Wilming, L. G., Aidinis, V., Allen, J. E., Ambesi-Impiombato, A., Apweiler, R., Aturaliya, R. N., Bailey, T. L., Bansal, M., Baxter, L., Beisel, K. W., Bersano, T., Bono, H., Chalk, A. M., Chiu, K. P., Choudhary, V., Christoffels, A., Clutterbuck, D. R., Crowe, M. L., Dalla, E., Dalrymple, B. P., de Bono, B., Della Gatta, G., di Bernardo, D., Down, T., Engstrom, P., Fagiolini, M., Faulkner, G., Fletcher, C. F., Fukushima, T., Furuno, M., Futaki, S., Gariboldi, M., Georgii-Hemming, P., Gingeras, T. R., Gojobori, T., Green, R. E., Gustincich, S., Harbers, M., Hayashi, Y., Hensch, T. K., Hirokawa, N., Hill, D., Huminiecki, L., Iacono, M., Ikeo, K., Iwama, A., Ishikawa, T., Jakt, M., Kanapin, A., Katoh, M., Kawasawa, Y., Kelso, J., Kitamura, H., Kitano, H., Kollias, G., Krishnan, S. P. T., Kruger, A., Kummerfeld, S. K., Kurochkin, I. V., Lareau, L. F., Lazarevic, D., Lipovich, L., Liu, J., Liuni, S., McWilliam, S., Babu, M. Madan, Madera, M., Marchionni, L., Matsuda, H., Matsuzawa, S., Miki, H., Mignone, F., Miyake, S., Morris, K., Mottagui-Tabar, S., Mulder, N., Nakano, N., Nakauchi, H., Ng, P., Nilsson, R., Nishiguchi, S., Nishikawa, S., Nori, F., Ohara, O., Okazaki, Y., Orlando, V., Pang, K. C., Pavan, W. J., Pavesi, G., Pesole, G., Petrovsky, N., Piazza, S., Reed, J., Reid, J. F., Ring, B. Z., Ringwald, M., Rost, B., Ruan, Y., Salzberg, S. L., Sandelin, A., Schneider, C., Schöbach, C., Sekiguchi, K., Semple, C. A. M., Seno, S., Sessa, L., Sheng, Y., Shibata, Y., Shimada, H., Shimada, K., Silva, D., Sinclair, B., Sperling, S., Stupka, E., Sugiura, K., Sultana, R., Takenaka, Y., Taki, K., Tammoja, K., Tan, S. L., Tang, S., Taylor, M. S., Tegner, J., Teichmann, S. A., Ueda, H. R., van Nimwegen, E., Verardo, R., Wei, C. L., Yagi, K., Yamanishi, H., Zabarovsky, E., Zhu, S., Zimmer, A., Hide, W., Bult, C., Grimmond, S. M., Teasdale, R. D., Liu, E. T., Brusic, V., Quackenbush, J., Wahlestedt, C., Mattick, J. S., Hume, D. A., Kai, C., Sasaki, D., Tomaru, Y., Fukuda, S., Kanamori-Katayama, M., Suzuki, M., Aoki, J., Arakawa, T., Iida, J., Imamura, K., Itoh, M., Kato, T., Kawaji, H., Kawagashira, N., Kawashima, T., Kojima, M., Kondo, S., Konno, H., Nakano, K., Ninomiya, N., Nishio, T., Okada, M., Plessy, C., Shibata, K., Shiraki, T., Suzuki, S., Tagami, M., Waki, K., Watahiki, A., Okamura-Oho, Y., Suzuki, H., and Kawai, J.

Published
2005

7. Discovery of widespread transcription initiation at microsatellites predictable by sequence-based deep neural network

Author

Grapotte M., Saraswat M., Bessiere C., Menichelli C., Ramilowski J. A., Severin J., Hayashizaki Y., Itoh M., Tagami M., Murata M., Kojima-Ishiyama M., Noma S., Noguchi S., Kasukawa T., Hasegawa A., Suzuki H., Nishiyori-Sueki H., Frith M. C., Abugessaisa I., Aitken S., Aken B. L., Alam I., Alam T., Alasiri R., Alhendi A. M. N., Alinejad-Rokny H., Alvarez M. J., Andersson R., Arakawa T., Araki M., Arbel T., Archer J., Archibald A. L., Arner E., Arner P., Asai K., Ashoor H., Astrom G., Babina M., Baillie J. K., Bajic V. B., Bajpai A., Baker S., Baldarelli R. M., Balic A., Bansal M., Batagov A. O., Batzoglou S., Beckhouse A. G., Beltrami A. P., Beltrami C. A., Bertin N., Bhattacharya S., Bickel P. J., Blake J. A., Blanchette M., Bodega B., Bonetti A., Bono H., Bornholdt J., Bttcher M., Bougouffa S., Boyd M., Breda J., Brombacher F., Brown J. B., Bult C. J., Burroughs A. M., Burt D. W., Busch A., Caglio G., Califano A., Cameron C. J., Cannistraci C. V., Carbone A., Carlisle A. J., Carninci P., Carter K. W., Cesselli D., Chang J. -C., Chen J. C., Chen Y., Chierici M., Christodoulou J., Ciani Y., Clark E. L., Coskun M., Dalby M., Dalla E., Daub C. O., Davis C. A., de Hoon M. J. L., de Rie D., Denisenko E., Deplancke B., Detmar M., Deviatiiarov R., Di Bernardo D., Diehl A. D., Dieterich L. C., Dimont E., Djebali S., Dohi T., Dostie J., Drablos F., Edge A. S. B., Edinger M., Ehrlund A., Ekwall K., Elofsson A., Endoh M., Enomoto H., Enomoto S., Faghihi M., Fagiolini M., Farach-Carson M. C., Faulkner G. J., Favorov A., Fernandes A. M., Ferrai C., Forrest A. R. R., Forrester L. M., Forsberg M., Fort A., Francescatto M., Freeman T. C., Frith M., Fukuda S., Funayama M., Furlanello C., Furuno M., Furusawa C., Gao H., Gazova I., Gebhard C., Geier F., Geijtenbeek T. B. H., Ghosh S., Ghosheh Y., Gingeras T. R., Gojobori T., Goldberg T., Goldowitz D., Gough J., Greco D., Gruber A. J., Guhl S., Guigo R., Guler R., Gusev O., Gustincich S., Ha T. J., Haberle V., Hale P., Hallstrom B. M., Hamada M., Handoko L., Hara M., Harbers M., Harrow J., Harshbarger J., Hase T., Hashimoto K., Hatano T., Hattori N., Hayashi R., Herlyn M., Hettne K., Heutink P., Hide W., Hitchens K. J., Sui S. H., 't Hoen P. A. C., Hon C. C., Hori F., Horie M., Horimoto K., Horton P., Hou R., Huang E., Huang Y., Hugues R., Hume D., Ienasescu H., Iida K., Ikawa T., Ikemura T., Ikeo K., Inoue N., Ishizu Y., Ito Y., Ivshina A. V., Jankovic B. R., Jenjaroenpun P., Johnson R., Jorgensen M., Jorjani H., Joshi A., Jurman G., Kaczkowski B., Kai C., Kaida K., Kajiyama K., Kaliyaperumal R., Kaminuma E., Kanaya T., Kaneda H., Kapranov P., Kasianov A. S., Katayama T., Kato S., Kawaguchi S., Kawai J., Kawaji H., Kawamoto H., Kawamura Y. I., Kawasaki S., Kawashima T., Kempfle J. S., Kenna T. J., Kere J., Khachigian L., Kiryu H., Kishima M., Kitajima H., Kitamura T., Kitano H., Klaric E., Klepper K., Klinken S. P., Kloppmann E., Knox A. J., Kodama Y., Kogo Y., Kojima M., Kojima S., Komatsu N., Komiyama H., Kono T., Koseki H., Koyasu S., Kratz A., Kukalev A., Kulakovskiy I., Kundaje A., Kunikata H., Kuo R., Kuo T., Kuraku S., Kuznetsov V. A., Kwon T. J., Larouche M., Lassmann T., Law A., Le-Cao K. -A., Lecellier C. -H., Lee W., Lenhard B., Lennartsson A., Li K., Li R., Lilje B., Lipovich L., Lizio M., Lopez G., Magi S., Mak G. K., Makeev V., Manabe R., Mandai M., Mar J., Maruyama K., Maruyama T., Mason E., Mathelier A., Matsuda H., Medvedeva Y. A., Meehan T. F., Mejhert N., Meynert A., Mikami N., Minoda A., Miura H., Miyagi Y., Miyawaki A., Mizuno Y., Morikawa H., Morimoto M., Morioka M., Morishita S., Moro K., Motakis E., Motohashi H., Mukarram A. K., Mummery C. L., Mungall C. J., Murakawa Y., Muramatsu M., Nagasaka K., Nagase T., Nakachi Y., Nakahara F., Nakai K., Nakamura K., Nakamura Y., Nakazawa T., Nason G. P., Nepal C., Nguyen Q. H., Nielsen L. K., Nishida K., Nishiguchi K. M., Nishiyori H., Nitta K., Notredame C., Ogishima S., Ohkura N., Ohno H., Ohshima M., Ohtsu T., Okada Y., Okada-Hatakeyama M., Okazaki Y., Oksvold P., Orlando V., Ow G. S., Ozturk M., Pachkov M., Paparountas T., Parihar S. P., Park S. -J., Pascarella G., Passier R., Persson H., Philippens I. H., Piazza S., Plessy C., Pombo A., Ponten F., Poulain S., Poulsen T. M., Pradhan S., Prezioso C., Pridans C., Qin X. -Y., Quackenbush J., Rackham O., Ramilowski J., Ravasi T., Rehli M., Rennie S., Rito T., Rizzu P., Robert C., Roos M., Rost B., Roudnicky F., Roy R., Rye M. B., Sachenkova O., Saetrom P., Sai H., Saiki S., Saito M., Saito A., Sakaguchi S., Sakai M., Sakaue S., Sakaue-Sawano A., Sandelin A., Sano H., Sasamoto Y., Sato H., Saxena A., Saya H., Schafferhans A., Schmeier S., Schmidl C., Schmocker D., Schneider C., Schueler M., Schultes E. A., Schulze-Tanzil G., Semple C. A., Seno S., Seo W., Sese J., Sheng G., Shi J., Shimoni Y., Shin J. W., SimonSanchez J., Sivertsson A., Sjostedt E., Soderhall C., Laurent G. S., Stoiber M. H., Sugiyama D., Summers K. M., Suzuki A. M., Suzuki K., Suzuki M., Suzuki N., Suzuki T., Swanson D. J., Swoboda R. K., Taguchi A., Takahashi H., Takahashi M., Takamochi K., Takeda S., Takenaka Y., Tam K. T., Tanaka H., Tanaka R., Tanaka Y., Tang D., Taniuchi I., Tanzer A., Tarui H., Taylor M. S., Terada A., Terao Y., Testa A. C., Thomas M., Thongjuea S., Tomii K., Triglia E. T., Toyoda H., Tsang H. G., Tsujikawa M., Uhlen M., Valen E., van de Wetering M., van Nimwegen E., Velmeshev D., Verardo R., Vitezic M., Vitting-Seerup K., von Feilitzen K., Voolstra C. R., Vorontsov I. E., Wahlestedt C., Wasserman W. W., Watanabe K., Watanabe S., Wells C. A., Winteringham L. N., Wolvetang E., Yabukami H., Yagi K., Yamada T., Yamaguchi Y., Yamamoto M., Yamamoto Y., Yamanaka Y., Yano K., Yasuzawa K., Yatsuka Y., Yo M., Yokokura S., Yoneda M., Yoshida E., Yoshida Y., Yoshihara M., Young R., Young R. S., Yu N. Y., Yumoto N., Zabierowski S. E., Zhang P. G., Zucchelli S., Zwahlen M., Chatelain C., Brehelin L., Grapotte, M., Saraswat, M., Bessiere, C., Menichelli, C., Ramilowski, J. A., Severin, J., Hayashizaki, Y., Itoh, M., Tagami, M., Murata, M., Kojima-Ishiyama, M., Noma, S., Noguchi, S., Kasukawa, T., Hasegawa, A., Suzuki, H., Nishiyori-Sueki, H., Frith, M. C., Abugessaisa, I., Aitken, S., Aken, B. L., Alam, I., Alam, T., Alasiri, R., Alhendi, A. M. N., Alinejad-Rokny, H., Alvarez, M. J., Andersson, R., Arakawa, T., Araki, M., Arbel, T., Archer, J., Archibald, A. L., Arner, E., Arner, P., Asai, K., Ashoor, H., Astrom, G., Babina, M., Baillie, J. K., Bajic, V. B., Bajpai, A., Baker, S., Baldarelli, R. M., Balic, A., Bansal, M., Batagov, A. O., Batzoglou, S., Beckhouse, A. G., Beltrami, A. P., Beltrami, C. A., Bertin, N., Bhattacharya, S., Bickel, P. J., Blake, J. A., Blanchette, M., Bodega, B., Bonetti, A., Bono, H., Bornholdt, J., Bttcher, M., Bougouffa, S., Boyd, M., Breda, J., Brombacher, F., Brown, J. B., Bult, C. J., Burroughs, A. M., Burt, D. W., Busch, A., Caglio, G., Califano, A., Cameron, C. J., Cannistraci, C. V., Carbone, A., Carlisle, A. J., Carninci, P., Carter, K. W., Cesselli, D., Chang, J. -C., Chen, J. C., Chen, Y., Chierici, M., Christodoulou, J., Ciani, Y., Clark, E. L., Coskun, M., Dalby, M., Dalla, E., Daub, C. O., Davis, C. A., de Hoon, M. J. L., de Rie, D., Denisenko, E., Deplancke, B., Detmar, M., Deviatiiarov, R., Di Bernardo, D., Diehl, A. D., Dieterich, L. C., Dimont, E., Djebali, S., Dohi, T., Dostie, J., Drablos, F., Edge, A. S. B., Edinger, M., Ehrlund, A., Ekwall, K., Elofsson, A., Endoh, M., Enomoto, H., Enomoto, S., Faghihi, M., Fagiolini, M., Farach-Carson, M. C., Faulkner, G. J., Favorov, A., Fernandes, A. M., Ferrai, C., Forrest, A. R. R., Forrester, L. M., Forsberg, M., Fort, A., Francescatto, M., Freeman, T. C., Frith, M., Fukuda, S., Funayama, M., Furlanello, C., Furuno, M., Furusawa, C., Gao, H., Gazova, I., Gebhard, C., Geier, F., Geijtenbeek, T. B. H., Ghosh, S., Ghosheh, Y., Gingeras, T. R., Gojobori, T., Goldberg, T., Goldowitz, D., Gough, J., Greco, D., Gruber, A. J., Guhl, S., Guigo, R., Guler, R., Gusev, O., Gustincich, S., Ha, T. J., Haberle, V., Hale, P., Hallstrom, B. M., Hamada, M., Handoko, L., Hara, M., Harbers, M., Harrow, J., Harshbarger, J., Hase, T., Hashimoto, K., Hatano, T., Hattori, N., Hayashi, R., Herlyn, M., Hettne, K., Heutink, P., Hide, W., Hitchens, K. J., Sui, S. H., 't Hoen, P. A. C., Hon, C. C., Hori, F., Horie, M., Horimoto, K., Horton, P., Hou, R., Huang, E., Huang, Y., Hugues, R., Hume, D., Ienasescu, H., Iida, K., Ikawa, T., Ikemura, T., Ikeo, K., Inoue, N., Ishizu, Y., Ito, Y., Ivshina, A. V., Jankovic, B. R., Jenjaroenpun, P., Johnson, R., Jorgensen, M., Jorjani, H., Joshi, A., Jurman, G., Kaczkowski, B., Kai, C., Kaida, K., Kajiyama, K., Kaliyaperumal, R., Kaminuma, E., Kanaya, T., Kaneda, H., Kapranov, P., Kasianov, A. S., Katayama, T., Kato, S., Kawaguchi, S., Kawai, J., Kawaji, H., Kawamoto, H., Kawamura, Y. I., Kawasaki, S., Kawashima, T., Kempfle, J. S., Kenna, T. J., Kere, J., Khachigian, L., Kiryu, H., Kishima, M., Kitajima, H., Kitamura, T., Kitano, H., Klaric, E., Klepper, K., Klinken, S. P., Kloppmann, E., Knox, A. J., Kodama, Y., Kogo, Y., Kojima, M., Kojima, S., Komatsu, N., Komiyama, H., Kono, T., Koseki, H., Koyasu, S., Kratz, A., Kukalev, A., Kulakovskiy, I., Kundaje, A., Kunikata, H., Kuo, R., Kuo, T., Kuraku, S., Kuznetsov, V. A., Kwon, T. J., Larouche, M., Lassmann, T., Law, A., Le-Cao, K. -A., Lecellier, C. -H., Lee, W., Lenhard, B., Lennartsson, A., Li, K., Li, R., Lilje, B., Lipovich, L., Lizio, M., Lopez, G., Magi, S., Mak, G. K., Makeev, V., Manabe, R., Mandai, M., Mar, J., Maruyama, K., Maruyama, T., Mason, E., Mathelier, A., Matsuda, H., Medvedeva, Y. A., Meehan, T. F., Mejhert, N., Meynert, A., Mikami, N., Minoda, A., Miura, H., Miyagi, Y., Miyawaki, A., Mizuno, Y., Morikawa, H., Morimoto, M., Morioka, M., Morishita, S., Moro, K., Motakis, E., Motohashi, H., Mukarram, A. K., Mummery, C. L., Mungall, C. J., Murakawa, Y., Muramatsu, M., Nagasaka, K., Nagase, T., Nakachi, Y., Nakahara, F., Nakai, K., Nakamura, K., Nakamura, Y., Nakazawa, T., Nason, G. P., Nepal, C., Nguyen, Q. H., Nielsen, L. K., Nishida, K., Nishiguchi, K. M., Nishiyori, H., Nitta, K., Notredame, C., Ogishima, S., Ohkura, N., Ohno, H., Ohshima, M., Ohtsu, T., Okada, Y., Okada-Hatakeyama, M., Okazaki, Y., Oksvold, P., Orlando, V., Ow, G. S., Ozturk, M., Pachkov, M., Paparountas, T., Parihar, S. P., Park, S. -J., Pascarella, G., Passier, R., Persson, H., Philippens, I. H., Piazza, S., Plessy, C., Pombo, A., Ponten, F., Poulain, S., Poulsen, T. M., Pradhan, S., Prezioso, C., Pridans, C., Qin, X. -Y., Quackenbush, J., Rackham, O., Ramilowski, J., Ravasi, T., Rehli, M., Rennie, S., Rito, T., Rizzu, P., Robert, C., Roos, M., Rost, B., Roudnicky, F., Roy, R., Rye, M. B., Sachenkova, O., Saetrom, P., Sai, H., Saiki, S., Saito, M., Saito, A., Sakaguchi, S., Sakai, M., Sakaue, S., Sakaue-Sawano, A., Sandelin, A., Sano, H., Sasamoto, Y., Sato, H., Saxena, A., Saya, H., Schafferhans, A., Schmeier, S., Schmidl, C., Schmocker, D., Schneider, C., Schueler, M., Schultes, E. A., Schulze-Tanzil, G., Semple, C. A., Seno, S., Seo, W., Sese, J., Sheng, G., Shi, J., Shimoni, Y., Shin, J. W., Simonsanchez, J., Sivertsson, A., Sjostedt, E., Soderhall, C., Laurent, G. S., Stoiber, M. H., Sugiyama, D., Summers, K. M., Suzuki, A. M., Suzuki, K., Suzuki, M., Suzuki, N., Suzuki, T., Swanson, D. J., Swoboda, R. K., Taguchi, A., Takahashi, H., Takahashi, M., Takamochi, K., Takeda, S., Takenaka, Y., Tam, K. T., Tanaka, H., Tanaka, R., Tanaka, Y., Tang, D., Taniuchi, I., Tanzer, A., Tarui, H., Taylor, M. S., Terada, A., Terao, Y., Testa, A. C., Thomas, M., Thongjuea, S., Tomii, K., Triglia, E. T., Toyoda, H., Tsang, H. G., Tsujikawa, M., Uhlen, M., Valen, E., van de Wetering, M., van Nimwegen, E., Velmeshev, D., Verardo, R., Vitezic, M., Vitting-Seerup, K., von Feilitzen, K., Voolstra, C. R., Vorontsov, I. E., Wahlestedt, C., Wasserman, W. W., Watanabe, K., Watanabe, S., Wells, C. A., Winteringham, L. N., Wolvetang, E., Yabukami, H., Yagi, K., Yamada, T., Yamaguchi, Y., Yamamoto, M., Yamamoto, Y., Yamanaka, Y., Yano, K., Yasuzawa, K., Yatsuka, Y., Yo, M., Yokokura, S., Yoneda, M., Yoshida, E., Yoshida, Y., Yoshihara, M., Young, R., Young, R. S., Yu, N. Y., Yumoto, N., Zabierowski, S. E., Zhang, P. G., Zucchelli, S., Zwahlen, M., Chatelain, C., Brehelin, L., Institute of Biotechnology, Biosciences, Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Computationnelle (IBC), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Méthodes et Algorithmes pour la Bioinformatique (MAB), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier (LIRMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), National Institute of Advanced Industrial Science and Technology (AIST), SANOFI Recherche, University of British Columbia (UBC), Experimental Immunology, Infectious diseases, AII - Infectious diseases, Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Montpellier (UM)

Subjects
0301 basic medicine, General Physics and Astronomy, Genome, Mice, 0302 clinical medicine, Transcription (biology), Promoter Regions, Genetic, Transcription Initiation, Genetic, 0303 health sciences, Multidisciplinary, 1184 Genetics, developmental biology, physiology, High-Throughput Nucleotide Sequencing, Neurodegenerative Diseases, 222 Other engineering and technologies, Genomics, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], humanities, Enhancer Elements, Genetic, Microsatellite Repeat, Transcription Initiation Site, Sequence motif, Transcription Initiation, Human, Enhancer Elements, Neural Networks, Science, 610 Medicine & health, Computational biology, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Promoter Regions, 03 medical and health sciences, Computer, Deep Learning, Tandem repeat, Genetic, Clinical Research, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Machine learning, Genetics, Animals, Humans, Polymorphism, Enhancer, Transcriptomics, Gene, A549 Cell, 030304 developmental biology, Polymorphism, Genetic, Neurodegenerative Disease, Base Sequence, Animal, Genome, Human, Human Genome, Computational Biology, Promoter, General Chemistry, 113 Computer and information sciences, Cap analysis gene expression, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Cardiovascular and Metabolic Diseases, A549 Cells, Minion, Generic health relevance, 3111 Biomedicine, Neural Networks, Computer, 610 Medizin und Gesundheit, 030217 neurology & neurosurgery, FANTOM consortium, Microsatellite Repeats
Abstract

Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism., Nature Communications, 12 (1), ISSN:2041-1723

Published
2020
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9. Whole-genome sequencing reveals new Alzheimer's disease-associated rare variants in loci related to synaptic function and neuronal development

Author

Prokopenko, D., Morgan, S.L., Mullin, K., Hofmann, O., Chapman, B., Kirchner, R., Amberkar, S., Wohlers, I., Lange, C., Hide, W., Bertram, L., and Tanzi, R.E.

Abstract

Introduction\ud \ud Genome-wide association studies have led to numerous genetic loci associated with Alzheimer's disease (AD). Whole-genome sequencing (WGS) now permits genome-wide analyses to identify rare variants contributing to AD risk.\ud \ud \ud \ud Methods\ud \ud We performed single-variant and spatial clustering–based testing on rare variants (minor allele frequency [MAF] ≤1%) in a family-based WGS-based association study of 2247 subjects from 605 multiplex AD families, followed by replication in 1669 unrelated individuals.\ud \ud \ud \ud Results\ud \ud We identified 13 new AD candidate loci that yielded consistent rare-variant signals in discovery and replication cohorts (4 from single-variant, 9 from spatial-clustering), implicating these genes: FNBP1L, SEL1L, LINC00298, PRKCH, C15ORF41, C2CD3, KIF2A, APC, LHX9, NALCN, CTNNA2, SYTL3, and CLSTN2.\ud \ud \ud \ud Discussion\ud \ud Downstream analyses of these novel loci highlight synaptic function, in contrast to common AD-associated variants, which implicate innate immunity and amyloid processing. These loci have not been associated previously with AD, emphasizing the ability of WGS to identify AD-associated rare variants, particularly outside of the exome.

Published
2021

10. Whole-genome sequencing reveals new Alzheimer's disease-associated rare variants in loci related to synaptic function and neuronal development

Author

Prokopenko, D, Morgan, SL, Mullin, K, Hofmann, O, Chapman, B, Kirchner, R, Amberkar, S, Wohlers, I, Lange, C, Hide, W, Bertram, L, Tanzi, RE, Prokopenko, D, Morgan, SL, Mullin, K, Hofmann, O, Chapman, B, Kirchner, R, Amberkar, S, Wohlers, I, Lange, C, Hide, W, Bertram, L, and Tanzi, RE

Abstract

INTRODUCTION: Genome-wide association studies have led to numerous genetic loci associated with Alzheimer's disease (AD). Whole-genome sequencing (WGS) now permits genome-wide analyses to identify rare variants contributing to AD risk. METHODS: We performed single-variant and spatial clustering-based testing on rare variants (minor allele frequency [MAF] ≤1%) in a family-based WGS-based association study of 2247 subjects from 605 multiplex AD families, followed by replication in 1669 unrelated individuals. RESULTS: We identified 13 new AD candidate loci that yielded consistent rare-variant signals in discovery and replication cohorts (4 from single-variant, 9 from spatial-clustering), implicating these genes: FNBP1L, SEL1L, LINC00298, PRKCH, C15ORF41, C2CD3, KIF2A, APC, LHX9, NALCN, CTNNA2, SYTL3, and CLSTN2. DISCUSSION: Downstream analyses of these novel loci highlight synaptic function, in contrast to common AD-associated variants, which implicate innate immunity and amyloid processing. These loci have not been associated previously with AD, emphasizing the ability of WGS to identify AD-associated rare variants, particularly outside of the exome.

Published
2021

11. Identification of Novel Alzheimer's Disease Loci Using Sex-Specific Family-Based Association Analysis of Whole-Genome Sequence Data

Author

Prokopenko, D, Hecker, J, Kirchner, R, Chapman, BA, Hoffman, O, Mullin, K, Hide, W, Bertram, L, Laird, N, DeMeo, DL, Lange, C, Tanzi, RE, Prokopenko, D, Hecker, J, Kirchner, R, Chapman, BA, Hoffman, O, Mullin, K, Hide, W, Bertram, L, Laird, N, DeMeo, DL, Lange, C, and Tanzi, RE

Abstract

With the advent of whole genome-sequencing (WGS) studies, family-based designs enable sex-specific analysis approaches that can be applied to only affected individuals; tests using family-based designs are attractive because they are completely robust against the effects of population substructure. These advantages make family-based association tests (FBATs) that use siblings as well as parents especially suited for the analysis of late-onset diseases such as Alzheimer's Disease (AD). However, the application of FBATs to assess sex-specific effects can require additional filtering steps, as sensitivity to sequencing errors is amplified in this type of analysis. Here, we illustrate the implementation of robust analysis approaches and additional filtering steps that can minimize the chances of false positive-findings due to sex-specific sequencing errors. We apply this approach to two family-based AD datasets and identify four novel loci (GRID1, RIOK3, MCPH1, ZBTB7C) showing sex-specific association with AD risk. Following stringent quality control filtering, the strongest candidate is ZBTB7C (Pinter = 1.83 × 10-7), in which the minor allele of rs1944572 confers increased risk for AD in females and protection in males. ZBTB7C encodes the Zinc Finger and BTB Domain Containing 7C, a transcriptional repressor of membrane metalloproteases (MMP). Members of this MMP family were implicated in AD neuropathology.

Published
2020

12. Project MinE: study design and pilot analyses of a large-scale whole-genome sequencing study in amyotrophic lateral sclerosis

Author

Project, M.A.S.C., van Rheenen, W., Pulit, S.L., Dekker, A.M., Al Khleifat, A., Brands, W.J., Iacoangeli, A., Kenna, K.P., Kavak, E., Kooyman, M., McLaughlin, R.L., Middelkoop, B., Moisse, M., Schellevis, R.D., Shatunov, A., Sproviero, W., Tazelaar, G.H.P., van der Spek, R.A.A., van Doormaal, P.T.C., van Eijk, K.R., van Vugt, J., Basak, A.N., Blair, I.P., Glass, J.D., Hardiman, O., Hide, W., Landers, J.E., Mora, J.S., Morrison, K.E., Newhouse, S., Robberecht, W., Shaw, C.E., Shaw, P.J., van Damme, P., van Es, M.A., Wray, N.R., Al-Chalabi, A., van Den Berg, L.H., and Veldink, J.H.

Abstract

The most recent genome-wide association study in amyotrophic lateral sclerosis (ALS) demonstrates a disproportionate contribution from low-frequency variants to genetic susceptibility to disease. We have therefore begun Project MinE, an international collaboration that seeks to analyze whole-genome sequence data of at least 15 000 ALS patients and 7500 controls. Here, we report on the design of Project MinE and pilot analyses of successfully sequenced 1169 ALS patients and 608 controls drawn from the Netherlands. As has become characteristic of sequencing studies, we find an abundance of rare genetic variation (minor allele frequency < 0.1%), the vast majority of which is absent in public datasets. Principal component analysis reveals local geographical clustering of these variants within The Netherlands. We use the whole-genome sequence data to explore the implications of poor geographical matching of cases and controls in a sequence-based disease study and to investigate how ancestry-matched, externally sequenced controls can induce false positive associations. Also, we have publicly released genome-wide minor allele counts in cases and controls, as well as results from genic burden tests.

Published
2018

15. The H-Invitational Database (H-InvDB), a comprehensive annotation resource for human genes and transcripts

Author

Yamasaki, C., Murakami, K., Fujii, Y., Sato, Y., Harada, E., Takeda, J., Taniya, T., Sakate, R., Kikugawa, S., Shimada, M., Tanino, M., Koyanagi, K.O., Barrero, R.A., Gough, C., Chun, H., Habara, T., Hanaoka, H., Hayakawa, Y., Hilton, P.B., Kaneko, Y., Kanno, M., Kawahara, Y., Kawamura, T., Matsuya, A., Nagata, N., Nishikata, K., Noda, A.O., Nurimoto, S., Saichi, N., Sakai, H., Sanbonmatsu, R., Shiba, R., Suzuki, M., Takabayashi, K., Takahashi, A., Tamura, T., Tanaka, M., Tanaka, S., Todokoro, F., Yamaguchi, K., Yamamoto, N., Okido, T., Mashima, J., Hashizume, A., Jin, L., Lee, K., Lin, Y., Nozaki, A., Sakai, K., Tada, M., Miyazaki, S., Makino, T., Ohyanagi, H., Osato, N., Tanaka, N., Suzuki, Y., Ikeo, K., Saitou, N., Sugawara, H., O'Donovan, C., Kulikova, T., Whitfield, E., Halligan, B., Shimoyama, M., Twigger, S., Yura, K., Kimura, K., Yasuda, T., Nishikawa, T., Akiyama, Y., Motono, C., Mukai, Y., Nagasaki, H., Suwa, M., Horton, P., Kikuno, R., Ohara, O., Lancet, D., Eveno, E., Graudens, E., Imbeaud, S., Debily, M., Hayashizaki, Y., Amid, C., Han, M., Osanger, A., Endo, T., Thomas, M.A., Hirakawa, M., Makalowski, W., Nakao, M., Kim, N., Yoo, H., de Souza, S.J., Bonaldo, M.D.F., Niimura, Y., Kuryshev, V., Schupp, I., Wiemann, S., Bellgard, M., Shionyu, M., Jia, L., Thierry-Mieg, D., Thierry-Mieg, J., Wagner, L., Zhang, Q., Go, M., Minoshima, S., Ohtsubo, M., Hanada, K., Tonellato, P., Isogai, T., Zhang, J., Lenhard, B., Kim, S., Chen, Z., Hinz, U., Estreicher, A., Nakai, K., Makalowska, I., Hide, W., Tiffin, N., Wilming, L., Chakraborty, R., Soares, M.B., Chiusano, M.L., Auffray, C., Yamaguchi-Kabata, Y., Itoh, T., Hishiki, T., Fukuchi, S., Nishikawa, K., Sugano, S., Nomura, N., Tateno, Y., Imanishi, T., Gojobori, T., Genexpress, Centre National de la Recherche Scientifique (CNRS), Yamasaki, C., Murakami, K., Fujii, Y., Sato, Y., Harada, E., Takeda, J., Taniya, T., Sakate, R., Kikugawa, S., Shimada, M., Tanino, M., Koyanagi, K. O., Barrero, R. A., Gough, C., Chun, H. W., Habara, T., Hanaoka, H., Hayakawa, Y., Hilton, P. B., Kaneko, Y., Kanno, M., Kawahara, Y., Kawamura, T., Matsuya, A., Nagata, N., Nishikata, K., Noda, A. O., Nurimoto, S., Saichi, N., Sakai, H., Sanbonmatsu, R., Shiba, R., Suzuki, M., Takabayashi, K., Takahashi, A., Tamura, T., Tanaka, M., Tanaka, S., Todokoro, F., Yamaguchi, K., Yamamoto, N., Okido, T., Mashima, J., Hashizume, A., Jin, L., Lee, K. B., Lin, Y. C., Nozaki, A., Sakai, K., Tada, M., Miyazaki, S., Makino, T., Ohyanagi, H., Osato, N., Tanaka, N., Suzuki, Y., Ikeo, K., Saitou, N., Sugawara, H., Odonovan, C., Kulikova, T., Whitfield, E., Halligan, B., Shimoyama, M., Twigger, S., Yura, K., Kimura, K., Yasuda, T., Nishikawa, T., Akiyama, Y., Motono, C., Mukai, Y., Nagasaki, H., Suwa, M., Horton, P., Kikuno, R., Ohara, O., Lancet, D., Eveno, E., Graudens, E., Imbeaud, S., Debily, M. A., Hayashizaki, Y., Amid, C., Han, M., Osanger, A., Endo, T., Thomas, M. A., Hirakawa, M., Makalowski, W., Nakao, M., Kim, N. S., Yoo, H. S., De Souza, S. J., Bonaldo Mde, F., Niimura, Y., Kuryshev, V., Schupp, I., Wiemann, S., Bellgard, M., Shionyu, M., Jia, L., Thierry Mieg, D., Thierry Mieg, J., Wagner, L., Zhang, Q., Go, M., Minoshima, S., Ohtsubo, M., Hanada, K., Tonellato, P., Isogai, T., Zhang, J., Lenhard, B., Kim, S., Chen, Z., Hinz, U., Estreicher, A., Nakai, K., Makalowska, I., Hide, W., Tiffin, N., Wilming, L., Chakraborty, R., Soares, M. B., Chiusano, MARIA LUISA, Auffray, C., Yamaguchi Kabata, Y., Itoh, T., Hishiki, T., Fukuchi, S., Nishikawa, K., Sugano, S., Nomura, N., Tateno, Y., Imanishi, T., and Gojobori, T.

Subjects
DNA, Complementary, [SDV]Life Sciences [q-bio], Pseudogene, Locus (genetics), Biology, computer.software_genre, User-Computer Interface, 03 medical and health sciences, Annotation, 0302 clinical medicine, Databases, Genetic, Genetics, Animals, Humans, Gene family, RNA, Messenger, Gene, database, 030304 developmental biology, Internet, 0303 health sciences, Human genome, Database, Alternative splicing, Chromosome Mapping, Proteins, Articles, Gene expression profiling, Genes, transcriptome, computer, 030217 neurology & neurosurgery
Abstract

International audience; Here we report the new features and improvements in our latest release of the H-Invitational Database (H-InvDB; http://www.h-invitational.jp/), a comprehensive annotation resource for human genes and transcripts. H-InvDB, originally developed as an integrated database of the human transcriptome based on extensive annotation of large sets of full-length cDNA (FLcDNA) clones, now provides annotation for 120 558 human mRNAs extracted from the International Nucleotide Sequence Databases (INSD), in addition to 54 978 human FLcDNAs, in the latest release H-InvDB_4.6. We mapped those human transcripts onto the human genome sequences (NCBI build 36.1) and determined 34 699 human gene clusters, which could define 34 057 (98.1%) protein-coding and 642 (1.9%) non-protein-coding loci; 858 (2.5%) transcribed loci overlapped with predicted pseudogenes. For all these transcripts and genes, we provide comprehensive annotation including gene structures, gene functions, alternative splicing variants, functional non-protein-coding RNAs, functional domains, predicted sub cellular localizations, metabolic pathways, predictions of protein 3D structure, mapping of SNPs and microsatellite repeat motifs, co-localization with orphan diseases, gene expression profiles, orthologous genes, protein-protein interactions (PPI) and annotation for gene families. The current H-InvDB annotation resources consist of two main views: Transcript view and Locus view and eight sub-databases: the DiseaseInfo Viewer, H-ANGEL, the Clustering Viewer, G-integra, the TOPO Viewer, Evola, the PPI view and the Gene family/group.

Published
2007
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16. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Author

Nicolas, A, Kenna, K, Renton, A, Ticozzi, N, Faghri, F, Chia, R, Dominov, J, Kenna, B, Nalls, M, Keagle, P, Rivera, A, van Rheenen, W, Murphy, N, van Vugt, J, Geiger, J, van der Spek, R, Pliner, H, Shankaracharya, N, Smith, B, Marangi, G, Topp, S, Abramzon, Y, Gkazi, A, Eicher, J, Kenna, A, Logullo, F, Simone, I, Logroscino, G, Salvi, F, Bartolomei, I, Borghero, G, Murru, M, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, M, Floris, G, Cannas, A, Capasso, M, Caponnetto, C, Mancardi, G, Origone, P, Mandich, P, Conforti, F, Cavallaro, S, Mora, G, Marinou, K, Sideri, R, Penco, S, Mosca, L, Lunetta, C, Pinter, G, Corbo, M, Riva, N, Carrera, P, Volanti, P, Mandrioli, J, Fini, N, Fasano, A, Tremolizzo, L, Arosio, A, Ferrarese, C, Trojsi, F, Tedeschi, G, Monsurrò, M, Piccirillo, G, Femiano, C, Ticca, A, Ortu, E, La Bella, V, Spataro, R, Colletti, T, Sabatelli, M, Zollino, M, Conte, A, Luigetti, M, Lattante, S, Santarelli, M, Petrucci, A, Pugliatti, M, Pirisi, A, Parish, L, Occhineri, P, Giannini, F, Battistini, S, Ricci, C, Benigni, M, Cau, T, Loi, D, Calvo, A, Moglia, C, Brunetti, M, Barberis, M, Restagno, G, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Canosa, A, Ilardi, A, Manera, U, Grassano, M, Tanel, R, Pisano, F, Mazzini, L, Messina, S, D'Alfonso, S, Corrado, L, Ferrucci, L, Harms, M, Goldstein, D, Shneider, N, Goutman, S, Simmons, Z, Miller, T, Chandran, S, Pal, S, Manousakis, G, Appel, S, Simpson, E, Wang, L, Baloh, R, Gibson, S, Bedlack, R, Lacomis, D, Sareen, D, Sherman, A, Bruijn, L, Penny, M, Moreno, C, Kamalakaran, S, Allen, A, Boone, B, Brown, R, Carulli, J, Chesi, A, Chung, W, Cirulli, E, Cooper, G, Couthouis, J, Day-Williams, A, Dion, P, Gitler, A, Glass, J, Han, Y, Harris, T, Hayes, S, Jones, A, Keebler, J, Krueger, B, Lasseigne, B, Levy, S, Lu, Y, Maniatis, T, McKenna-Yasek, D, Myers, R, Petrovski, S, Pulst, S, Raphael, A, Ravits, J, Ren, Z, Rouleau, G, Sapp, P, Sims, K, Staropoli, J, Waite, L, Wang, Q, Wimbish, J, Xin, W, Phatnani, H, Kwan, J, Broach, J, Arcila-Londono, X, Lee, E, Van Deerlin, V, Fraenkel, E, Ostrow, L, Baas, F, Zaitlen, N, Berry, J, Malaspina, A, Fratta, P, Cox, G, Thompson, L, Finkbeiner, S, Dardiotis, E, Hornstein, E, Macgowan, D, Heiman-Patterson, T, Hammell, M, Patsopoulos, N, Dubnau, J, Nath, A, Musunuri, R, Evani, U, Abhyankar, A, Zody, M, Kaye, J, Wyman, S, Lenail, A, Lima, L, Rothstein, J, Svendsen, C, Van Eyk, J, Maragakis, N, Kolb, S, Cudkowicz, M, Baxi, E, Benatar, M, Taylor, J, Wu, G, Rampersaud, E, Wuu, J, Rademakers, R, Züchner, S, Schule, R, Mccauley, J, Hussain, S, Cooley, A, Wallace, M, Clayman, C, Barohn, R, Statland, J, Swenson, A, Jackson, C, Trivedi, J, Khan, S, Katz, J, Jenkins, L, Burns, T, Gwathmey, K, Caress, J, Mcmillan, C, Elman, L, Pioro, E, Heckmann, J, So, Y, Walk, D, Maiser, S, Zhang, J, Silani, V, Gellera, C, Ratti, A, Taroni, F, Lauria, G, Verde, F, Fogh, I, Tiloca, C, Comi, G, Sorarù, G, Cereda, C, De Marchi, F, Corti, S, Ceroni, M, Siciliano, G, Filosto, M, Inghilleri, M, Peverelli, S, Colombrita, C, Poletti, B, Maderna, L, Del Bo, R, Gagliardi, S, Querin, G, Bertolin, C, Pensato, V, Castellotti, B, Camu, W, Mouzat, K, Lumbroso, S, Corcia, P, Meininger, V, Besson, G, Lagrange, E, Clavelou, P, Guy, N, Couratier, P, Vourch, P, Danel, V, Bernard, E, Lemasson, G, Laaksovirta, H, Myllykangas, L, Jansson, L, Valori, M, Ealing, J, Hamdalla, H, Rollinson, S, Pickering-Brown, S, Orrell, R, Sidle, K, Hardy, J, Singleton, A, Johnson, J, Arepalli, S, Polak, M, Asress, S, Al-Sarraj, S, King, A, Troakes, C, Vance, C, de Belleroche, J, ten Asbroek, A, Muñoz-Blanco, J, Hernandez, D, Ding, J, Gibbs, J, Scholz, S, Floeter, M, Campbell, R, Landi, F, Bowser, R, Kirby, J, Pamphlett, R, Gerhard, G, Dunckley, T, Brady, C, Kowall, N, Troncoso, J, Le Ber, I, Kamel, F, Van Den Bosch, L, Strom, T, Meitinger, T, Shatunov, A, Van Eijk, K, de Carvalho, M, Kooyman, M, Middelkoop, B, Moisse, M, Mclaughlin, R, Van Es, M, Weber, M, Boylan, K, Van Blitterswijk, M, Morrison, K, Basak, A, Mora, J, Drory, V, Shaw, P, Turner, M, Talbot, K, Hardiman, O, Williams, K, Fifita, J, Nicholson, G, Blair, I, Esteban-Pérez, J, García-Redondo, A, Al-Chalabi, A, Al Kheifat, A, Andersen, P, Chio, A, Cooper-Knock, J, Dekker, A, Redondo, A, Gotkine, M, Hide, W, Iacoangeli, A, Kiernan, M, Landers, J, Mill, J, Neto, M, Pardina, J, Newhouse, S, Pinto, S, Pulit, S, Robberecht, W, Shaw, C, Sproviero, W, Tazelaar, G, van Damme, P, van den Berg, L, van Eijk, K, van Es, M, Veldink, J, Zatz, M, Bauer, D, Twine, N, Rogaeva, E, Zinman, L, Brice, A, Feldman, E, Ludolph, A, Weishaupt, J, Trojanowski, J, Stone, D, Tienari, P, Chiò, A, Traynor, B, Nicolas, Aude, Kenna, Kevin P., Renton, Alan E., Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A., Kenna, Brendan J., Nalls, Mike A., Keagle, Pamela, Rivera, Alberto M., van Rheenen, Wouter, Murphy, Natalie A., van Vugt, Joke J. F. A., Geiger, Joshua T., van der Spek, Rick, Pliner, Hannah A., Shankaracharya, null, Smith, Bradley N., Marangi, Giuseppe, Topp, Simon D., Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D., Kenna, Aoife, Logullo, Francesco O., Simone, Isabella, Logroscino, Giancarlo, Salvi, Fabrizio, Bartolomei, Ilaria, Borghero, Giuseppe, Murru, Maria Rita, Costantino, Emanuela, Pani, Carla, Puddu, Roberta, Caredda, Carla, Piras, Valeria, Tranquilli, Stefania, Cuccu, Stefania, Corongiu, Daniela, Melis, Maurizio, Milia, Antonio, Marrosu, Francesco, Marrosu, Maria Giovanna, Floris, Gianluca, Cannas, Antonino, Capasso, Margherita, Caponnetto, Claudia, Mancardi, Gianluigi, Origone, Paola, Mandich, Paola, Conforti, Francesca L., Cavallaro, Sebastiano, Mora, Gabriele, Marinou, Kalliopi, Sideri, Riccardo, Penco, Silvana, Mosca, Lorena, Lunetta, Christian, Pinter, Giuseppe Lauria, Corbo, Massimo, Riva, Nilo, Carrera, Paola, Volanti, Paolo, Mandrioli, Jessica, Fini, Nicola, Fasano, Antonio, Tremolizzo, Lucio, Arosio, Alessandro, Ferrarese, Carlo, Trojsi, Francesca, Tedeschi, Gioacchino, Monsurrò, Maria Rosaria, Piccirillo, Giovanni, Femiano, Cinzia, Ticca, Anna, Ortu, Enzo, La Bella, Vincenzo, Spataro, Rossella, Colletti, Tiziana, Sabatelli, Mario, Zollino, Marcella, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Santarelli, Marialuisa, Petrucci, Antonio, Pugliatti, Maura, Pirisi, Angelo, Parish, Leslie D., Occhineri, Patrizia, Giannini, Fabio, Battistini, Stefania, Ricci, Claudia, Benigni, Michele, Cau, Tea B., Loi, Daniela, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Barberis, Marco, Restagno, Gabriella, Casale, Federico, Marrali, Giuseppe, Fuda, Giuseppe, Ossola, Irene, Cammarosano, Stefania, Canosa, Antonio, Ilardi, Antonio, Manera, Umberto, Grassano, Maurizio, Tanel, Raffaella, Pisano, Fabrizio, Mazzini, Letizia, Messina, Sonia, D'Alfonso, Sandra, Corrado, Lucia, Ferrucci, Luigi, Harms, Matthew B., Goldstein, David B., Shneider, Neil A., Goutman, Stephen, Simmons, Zachary, Miller, Timothy M., Chandran, Siddharthan, Pal, Suvankar, Manousakis, George, Appel, Stanley, Simpson, Ericka, Wang, Leo, Baloh, Robert H., Gibson, Summer, Bedlack, Richard S., Lacomis, David, Sareen, Dhruv, Sherman, Alexander, Bruijn, Lucie, Penny, Michelle, Moreno, Cristiane de Araujo Martins, Kamalakaran, Sitharthan, Allen, Andrew S., Boone, Braden E., Brown, Robert, Carulli, John P., Chesi, Alessandra, Chung, Wendy K., Cirulli, Elizabeth T., Cooper, Gregory M., Couthouis, Julien, Day-Williams, Aaron G., Dion, Patrick A., Gitler, Aaron D., Glass, Jonathan D., Han, Yujun, Harris, Tim, Hayes, Sebastian D., Jones, Angela L., Keebler, Jonathan, Krueger, Brian J., Lasseigne, Brittany N., Levy, Shawn E., Lu, Yi-Fan, Maniatis, Tom, McKenna-Yasek, Diane, Myers, Richard M., Petrovski, Slavé, Pulst, Stefan M., Raphael, Alya R., Ravits, John M., Ren, Zhong, Rouleau, Guy A., Sapp, Peter C., Sims, Katherine B., Staropoli, John F., Waite, Lindsay L., Wang, Quanli, Wimbish, Jack R., Xin, Winnie W., Phatnani, Hemali, Kwan, Justin, Broach, James R., Arcila-Londono, Ximena, Lee, Edward B., Van Deerlin, Vivianna M., Fraenkel, Ernest, Ostrow, Lyle W., Baas, Frank, Zaitlen, Noah, Berry, James D., Malaspina, Andrea, Fratta, Pietro, Cox, Gregory A., Thompson, Leslie M., Finkbeiner, Steven, Dardiotis, Efthimios, Hornstein, Eran, MacGowan, Daniel J., Heiman-Patterson, Terry, Hammell, Molly G., Patsopoulos, Nikolaos A., Dubnau, Joshua, Nath, Avindra, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C., Kaye, Julia, Wyman, Stacia, LeNail, Alexander, Lima, Leandro, Rothstein, Jeffrey D., Svendsen, Clive N., Van Eyk, Jenny, Maragakis, Nicholas J., Kolb, Stephen J., Cudkowicz, Merit, Baxi, Emily, Wyman, Stacia K., Van Eyk, Jennifer E., Benatar, Michael, Taylor, J. Paul, Wu, Gang, Rampersaud, Evadnie, Wuu, Joanne, Rademakers, Rosa, Züchner, Stephan, Schule, Rebecca, McCauley, Jacob, Hussain, Sumaira, Cooley, Anne, Wallace, Marielle, Clayman, Christine, Barohn, Richard, Statland, Jeffrey, Ravits, John, Swenson, Andrea, Jackson, Carlayne, Trivedi, Jaya, Khan, Shaida, Katz, Jonathan, Jenkins, Liberty, Burns, Ted, Gwathmey, Kelly, Caress, James, McMillan, Corey, Elman, Lauren, Pioro, Erik, Heckmann, Jeannine, So, Yuen, Walk, David, Maiser, Samuel, Zhang, Jinghui, Silani, Vincenzo, Gellera, Cinzia, Ratti, Antonia, Taroni, Franco, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P., Sorarù, Gianni, Cereda, Cristina, De Marchi, Fabiola, Corti, Stefania, Ceroni, Mauro, Siciliano, Gabriele, Filosto, Massimiliano, Inghilleri, Maurizio, Peverelli, Silvia, Colombrita, Claudia, Poletti, Barbara, Maderna, Luca, Del Bo, Roberto, Gagliardi, Stella, Querin, Giorgia, Bertolin, Cinzia, Pensato, Viviana, Castellotti, Barbara, Camu, William, Mouzat, Kevin, Lumbroso, Serge, Corcia, Philippe, Meininger, Vincent, Besson, Gérard, Lagrange, Emmeline, Clavelou, Pierre, Guy, Nathalie, Couratier, Philippe, Vourch, Patrick, Danel, Véronique, Bernard, Emilien, Lemasson, Gwendal, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W., Sidle, Katie C., Hardy, John, Singleton, Andrew B., Johnson, Janel O., Arepalli, Sampath, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, ten Asbroek, Anneloor L. M. A., Muñoz-Blanco, José Luis, Hernandez, Dena G., Ding, Jinhui, Gibbs, J. Raphael, Scholz, Sonja W., Floeter, Mary Kay, Campbell, Roy H., Landi, Francesco, Bowser, Robert, MacGowan, Daniel J. L., Kirby, Janine, Pioro, Erik P., Pamphlett, Roger, Broach, James, Gerhard, Glenn, Dunckley, Travis L., Brady, Christopher B., Kowall, Neil W., Troncoso, Juan C., Le Ber, Isabelle, Heiman-Patterson, Terry D., Kamel, Freya, Van Den Bosch, Ludo, Strom, Tim M., Meitinger, Thomas, Shatunov, Aleksey, Van Eijk, Kristel R., de Carvalho, Mamede, Kooyman, Maarten, Middelkoop, Bas, Moisse, Mattieu, McLaughlin, Russell L., Van Es, Michael A., Weber, Markus, Boylan, Kevin B., Van Blitterswijk, Marka, Morrison, Karen E., Basak, A. 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Abstract

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS. Using a large-scale genome-wide association study and exome sequencing, we identified KIF5A as a novel gene associated with ALS. Our data broaden the phenotype resulting from mutations in KIF5A and highlight the importance of cytoskeletal defects in the pathogenesis of ALS.

Published
2018

17. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Author

Nicolas, A., Kenna, K. P., Renton, A. E., Ticozzi, N., Faghri, F., Chia, R., Dominov, J. A., Kenna, B. J., Nalls, M. A., Keagle, P., Rivera, A. M., van Rheenen, W., Murphy, N. A., van Vugt, J. J. F. A., Geiger, J. T., Van der Spek, R. A., Pliner, H. A., Shankaracharya, Smith, B. N., Marangi, Giuseppe, Topp, S. D., Abramzon, Y., Gkazi, A. S., Eicher, J. D., Kenna, A., Logullo, F. O., Simone, I. L., Logroscino, Giandomenico, Salvi, F., Bartolomei, I., Borghero, G., Murru, M. R., Costantino, E., Pani, C., Puddu, R., Caredda, C., Piras, V., Tranquilli, S., Cuccu, S., Corongiu, D., Melis, M., Milia, A., Marrosu, F., Marrosu, M. G., Floris, G., Cannas, A., Capasso, Monica, Caponnetto, C., Mancardi, G., Origone, P., Mandich, P., Conforti, F. L., Cavallaro, S., Mora, G., Marinou, K., Sideri, R., Penco, S., Mosca, Luigi, Lunetta, C., Pinter, G. L., Corbo, M., Riva, N., Carrera, P., Volanti, P., Mandrioli, J., Fini, N., Fasano, Alfonso, Tremolizzo, L., Arosio, A., Ferrarese, C., Trojsi, F., Tedeschi, G., Monsurro, M. R., Piccirillo, G., Femiano, C., Ticca, A., Ortu, E., La Bella, V., Spataro, R., Colletti, T., Sabatelli, Mario, Zollino, Marcella, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Santarelli, M., Petrucci, A., Pugliatti, M., Pirisi, A., Parish, L. D., Occhineri, P., Giannini, F., Battistini, S., Ricci, C., Benigni, M., Cau, T. B., Loi, D., Calvo, A., Moglia, C., Brunetti, M., Barberis, M., Restagno, G., Casale, F., Marrali, G., Fuda, G., Ossola, I., Cammarosano, S., Canosa, A., Ilardi, A., Manera, U., Grassano, M., Tanel, R., Pisano, F., Mazzini, L., Messina, S., D'Alfonso, Sandra, Corrado, L., Ferrucci, L., Harms, M. B., Goldstein, D. B., Shneider, N. A., Goutman, S. A., Simmons, Z., Miller, T. M., Chandran, S., Pal, S., Manousakis, G., Appel, S. H., Simpson, E., Wang, L., Baloh, R. H., Gibson, S. B., Bedlack, R., Lacomis, D., Sareen, D., Sherman, A., Bruijn, L., Penny, M., Moreno, C. D. A. M., Kamalakaran, S., Allen, A. S., Boone, B. E., Brown, R. H., Carulli, J. P., Chesi, A., Chung, W. K., Cirulli, E. T., Cooper, G. M., Couthouis, J., Day-Williams, A. G., Dion, P. A., Gitler, A. D., Glass, J. D., Han, Y., Harris, T., Hayes, S. D., Jones, A. L., Keebler, J., Krueger, B. J., Lasseigne, B. N., Levy, S. E., Lu, Y. -F., Maniatis, T., McKenna-Yasek, D., Myers, R. M., Petrovski, S., Pulst, S. M., Raphael, A. R., Ravits, J. M., Ren, Z., Rouleau, G. A., Sapp, P. C., Sims, K. B., Staropoli, J. F., Waite, L. L., Wang, Quanquan, Wimbish, J. R., Xin, W. W., Phatnani, H., Kwan, J., Broach, J., Arcila-Londono, X., Lee, E. B., Van Deerlin, V. M., Fraenkel, E., Ostrow, L. W., Baas, F., Zaitlen, N., Berry, J. D., Malaspina, A., Fratta, P., Cox, G. A., Thompson, L. M., Finkbeiner, S., Dardiotis, E., Hornstein, E., Macgowan, D. J. L., Heiman-Patterson, T., Hammell, M. G., Patsopoulos, N. A., Dubnau, J., Nath, A., Musunuri, R. L., Evani, U. S., Abhyankar, A., Zody, M. C., Kaye, J., Wyman, S. K., Lenail, A., Lima, L., Rothstein, J. D., Svendsen, C. N., Van Eyk, J. E., Maragakis, N. J., Kolb, S. J., Cudkowicz, M., Baxi, E., Benatar, M., Taylor, J. P., Wu, G., Rampersaud, E., Wuu, J., Rademakers, R., Zuchner, S., Schule, R., Mccauley, J., Hussain, S., Cooley, A., Wallace, M., Clayman, C., Barohn, R., Statland, J., Swenson, A., Jackson, C., Trivedi, J., Khan, S., Katz, J., Jenkins, L., Burns, T., Gwathmey, K., Caress, J., Mcmillan, C., Elman, L., Pioro, E. P., Heckmann, J., So, Y., Walk, D., Maiser, S., Zhang, J., Silani, V., Gellera, C., Ratti, A., Taroni, F., Lauria, G., Verde, F., Fogh, I., Tiloca, C., Comi, G. P., Soraru, G., Cereda, C., De Marchi, F., Corti, S., Ceroni, M., Siciliano, Giovanni, Filosto, M., Inghilleri, M., Peverelli, S., Colombrita, C., Poletti, B., Maderna, L., Del Bo, R., Gagliardi, S., Querin, G., Bertolin, C., Pensato, V., Castellotti, B., Camu, W., Mouzat, K., Lumbroso, S., Corcia, P., Meininger, V., Besson, G., Lagrange, E., Clavelou, P., Guy, N., Couratier, P., Vourch, P., Danel, V., Bernard, E., Lemasson, G., Laaksovirta, H., Myllykangas, L., Jansson, L., Valori, Vanna Maria, Ealing, J., Hamdalla, H., Rollinson, S., Pickering-Brown, S., Orrell, R. W., Sidle, K. C., Hardy, J., Singleton, A. B., Johnson, J. O., Arepalli, S., Polak, M., Asress, S., Al-Sarraj, S., King, A., Troakes, C., Vance, C., de Belleroche, J., ten Asbroek, A. L. M. A., Munoz-Blanco, J. L., Hernandez, D. G., Ding, J., Gibbs, J. R., Scholz, S. W., Floeter, M. K., Campbell, R. H., Landi, Francesco, Bowser, R., Kirby, J., Pamphlett, R., Gerhard, G., Dunckley, T. L., Brady, C. B., Kowall, N. W., Troncoso, J. C., Le Ber, I., Heiman-Patterson, T. D., Kamel, F., Van Den Bosch, L., Strom, T. M., Meitinger, T., Shatunov, A., Van Eijk, K. R., de Carvalho, M., Kooyman, M., Middelkoop, B., Moisse, M., Mclaughlin, R. L., Van Es, M. A., Weber, M., Boylan, K. B., Van Blitterswijk, M., Morrison, K. E., Basak, A. N., Mora, J. S., Drory, V. E., Shaw, P. J., Turner, M. R., Talbot, K., Hardiman, O., Williams, K. L., Fifita, J. A., Nicholson, G. A., Blair, I. P., Esteban-Perez, J., Garcia-Redondo, A., Al-Chalabi, A., Al Kheifat, A., Andersen, P. M., Chio, A., Cooper-Knock, J., Dekker, A., Redondo, A. G., Gotkine, M., Hide, W., Iacoangeli, A., Kiernan, M., Landers, J. E., Mill, J., Neto, M. M., Pardina, J. M., Newhouse, S., Pinto, S., Pulit, S., Robberecht, W., Shaw, C., Sproviero, W., Tazelaar, G., Van Damme, P., van den Berg, L. H., van Vugt, J., Veldink, J. H., Zatz, M., Bauer, D. C., Twine, N. A., Rogaeva, E., Zinman, L., Brice, A., Feldman, E. L., Ludolph, A. C., Weishaupt, J. H., Trojanowski, J. Q., Stone, D. J., Tienari, P., Shaw, C. E., Traynor, B. J., Marangi G. (ORCID:0000-0002-6898-8882), Logroscino G. (ORCID:0000-0003-1301-5343), Capasso M., Mosca L. (ORCID:0000-0003-4641-0841), Fasano A., Sabatelli M. (ORCID:0000-0001-6635-4985), Zollino M. (ORCID:0000-0003-4871-9519), Conte A., Luigetti M. (ORCID:0000-0001-7539-505X), Lattante S. (ORCID:0000-0003-2891-0340), D'Alfonso S., Siciliano G., Valori M., Landi F. (ORCID:0000-0002-3472-1389), Nicolas, A., Kenna, K. P., Renton, A. E., Ticozzi, N., Faghri, F., Chia, R., Dominov, J. A., Kenna, B. J., Nalls, M. A., Keagle, P., Rivera, A. M., van Rheenen, W., Murphy, N. A., van Vugt, J. J. F. A., Geiger, J. T., Van der Spek, R. A., Pliner, H. A., Shankaracharya, Smith, B. N., Marangi, Giuseppe, Topp, S. D., Abramzon, Y., Gkazi, A. S., Eicher, J. D., Kenna, A., Logullo, F. O., Simone, I. L., Logroscino, Giandomenico, Salvi, F., Bartolomei, I., Borghero, G., Murru, M. R., Costantino, E., Pani, C., Puddu, R., Caredda, C., Piras, V., Tranquilli, S., Cuccu, S., Corongiu, D., Melis, M., Milia, A., Marrosu, F., Marrosu, M. G., Floris, G., Cannas, A., Capasso, Monica, Caponnetto, C., Mancardi, G., Origone, P., Mandich, P., Conforti, F. L., Cavallaro, S., Mora, G., Marinou, K., Sideri, R., Penco, S., Mosca, Luigi, Lunetta, C., Pinter, G. L., Corbo, M., Riva, N., Carrera, P., Volanti, P., Mandrioli, J., Fini, N., Fasano, Alfonso, Tremolizzo, L., Arosio, A., Ferrarese, C., Trojsi, F., Tedeschi, G., Monsurro, M. R., Piccirillo, G., Femiano, C., Ticca, A., Ortu, E., La Bella, V., Spataro, R., Colletti, T., Sabatelli, Mario, Zollino, Marcella, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Santarelli, M., Petrucci, A., Pugliatti, M., Pirisi, A., Parish, L. D., Occhineri, P., Giannini, F., Battistini, S., Ricci, C., Benigni, M., Cau, T. B., Loi, D., Calvo, A., Moglia, C., Brunetti, M., Barberis, M., Restagno, G., Casale, F., Marrali, G., Fuda, G., Ossola, I., Cammarosano, S., Canosa, A., Ilardi, A., Manera, U., Grassano, M., Tanel, R., Pisano, F., Mazzini, L., Messina, S., D'Alfonso, Sandra, Corrado, L., Ferrucci, L., Harms, M. B., Goldstein, D. B., Shneider, N. A., Goutman, S. A., Simmons, Z., Miller, T. M., Chandran, S., Pal, S., Manousakis, G., Appel, S. H., Simpson, E., Wang, L., Baloh, R. H., Gibson, S. B., Bedlack, R., Lacomis, D., Sareen, D., Sherman, A., Bruijn, L., Penny, M., Moreno, C. D. A. M., Kamalakaran, S., Allen, A. S., Boone, B. E., Brown, R. H., Carulli, J. P., Chesi, A., Chung, W. K., Cirulli, E. T., Cooper, G. M., Couthouis, J., Day-Williams, A. G., Dion, P. A., Gitler, A. D., Glass, J. D., Han, Y., Harris, T., Hayes, S. D., Jones, A. L., Keebler, J., Krueger, B. J., Lasseigne, B. N., Levy, S. E., Lu, Y. -F., Maniatis, T., McKenna-Yasek, D., Myers, R. M., Petrovski, S., Pulst, S. M., Raphael, A. R., Ravits, J. M., Ren, Z., Rouleau, G. A., Sapp, P. C., Sims, K. B., Staropoli, J. F., Waite, L. L., Wang, Quanquan, Wimbish, J. R., Xin, W. W., Phatnani, H., Kwan, J., Broach, J., Arcila-Londono, X., Lee, E. B., Van Deerlin, V. M., Fraenkel, E., Ostrow, L. W., Baas, F., Zaitlen, N., Berry, J. D., Malaspina, A., Fratta, P., Cox, G. A., Thompson, L. M., Finkbeiner, S., Dardiotis, E., Hornstein, E., Macgowan, D. J. L., Heiman-Patterson, T., Hammell, M. G., Patsopoulos, N. A., Dubnau, J., Nath, A., Musunuri, R. L., Evani, U. S., Abhyankar, A., Zody, M. C., Kaye, J., Wyman, S. K., Lenail, A., Lima, L., Rothstein, J. D., Svendsen, C. N., Van Eyk, J. E., Maragakis, N. J., Kolb, S. J., Cudkowicz, M., Baxi, E., Benatar, M., Taylor, J. P., Wu, G., Rampersaud, E., Wuu, J., Rademakers, R., Zuchner, S., Schule, R., Mccauley, J., Hussain, S., Cooley, A., Wallace, M., Clayman, C., Barohn, R., Statland, J., Swenson, A., Jackson, C., Trivedi, J., Khan, S., Katz, J., Jenkins, L., Burns, T., Gwathmey, K., Caress, J., Mcmillan, C., Elman, L., Pioro, E. P., Heckmann, J., So, Y., Walk, D., Maiser, S., Zhang, J., Silani, V., Gellera, C., Ratti, A., Taroni, F., Lauria, G., Verde, F., Fogh, I., Tiloca, C., Comi, G. P., Soraru, G., Cereda, C., De Marchi, F., Corti, S., Ceroni, M., Siciliano, Giovanni, Filosto, M., Inghilleri, M., Peverelli, S., Colombrita, C., Poletti, B., Maderna, L., Del Bo, R., Gagliardi, S., Querin, G., Bertolin, C., Pensato, V., Castellotti, B., Camu, W., Mouzat, K., Lumbroso, S., Corcia, P., Meininger, V., Besson, G., Lagrange, E., Clavelou, P., Guy, N., Couratier, P., Vourch, P., Danel, V., Bernard, E., Lemasson, G., Laaksovirta, H., Myllykangas, L., Jansson, L., Valori, Vanna Maria, Ealing, J., Hamdalla, H., Rollinson, S., Pickering-Brown, S., Orrell, R. W., Sidle, K. C., Hardy, J., Singleton, A. B., Johnson, J. O., Arepalli, S., Polak, M., Asress, S., Al-Sarraj, S., King, A., Troakes, C., Vance, C., de Belleroche, J., ten Asbroek, A. L. M. A., Munoz-Blanco, J. L., Hernandez, D. G., Ding, J., Gibbs, J. R., Scholz, S. W., Floeter, M. K., Campbell, R. H., Landi, Francesco, Bowser, R., Kirby, J., Pamphlett, R., Gerhard, G., Dunckley, T. L., Brady, C. B., Kowall, N. W., Troncoso, J. C., Le Ber, I., Heiman-Patterson, T. D., Kamel, F., Van Den Bosch, L., Strom, T. M., Meitinger, T., Shatunov, A., Van Eijk, K. R., de Carvalho, M., Kooyman, M., Middelkoop, B., Moisse, M., Mclaughlin, R. L., Van Es, M. A., Weber, M., Boylan, K. B., Van Blitterswijk, M., Morrison, K. E., Basak, A. N., Mora, J. S., Drory, V. E., Shaw, P. J., Turner, M. R., Talbot, K., Hardiman, O., Williams, K. L., Fifita, J. A., Nicholson, G. A., Blair, I. P., Esteban-Perez, J., Garcia-Redondo, A., Al-Chalabi, A., Al Kheifat, A., Andersen, P. M., Chio, A., Cooper-Knock, J., Dekker, A., Redondo, A. G., Gotkine, M., Hide, W., Iacoangeli, A., Kiernan, M., Landers, J. E., Mill, J., Neto, M. M., Pardina, J. M., Newhouse, S., Pinto, S., Pulit, S., Robberecht, W., Shaw, C., Sproviero, W., Tazelaar, G., Van Damme, P., van den Berg, L. H., van Vugt, J., Veldink, J. H., Zatz, M., Bauer, D. C., Twine, N. A., Rogaeva, E., Zinman, L., Brice, A., Feldman, E. L., Ludolph, A. C., Weishaupt, J. H., Trojanowski, J. Q., Stone, D. J., Tienari, P., Shaw, C. E., Traynor, B. J., Marangi G. (ORCID:0000-0002-6898-8882), Logroscino G. (ORCID:0000-0003-1301-5343), Capasso M., Mosca L. (ORCID:0000-0003-4641-0841), Fasano A., Sabatelli M. (ORCID:0000-0001-6635-4985), Zollino M. (ORCID:0000-0003-4871-9519), Conte A., Luigetti M. (ORCID:0000-0001-7539-505X), Lattante S. (ORCID:0000-0003-2891-0340), D'Alfonso S., Siciliano G., Valori M., and Landi F. (ORCID:0000-0002-3472-1389)

Abstract

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS. Using a large-scale genome-wide association study and exome sequencing, we identified KIF5A as a novel gene associated with ALS. Our data broaden the phenotype resulting from mutations in KIF5A and highlight the importance of cytoskeletal defects in the pathogenesis of ALS.

Published
2018

18. Integrated Genomic Analysis of Diverse Induced Pluripotent Stem Cells from the Progenitor Cell Biology Consor tium

Author

Salomonis, N., Dexheimer, P.J., Omberg, L., Schroll, R., Bush, S., Huo, J., Schriml, L., Ho Sui, S., Keddache, M., Mayhew, C., Shanmukhappa, S.K., Wells, J., Daily, K., Hubler, S., Wang, Y., Zambidis, E., Margolin, A., Hide, W., Hatzopoulos, A.K., Malik, P., Cancelas, J.A., Aronow, B.J., and Lutzko, C.

Abstract

The rigorous characterization of distinct induced pluripotent stem cells (iPSC) derived from multiple reprogramming technologies,\ud somatic sources, and donors is required to understand potential sources of variability and downstream potential. To achieve this goal,\ud the Progenitor Cell Biology Consortium performed comprehensive experimental and genomic analyses of 58 iPSC from ten laboratories\ud generated using a variety of reprogramming genes, vectors, and cells. Associated global molecular characterization studies identified functionally\ud informative correlations in gene expression, DNA methylation, and/or copy-number variation among key developmental and\ud oncogenic regulators as a result of donor, sex, line stability, reprogramming technology, and cell of origin. Furthermore, X-chromosome\ud inactivation in PSC produced highly correlated differences in teratoma-lineage staining and regulator expression upon differentiation.\ud All experimental results, and raw, processed, and metadata from these analyses, including powerful tools, are interactively accessible\ud from a new online portal at https://www.synapse.org to serve as a reusable resource for the stem cell community.

Published
2016

21. The statistical geometry of transcriptome divergence in cell-type evolution and cancer

Author

Liang, C, Alam, I, Albanese, D, Altschuler, G, Andersson, R, Arakawa, T, Archer, J, Arner, E, Arner, P, Babina, M, Baillie, K, Bajic, V, Baker, S, Balic, A, Balwierz, P, Beckhouse, A, Bertin, N, Blake, Ja, Blumenthal, A, Bodega, B, Bonetti, A, Briggs, J, Brombacher, F, Burroughs, M, Califano, A, Cannistraci, C, Carbajo, D, Carninci, P, Chen, Yang, Chierici, M, Ciani, Y, Clevers, H, Dalla, Emiliano, Daub, C, Davis, C, De Hoon, M, De Lima Morais, D, Dermar, M, Diehl, A, Dimont, E, Dohl, T, Drabros, F, Edge, A, Edinger, M, Ekwall, K, Endoh, M, Enomoto, H, Fagiolini, M, Fairbairn, L, Fang, H, Farach Carson, Mc, Faulkner, G, Favorov, A, Fisher, M, Forrest, A, Francescatto, M, Freeman, T, Frith, M, Fujita, R, Fukuda, S, Furlanello, C, Furuno, M, Furusawa, J, Geijtenbeek, Tb, Gibson, A, Gingeras, T, Goldowithz, D, Gough, J, Guhl, S, Guler, R, Gustincich, Stefano, Ha, T, Haberle, V, Hamaguchi, M, Hara, M, Harbers, M, Harshbarger, J, Hasegawa, A, Hasegawa, Y, Hashimoto, T, Hayashizaki, Y, Herlyn, M, Heutink, P, Hide, W, Hitchens, K, Ho Sui, S, Hofmann, O, Hoof, I, Hori, F, Hume, D, Huminiecki, L, Iida, K, Ikawa, T, Ishizu, Y, Itoh, M, Jankovic, B, Jia, H, Jorgensen, M, Joshi, A, Jurman, G, Kaczkowski, B, Kai, C, Kaida, K, Kaiho, A, Kajiyama, K, Kanamori Katayama, M, Kasianov, A, Kasukawa, T, Katayama, S, Kato Ishikawa, S, Kawaguchi, S, Kawai, J, Kawaji, H, Kawamoto, H, Kawamura, Y, Kawashima, T, Kempfle, J, Kenna, T, Kere, J, Khachigian, L, Kitamura, T, Klinken, P, Knox, A, Kojima, M, Kojima, S, Kondo, N, Koseki, H, Koyasu, S, Krampitz, S, Kubosaki, A, Kulakovskiy, I, Kwon, At, Laros, J, Lassmann, T, Lenhard, B, Lennartsson, A, Li, K, Lilji, B, Lipovich, L, Lizio, M, Mackay Sim, A, Makeev, V, Manabe, R, Mar, J, Marchand, B, Mathelier, A, Medvedeva, Y, Meehan, Tf, Mejhert, N, Meynert, A, Mizuno, Y, Morikawa, H, Morimoto, M, Moro, K, Motakis, E, Motohashi, H, Mummery, C, Mungall, Cj, Murata, M, Nagao Sato, S, Nakachi, Y, Nakahara, F, Nakamura, T, Nakamura, Y, Nakazato, K, Ninomiya Fukuda, N, Nishiyori Sueki, H, Noma, S, Nozaki, T, Ogishima, S, Ohkura, N, Ohmiya, H, Ohno, H, Ohshima, M, Okada Hatakeyama, M, Okazaki, Y, Orlando, V, Ovchinnikov, D, Pain, A, Passier, R, Persson, H, Piazza, Silvano, Plessy, C, Pradhan Bhatt, S, Prendergast, J, Rackham, O, Ramilowski, J, Rashid, M, Ravasi, T, Rehli, M, Rizzu, P, Roncador, M, Roy, S, Rye, M, Saijyo, E, Sajantila, A, Saka, A, Sakaguchi, S, Sakai, M, Sandelin, A, Sato, H, Satoh, H, Suzana, S, Alka, S, Schaefer, U, Schmeier, S, Schmidl, C, Schneider, C, Schultes, Ea, Schulze Tanzil, G, Schwegmann, A, Semple, C, Sengstag, T, Severin, J, Sheng, G, Shimoji, H, Shimoni, Y, Shin, J, Simon, C, Sugiyama, D, Sugiyama, T, Summers, K, Suzuki, H, Suzuki, M, Suzuki, N, Swoboda, R, Hoen P, T, Tagami, M, Takahashi, N, Takai, J, Tanaka, H, Tatsukawa, H, Tatum, Z, Taylor, M, Thompson, M, Toyoda, H, Toyoda, T, Valen, E, Van De Wetering, M, Van Den Berg, L, Van Nimwegen, E, Verardo, R, Vijayan, D, Vitezic, M, Vorontzov, I, Wasserman, W, Watanabe, S, Wells, C, Winteringham, L, Wolvetang, E, Wood, Ej, Yamaguchi, Y, Yamamoto, M, Yoneda, M, Yonekura, Y, Yoshida, Shin'Ichirou, Young, R, Zabierowski, Se, Zhang, P, Zhao, X, Zucchelli, Silvia, Forrest, Ar, Wagner, Gp, Hubrecht Institute for Developmental Biology and Stem Cell Research, AII - Amsterdam institute for Infection and Immunity, Infectious diseases, and Experimental Immunology

Subjects
Cell type, General Physics and Astronomy, rna-seq data, phylogenetic networks, Biology, ENCODE, General Biochemistry, Genetics and Molecular Biology, Divergence, Transcriptome, Models, Settore BIO/13 - Biologia Applicata, Neoplasms, Humans, Genetics, Models, Statistical, Multidisciplinary, Statistical model, General Chemistry, Statistical, Biological Evolution, Body plan, Tree structure, Evolutionary biology, Cancer cell
Abstract

In evolution, body plan complexity increases due to an increase in the number of individualized cell types. Yet, there is very little understanding of the mechanisms that produce this form of organismal complexity. One model for the origin of novel cell types is the sister cell-type model. According to this model, each cell type arises together with a sister cell type through specialization from an ancestral cell type. A key prediction of the sister cell-type model is that gene expression profiles of cell types exhibit tree structure. Here we present a statistical model for detecting tree structure in transcriptomic data and apply it to transcriptomes from ENCODE and FANTOM5. We show that transcriptomes of normal cells harbour substantial amounts of hierarchical structure. In contrast, cancer cell lines have less tree structure, suggesting that the emergence of cancer cells follows different principles from that of evolutionary cell-type origination.

Published
2015
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22. Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation

Author

Morikawa, H, Ohkura, N, Vandenbon, A, Itoh, M, Nagao Sato, S, Kawaji, H, Lassmann, T, Carninci, P, Hayashizaki, Y, Forrest, Ar, Standley, Dm, Date, H, Sakaguchi, S, FANTOM Consortium (Forrest AR, Rehli, M, Baillie, Jk, de Hoon MJ, Haberle, V, Kulakovskiy, Iv, Lizio, M, Andersson, R, Mungall, Cj, Meehan, Tf, Schmeier, S, Bertin, N, Jørgensen, M, Dimont, E, Arner, E, Schmidl, C, Schaefer, U, Medvedeva, Ya, Plessy, C, Vitezic, M, Severin, J, Semple, Ca, Ishizu, Y, Francescatto, M, Alam, I, Albanese, D, Altschuler, Gm, Archer, Ja, Arner, P, Babina, M, Baker, S, Balwierz, Pj, Beckhouse, Ag, Pradhan Bhatt, S, Blake, Ja, Blumenthal, A, Bodega, B, Bonetti, A, Briggs, J, Brombacher, F, Burroughs, Am, Califano, A, Cannistraci, Cv, Carbajo, D, Chen, Y, Chierici, M, Ciani, Y, Clevers, Hc, Dalla, E, Davis, Ca, Deplancke, B, Detmar, M, Diehl, Ad, Dohi, T, Drabløs, F, Edge, As, Edinger, M, Ekwall, K, Endoh, M, Enomoto, H, Fagiolini, M, Fairbairn, L, Fang, H, Farach Carson MC, Faulkner, Gj, Favorov, Av, Fisher, Me, Frith, Mc, Fujita, R, Fukuda, S, Furlanello, C, Furuno, M, Furusawa, J, Geijtenbeek, Tb, Gibson, A, Gingeras, T, Goldowitz, D, Gough, J, Guhl, S, Guler, R, Gustincich, Stefano, Ha, Tj, Hamaguchi, M, Hara, M, Harbers, M, Harshbarger, J, Hasegawa, A, Hasegawa, Y, Hashimoto, T, Herlyn, M, Hitchens, Kj, Ho Sui SJ, Hofmann, Om, Hoof, I, Hori, F, Huminiecki, L, Iida, K, Ikawa, T, Jankovic, Br, Jia, H, Joshi, A, Jurman, G, Kaczkowski, B, Kai, C, Kaida, K, Kaiho, A, Kajiyama, K, Kanamori Katayama, M, Kasianov, As, Kasukawa, T, Katayama, S, Kato, S, Kawaguchi, S, Kawamoto, H, Kawamura, Yi, Kawashima, T, Kempfle, Js, Kenna, Tj, Kere, J, Khachigian, Lm, Kitamura, T, Klinken, Sp, Knox, Aj, Kojima, M, Kojima, S, Kondo, N, Koseki, H, Koyasu, S, Krampitz, S, Kubosaki, A, Kwon, At, Laros, Jf, Lee, W, Lennartsson, A, Li, K, Lilje, B, Lipovich, L, Mackay Sim, A, Manabe, R, Mar, Jc, Marchand, B, Mathelier, A, Mejhert, N, Meynert, A, Mizuno, Y, Morais, Da, Morimoto, M, Moro, K, Motakis, E, Motohashi, H, Mummery, Cl, Murata, M, Nakachi, Y, Nakahara, F, Nakamura, T, Nakamura, Y, Nakazato, K, van Nimwegen, E, Ninomiya, N, Nishiyori, H, Noma, S, Nozaki, T, Ogishima, S, Ohmiya, H, Ohno, H, Ohshima, M, Okada Hatakeyama, M, Okazaki, Y, Orlando, V, Ovchinnikov, Da, Pain, A, Passier, R, Patrikakis, M, Persson, H, Piazza, S, Prendergast, Jg, Rackham, Oj, Ramilowski, Ja, Rashid, M, Ravasi, T, Rizzu, P, Roncador, M, Roy, S, Rye, Mb, Saijyo, E, Sajantila, A, Saka, A, Sakai, M, Sato, H, Satoh, H, Savvi, S, Saxena, A, Schneider, C, Schultes, Ea, Schulze Tanzil GG, Schwegmann, A, Sengstag, T, Sheng, G, Shimoji, H, Shimoni, Y, Shin, Jw, Simon, C, Sugiyama, D, Sugiyama, T, Suzuki, M, Swoboda, Rk, 't Hoen PA, Tagami, M, Takahashi, N, Takai, J, Tanaka, H, Tatsukawa, H, Tatum, Z, Thompson, M, Toyoda, H, Toyoda, T, Valen, E, van de Wetering, M, van den Berg LM, Verardo, R, Vijayan, D, Vorontsov, Ie, Wasserman, Ww, Watanabe, S, Wells, Ca, Winteringham, Ln, Wolvetang, E, Wood, Ej, Yamaguchi, Y, Yamamoto, M, Yoneda, M, Yonekura, Y, Yoshida, S, Zabierowski, Se, Zhang, Pg, Zhao, X, Zucchelli, S, Summers, Km, Suzuki, H, Daub, Co, Kawai, J, Heutink, P, Hide, W, Freeman, Tc, Lenhard, B, Bajic, Vb, Taylor, Ms, Makeev, Vj, Sandelin, A, Hume, Da, Hayashizaki, Y., AII - Amsterdam institute for Infection and Immunity, Infectious diseases, Experimental Immunology, and Hubrecht Institute for Developmental Biology and Stem Cell Research

Subjects
Transcription, Genetic, Regulatory T cell, T-Lymphocytes, Down-Regulation, chemical and pharmacologic phenomena, Biology, Inbred C57BL, T-Lymphocytes, Regulatory, Epigenesis, Genetic, Mice, Genetic, Settore BIO/13 - Biologia Applicata, medicine, Transcriptional regulation, Animals, Epigenetics, Gene, Inbred BALB C, Genetics, Regulation of gene expression, Mice, Inbred BALB C, Multidisciplinary, Binding Sites, FOXP3, hemic and immune systems, Forkhead Transcription Factors, DNA Methylation, Biological Sciences, Regulatory, Cap analysis gene expression, Mice, Inbred C57BL, medicine.anatomical_structure, Gene Expression Regulation, DNA methylation, Transcription, Epigenesis
Abstract

Naturally occurring regulatory T (Treg) cells, which specifically express the transcription factor forkhead box P3 (Foxp3), are engaged in the maintenance of immunological self-tolerance and homeostasis. By transcriptional start site cluster analysis, we assessed here how genome-wide patterns of DNA methylation or Foxp3 binding sites were associated with Treg-specific gene expression. We found that Treg-specific DNA hypomethylated regions were closely associated with Treg up-regulated transcriptional start site clusters, whereas Foxp3 binding regions had no significant correlation with either up- or down-regulated clusters in nonactivated Treg cells. However, in activated Treg cells, Foxp3 binding regions showed a strong correlation with down-regulated clusters. In accordance with these findings, the above two features of activation-dependent gene regulation in Treg cells tend to occur at different locations in the genome. The results collectively indicate that Treg-specific DNA hypomethylation is instrumental in gene up-regulation in steady state Treg cells, whereas Foxp3 down-regulates the expression of its target genes in activated Treg cells. Thus, the two events seem to play distinct but complementary roles in Treg-specific gene expression.

Published
2014
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23. Iterative sorting reveals CD133+and CD133-melanoma cells as phenotypically distinct populations

Author

Grasso, C, Anaka, M, Hofmann, O, Sompallae, R, Broadley, K, Hide, W, Berridge, MV, Cebon, J, Behren, A, McConnell, MJ, Grasso, C, Anaka, M, Hofmann, O, Sompallae, R, Broadley, K, Hide, W, Berridge, MV, Cebon, J, Behren, A, and McConnell, MJ

Abstract

BACKGROUND: The heterogeneity and tumourigenicity of metastatic melanoma is attributed to a cancer stem cell model, with CD133 considered to be a cancer stem cell marker in melanoma as well as other tumours, but its role has remained controversial. METHODS: We iteratively sorted CD133+ and CD133- cells from 3 metastatic melanoma cell lines, and observed tumourigenicity and phenotypic characteristics over 7 generations of serial xeno-transplantation in NOD/SCID mice. RESULTS: We demonstrate that iterative sorting is required to make highly pure populations of CD133+ and CD133- cells from metastatic melanoma, and that these two populations have distinct characteristics not related to the cancer stem cell phenotype. In vitro, gene set enrichment analysis indicated CD133+ cells were related to a proliferative phenotype, whereas CD133- cells were of an invasive phenotype. However, in vivo, serial transplantation of CD133+ and CD133- tumours over 7 generations showed that both populations were equally able to initiate and propagate tumours. Despite this, both populations remained phenotypically distinct, with CD133- cells only able to express CD133 in vivo and not in vitro. Loss of CD133 from the surface of a CD133+ cell was observed in vitro and in vivo, however CD133- cells derived from CD133+ retained the CD133+ phenotype, even in the presence of signals from the tumour microenvironment. CONCLUSION: We show for the first time the necessity of iterative sorting to isolate pure marker-positive and marker-negative populations for comparative studies, and present evidence that despite CD133+ and CD133- cells being equally tumourigenic, they display distinct phenotypic differences, suggesting CD133 may define a distinct lineage in melanoma.

Published
2016

24. Genome sequence of the tsetse fly (Glossina morsitans) : vector of African trypanosomiasis

Author

Watanabe, J., Hattori, M., Berriman, M., Lehane, M. J., Hall, N., Solano, Philippe, Aksoy, S., Hide, W., Toure, Y., Attardo, G. M., Darby, A. C., Toyoda, A., Hertz-Fowler, C., Larkin, D. M., Cotton, J. A., Sanders, M. J., Swain, M. T., Quail, M. A., Inoue, N., and Ravel, Sophie

Abstract

Tsetse flies are the sole vectors of human African trypanosomiasis throughout sub-Saharan Africa. Both sexes of adult tsetse feed exclusively on blood and contribute to disease transmission. Notable differences between tsetse and other disease vectors include obligate microbial symbioses, viviparous reproduction, and lactation. Here, we describe the sequence and annotation of the 366-megabase Glossina morsitans morsitans genome. Analysis of the genome and the 12,308 predicted protein-encoding genes led to multiple discoveries, including chromosomal integrations of bacterial (Wolbachia) genome sequences, a family of lactation-specific proteins, reduced complement of host pathogen recognition proteins, and reduced olfaction/ chemosensory associated genes. These genome data provide a foundation for research into trypanosomiasis prevention and yield important insights with broad implications for multiple aspects of tsetse biology.

Published
2014

25. ISA software suite: supporting standards-compliant experimental\ud annotation and enabling curation at the community level\ud

Author

Rocca-Serra, P., Brandizi, M., Maguire, E., Sklyar, N., Taylor, C., Begley, K., Field, D., Harris, S., Hide, W., Hofmann, O., Neumann, S., Sterk, P., Tong, W., and Sansone, S-A.

Abstract

The first open source software suite for experimentalists and curators that (i) assists in the annotation and local management of experimental metadata from high-throughput studies employing one or a combination of omics and other technologies; (ii) empowers users to uptake community-defined checklists and ontologies; and (iii) facilitates submission to international public repositories.

Published
2010

27. Ten simple rules for organizing a virtual conference--anywhere

Author

Gichora, N.N., Fatumo, S.A., Ngara, M.V., Chelbat, N., Ramdayal, K., Opap, K.B., Siwo, G.H., Adebiyi, M.O., El Gonnouni, A., Zofou, D., Maurady, A.A.M., Adebiyi, E.F., de Villiers, E.P., Masiga, D.K., Bizzaro, J.W., Suravajhala, P., Ommeh, S.C., Hide, W., and Bourne, PE

Published
2010

28. Simplified ontologies allowing comparison of developmental\ud mammalian gene expression

Author

Kruger, A., Hofmann, O., Carninci, P., Hayashizaki, Y., and Hide, W.

Abstract

Model organisms represent an important resource for understanding the fundamental aspects of\ud mammalian biology. Mapping of biological phenomena between model organisms is complex and if\ud it is to be meaningful, a simplified representation can be a powerful means for comparison. The\ud Developmental eVOC ontologies presented here are simplified orthogonal ontologies describing\ud the temporal and spatial distribution of developmental human and mouse anatomy. We\ud demonstrate the ontologies by identifying genes showing a bias for developmental brain expression\ud in human and mouse.

Published
2007

29. Integrative Annotation of 21,037 Human Genes\ud Validated by Full-Length cDNA Clones

Author

Imanishi, T., Itoh, T., Suzuki, Y., O'Donovan, C., Fukuchi, S., Koyanagi, K.O., Barrero, R.A., Tamura, T., Yamaguchi-Kabata, Y., Tanino, M., Yura, K., Miyazaki, S., Ikeo, K., Homma, K., Kasprzyk, A., Nishikawa, T., Hirakawa, M., Thierry-Mieg, J., Thierry-Mieg, D., Ashurst, J., Jia, L., Nakao, M., Thomas, M.A., Mulder, N., Karavidopoulou, Y., Jin, L., Kim, S., Yasuda, T., Lenhard, B., Eveno, E., Yamasaki, C., Takeda, J., Gough, C., Hilton, P., Fujii, Y., Sakai, H., Tanaka, S., Amid, C., Bellgard, M., De Fatima Bonaldo, M., Bono, H., Bromberg, S.K., Brookes, A.J., Bruford, E., Carninci, P., Chelala, C., Couillault, C., de Souza, S.J., Debily, M., Devignes, M., Dubchak, I., Endo, T., Estreicher, A., Eyras, E., Fukami-Kobayashi, K., Gopinath, G.R., Graudens, E., Hahn, Y., Han, M., Han, Z., Hanada, K., Hanaoka, H., Harada, E., Hinz, U., Hishiki, T., Hopkinson, I., Imbeaud, S., Inoko, H., Kanapin, A., Kaneko, Y., Kasukawa, T., Kersey, P., Kikuno, R., Kimura, K., Korn, B., Kuryshev, V., Makalowska, I., Makino, T., Mano, S., Mariage-Samson, R., Mashima, J., Matsuda, H., Mewes, H., Minoshima, S., Nagai, K., Nagasaki, H., Nagata, N., Nigam, R., Ogasawara, O., Ohara, O., Ohtsubo, M., Okido, T., Oota, S., Ota, M., Ota, T., Otsuki, T., Piatier-Tonneau, D., Poustka, A., Ren, S., Saitou, N., Sakai, K., Sakamoto, S., Sakate, R., Schupp, I., Servant, F., Sherry, S., Shiba, R., Shimizu, N., Shimoyama, M., Simpson, A.J., Soares, B., Steward, C., Suwa, M., Suzuki, M., Takahashi, A., Tamiya, G., Tanaka, H., Taylor, T., Terwilliger, J.D., Unneberg, P., Veeramachaneni, V., Watanabe, S., Wilming, L., Yasuda, N., Yoo, H-S., Stodolsky, M., Makalowski, W., Go, M., Nakai, K., Takagi, T., Kanehisa, M., Sakaki, Y., Quackenbush, J., Okazaki, Y., Hayashizaki, Y., Hide, W., Chakraborty, R., Nishikawa, K., Sugawara, H., Tateno, Y., Chen, Z., Oishi, M., Tonellato, P., Apweiler, R., Okubo, K., Wagner, L., Wiemann, S., Strausberg, R.L., Isogai, T., Auffray, C., Nomura, N., Gojobori, T., and Sugano, S.

Abstract

The human genome sequence defines our inherent biological potential; the realization of the biology encoded therein\ud requires knowledge of the function of each gene. Currently, our knowledge in this area is still limited. Several lines of\ud investigation have been used to elucidate the structure and function of the genes in the human genome. Even so, gene\ud prediction remains a difficult task, as the varieties of transcripts of a gene may vary to a great extent. We thus\ud performed an exhaustive integrative characterization of 41,118 full-length cDNAs that capture the gene transcripts as\ud complete functional cassettes, providing an unequivocal report of structural and functional diversity at the gene level.\ud Our international collaboration has validated 21,037 human gene candidates by analysis of high-quality full-length\ud cDNA clones through curation using unified criteria. This led to the identification of 5,155 new gene candidates. It also\ud manifested the most reliable way to control the quality of the cDNA clones. We have developed a human gene\ud database, called the H-Invitational Database (H-InvDB; http://www.h-invitational.jp/). It provides the following:\ud integrative annotation of human genes, description of gene structures, details of novel alternative splicing isoforms,\ud non-protein-coding RNAs, functional domains, subcellular localizations, metabolic pathways, predictions of protein\ud three-dimensional structure, mapping of known single nucleotide polymorphisms (SNPs), identification of polymorphic\ud microsatellite repeats within human genes, and comparative results with mouse full-length cDNAs. The H-InvDB\ud analysis has shown that up to 4% of the human genome sequence (National Center for Biotechnology Information\ud build 34 assembly) may contain misassembled or missing regions. We found that 6.5% of the human gene candidates\ud (1,377 loci) did not have a good protein-coding open reading frame, of which 296 loci are strong candidates for nonprotein-coding\ud RNA genes. In addition, among 72,027 uniquely mapped SNPs and insertions/deletions localized within\ud human genes, 13,215 nonsynonymous SNPs, 315 nonsense SNPs, and 452 indels occurred in coding regions. Together\ud with 25 polymorphic microsatellite repeats present in coding regions, they may alter protein structure, causing\ud phenotypic effects or resulting in disease. The H-InvDB platform represents a substantial contribution to resources\ud needed for the exploration of human biology and pathology

Published
2004

30. Comparison of Illumina and 454 Deep Sequencing in Participants Failing Raltegravir-Based Antiretroviral Therapy

Author

Kaderali, L, Li, JZ, Chapman, B, Charlebois, P, Hofmann, O, Weiner, B, Porter, AJ, Samuel, R, Vardhanabhuti, S, Zheng, L, Eron, J, Taiwo, B, Zody, MC, Henn, MR, Kuritzkes, DR, Hide, W, Kaderali, L, Li, JZ, Chapman, B, Charlebois, P, Hofmann, O, Weiner, B, Porter, AJ, Samuel, R, Vardhanabhuti, S, Zheng, L, Eron, J, Taiwo, B, Zody, MC, Henn, MR, Kuritzkes, DR, and Hide, W

Abstract

BACKGROUND: The impact of raltegravir-resistant HIV-1 minority variants (MVs) on raltegravir treatment failure is unknown. Illumina sequencing offers greater throughput than 454, but sequence analysis tools for viral sequencing are needed. We evaluated Illumina and 454 for the detection of HIV-1 raltegravir-resistant MVs. METHODS: A5262 was a single-arm study of raltegravir and darunavir/ritonavir in treatment-naïve patients. Pre-treatment plasma was obtained from 5 participants with raltegravir resistance at the time of virologic failure. A control library was created by pooling integrase clones at predefined proportions. Multiplexed sequencing was performed with Illumina and 454 platforms at comparable costs. Illumina sequence analysis was performed with the novel snp-assess tool and 454 sequencing was analyzed with V-Phaser. RESULTS: Illumina sequencing resulted in significantly higher sequence coverage and a 0.095% limit of detection. Illumina accurately detected all MVs in the control library at ≥0.5% and 7/10 MVs expected at 0.1%. 454 sequencing failed to detect any MVs at 0.1% with 5 false positive calls. For MVs detected in the patient samples by both 454 and Illumina, the correlation in the detected variant frequencies was high (R2 = 0.92, P<0.001). Illumina sequencing detected 2.4-fold greater nucleotide MVs and 2.9-fold greater amino acid MVs compared to 454. The only raltegravir-resistant MV detected was an E138K mutation in one participant by Illumina sequencing, but not by 454. CONCLUSIONS: In participants of A5262 with raltegravir resistance at virologic failure, baseline raltegravir-resistant MVs were rarely detected. At comparable costs to 454 sequencing, Illumina demonstrated greater depth of coverage, increased sensitivity for detecting HIV MVs, and fewer false positive variant calls.

Published
2014

31. Divergent LIN28-mRNA associations result in translational suppression upon the initiation of differentiation

Author

Tan, S., Altschuler, G., Zhao, T., Ang, H., Yang, H., Lim, B., Vardy, L., Hide, W., Thomson, A., Lareu, Ricky R., Tan, S., Altschuler, G., Zhao, T., Ang, H., Yang, H., Lim, B., Vardy, L., Hide, W., Thomson, A., and Lareu, Ricky R.

Abstract

LIN28 function is fundamental to the activity and behavior of human embryonic stem cells (hESCs) and induced pluripotent stem cells. Its main roles in these cell types are the regulation of translational efficiency and let-7 miRNA maturation. However, LIN28-associated mRNA cargo shifting and resultant regulation of translational efficiency upon the initiation of differentiation remain unknown. An RNA-immunoprecipitation and microarray analysis protocol, eRIP, that has high specificity and sensitivity was developed to test endogenous LIN28-associated mRNA cargo shifting. A combined eRIP and polysome analysis of early stage differentiation of hESCs with two distinct differentiation cues revealed close similarities between the dynamics of LIN28 association and translational modulation of genes involved in the Wnt signaling, cell cycle, RNA metabolism and proteasomal pathways. Our data demonstrate that change in translational efficiency is a major contributor to early stages of differentiation of hESCs, in which LIN28 plays a central role. This implies that eRIP analysis of LIN28-associated RNA cargoes may be used for rapid functional quality control of pluripotent stem cells under manufacture for therapeutic applications.

Published
2014

32. A network of epigenetic regulators guides developmental haematopoiesis in vivo

Author

Huang, H-T, Kathrein, KL, Barton, A, Gitlin, Z, Huang, Y-H, Ward, TP, Hofmann, O, Dibiase, A, Song, A, Tyekucheva, S, Hide, W, Zhou, Y, Zon, LI, Huang, H-T, Kathrein, KL, Barton, A, Gitlin, Z, Huang, Y-H, Ward, TP, Hofmann, O, Dibiase, A, Song, A, Tyekucheva, S, Hide, W, Zhou, Y, and Zon, LI

Abstract

The initiation of cellular programs is orchestrated by key transcription factors and chromatin regulators that activate or inhibit target gene expression. To generate a compendium of chromatin factors that establish the epigenetic code during developmental haematopoiesis, a large-scale reverse genetic screen was conducted targeting orthologues of 425 human chromatin factors in zebrafish. A set of chromatin regulators was identified that target different stages of primitive and definitive blood formation, including factors not previously implicated in haematopoiesis. We identified 15 factors that regulate development of primitive erythroid progenitors and 29 factors that regulate development of definitive haematopoietic stem and progenitor cells. These chromatin factors are associated with SWI/SNF and ISWI chromatin remodelling, SET1 methyltransferase, CBP-p300-HBO1-NuA4 acetyltransferase, HDAC-NuRD deacetylase, and Polycomb repressive complexes. Our work provides a comprehensive view of how specific chromatin factors and their associated complexes play a major role in the establishment of haematopoietic cells in vivo.

Published
2013

33. A comprehensive promoter landscape identifies a novel promoter for CD133 in restricted tissues, cancers, and stem cells.

Author

Sompallae, R, Hofmann, O, Maher, CA, Gedye, C, Behren, A, Vitezic, M, Daub, CO, Devalle, S, Caballero, OL, Carninci, P, Hayashizaki, Y, Lawlor, ER, Cebon, J, Hide, W, Sompallae, R, Hofmann, O, Maher, CA, Gedye, C, Behren, A, Vitezic, M, Daub, CO, Devalle, S, Caballero, OL, Carninci, P, Hayashizaki, Y, Lawlor, ER, Cebon, J, and Hide, W

Abstract

PROM1 is the gene encoding prominin-1 or CD133, an important cell surface marker for the isolation of both normal and cancer stem cells. PROM1 transcripts initiate at a range of transcription start sites (TSS) associated with distinct tissue and cancer expression profiles. Using high resolution Cap Analysis of Gene Expression (CAGE) sequencing we characterize TSS utilization across a broad range of normal and developmental tissues. We identify a novel proximal promoter (P6) within CD133(+) melanoma cell lines and stem cells. Additional exon array sampling finds P6 to be active in populations enriched for mesenchyme, neural stem cells and within CD133(+) enriched Ewing sarcomas. The P6 promoter is enriched with respect to previously characterized PROM1 promoters for a HMGI/Y (HMGA1) family transcription factor binding site motif and exhibits different epigenetic modifications relative to the canonical promoter region of PROM1.

Published
2013

34. Integrating Murine Gene Expression Studies to Understand Obstructive Lung Disease Due to Chronic Inhaled Endotoxin

Author

Lenburg, M, Lai, PS, Hofmann, O, Baron, RM, Cernadas, M, Meng, QR, Bresler, HS, Brass, DM, Yang, IV, Schwartz, DA, Christiani, DC, Hide, W, Lenburg, M, Lai, PS, Hofmann, O, Baron, RM, Cernadas, M, Meng, QR, Bresler, HS, Brass, DM, Yang, IV, Schwartz, DA, Christiani, DC, and Hide, W

Abstract

RATIONALE: Endotoxin is a near ubiquitous environmental exposure that that has been associated with both asthma and chronic obstructive pulmonary disease (COPD). These obstructive lung diseases have a complex pathophysiology, making them difficult to study comprehensively in the context of endotoxin. Genome-wide gene expression studies have been used to identify a molecular snapshot of the response to environmental exposures. Identification of differentially expressed genes shared across all published murine models of chronic inhaled endotoxin will provide insight into the biology underlying endotoxin-associated lung disease. METHODS: We identified three published murine models with gene expression profiling after repeated low-dose inhaled endotoxin. All array data from these experiments were re-analyzed, annotated consistently, and tested for shared genes found to be differentially expressed. Additional functional comparison was conducted by testing for significant enrichment of differentially expressed genes in known pathways. The importance of this gene signature in smoking-related lung disease was assessed using hierarchical clustering in an independent experiment where mice were exposed to endotoxin, smoke, and endotoxin plus smoke. RESULTS: A 101-gene signature was detected in three murine models, more than expected by chance. The three model systems exhibit additional similarity beyond shared genes when compared at the pathway level, with increasing enrichment of inflammatory pathways associated with longer duration of endotoxin exposure. Genes and pathways important in both asthma and COPD were shared across all endotoxin models. Mice exposed to endotoxin, smoke, and smoke plus endotoxin were accurately classified with the endotoxin gene signature. CONCLUSIONS: Despite the differences in laboratory, duration of exposure, and strain of mouse used in three experimental models of chronic inhaled endotoxin, surprising similarities in gene expression were observe

Published
2013

35. A prioritization analysis of disease association by data-mining of functional annotation of human genes

Author

Taniya, T., Tanaka, S., Yamaguchi-Kabata, Y., Hanaoka, H., Yamasaki, C., Maekawa, H., Barrero, R.A., Lenhard, B., Datta, M.W., Shimoyama, M., Bumgarner, R., Chakraborty, R., Hopkinson, I., Jia, L., Hide, W., Auffray, C., Minoshima, S., Imanishi, T., Gojobori, T., Taniya, T., Tanaka, S., Yamaguchi-Kabata, Y., Hanaoka, H., Yamasaki, C., Maekawa, H., Barrero, R.A., Lenhard, B., Datta, M.W., Shimoyama, M., Bumgarner, R., Chakraborty, R., Hopkinson, I., Jia, L., Hide, W., Auffray, C., Minoshima, S., Imanishi, T., and Gojobori, T.

Abstract

Complex diseases result from contributions of multiple genes that act in concert through pathways. Here we present a method to prioritize novel candidates of disease-susceptibility genes depending on the biological similarities to the known disease-related genes. The extent of disease-susceptibility of a gene is prioritized by analyzing seven features of human genes captured in H-InvDB. Taking rheumatoid arthritis (RA) and prostate cancer (PC) as two examples, we evaluated the efficiency of our method. Highly scored genes obtained included TNFSF12 and OSM as candidate disease genes for RA and PC, respectively. Subsequent characterization of these genes based upon an extensive literature survey reinforced the validity of these highly scored genes as possible disease-susceptibility genes. Our approach, Prioritization ANalysis of Disease Association (PANDA), is an efficient and cost-effective method to narrow down a large set of genes into smaller subsets that are most likely to be involved in the disease pathogenesis.

Published
2012

36. The Stem Cell Discovery Engine: an integrated repository and analysis system for cancer stem cell comparisons

Author

Sui, SJH, Begley, K, Reilly, D, Chapman, B, McGovern, R, Rocca-Sera, P, Maguire, E, Altschuler, GM, Hansen, TAA, Sompallae, R, Krivtsov, A, Shivdasani, RA, Armstrong, SA, Culhane, AC, Correll, M, Sansone, S-A, Hofmann, O, Hide, W, Sui, SJH, Begley, K, Reilly, D, Chapman, B, McGovern, R, Rocca-Sera, P, Maguire, E, Altschuler, GM, Hansen, TAA, Sompallae, R, Krivtsov, A, Shivdasani, RA, Armstrong, SA, Culhane, AC, Correll, M, Sansone, S-A, Hofmann, O, and Hide, W

Abstract

Mounting evidence suggests that malignant tumors are initiated and maintained by a subpopulation of cancerous cells with biological properties similar to those of normal stem cells. However, descriptions of stem-like gene and pathway signatures in cancers are inconsistent across experimental systems. Driven by a need to improve our understanding of molecular processes that are common and unique across cancer stem cells (CSCs), we have developed the Stem Cell Discovery Engine (SCDE)-an online database of curated CSC experiments coupled to the Galaxy analytical framework. The SCDE allows users to consistently describe, share and compare CSC data at the gene and pathway level. Our initial focus has been on carefully curating tissue and cancer stem cell-related experiments from blood, intestine and brain to create a high quality resource containing 53 public studies and 1098 assays. The experimental information is captured and stored in the multi-omics Investigation/Study/Assay (ISA-Tab) format and can be queried in the data repository. A linked Galaxy framework provides a comprehensive, flexible environment populated with novel tools for gene list comparisons against molecular signatures in GeneSigDB and MSigDB, curated experiments in the SCDE and pathways in WikiPathways. The SCDE is available at http://discovery.hsci.harvard.edu.

Published
2012

37. Population Differences in Transcript-Regulator Expression Quantitative Trait Loci

Author

Kliebenstein, DJ, Bushel, PR, McGovern, R, Liu, L, Hofmann, O, Huda, A, Lu, J, Hide, W, Lin, X, Kliebenstein, DJ, Bushel, PR, McGovern, R, Liu, L, Hofmann, O, Huda, A, Lu, J, Hide, W, and Lin, X

Abstract

Gene expression quantitative trait loci (eQTL) are useful for identifying single nucleotide polymorphisms (SNPs) associated with diseases. At times, a genetic variant may be associated with a master regulator involved in the manifestation of a disease. The downstream target genes of the master regulator are typically co-expressed and share biological function. Therefore, it is practical to screen for eQTLs by identifying SNPs associated with the targets of a transcript-regulator (TR). We used a multivariate regression with the gene expression of known targets of TRs and SNPs to identify TReQTLs in European (CEU) and African (YRI) HapMap populations. A nominal p-value of <1×10(-6) revealed 234 SNPs in CEU and 154 in YRI as TReQTLs. These represent 36 independent (tag) SNPs in CEU and 39 in YRI affecting the downstream targets of 25 and 36 TRs respectively. At a false discovery rate (FDR) = 45%, one cis-acting tag SNP (within 1 kb of a gene) in each population was identified as a TReQTL. In CEU, the SNP (rs16858621) in Pcnxl2 was found to be associated with the genes regulated by CREM whereas in YRI, the SNP (rs16909324) was linked to the targets of miRNA hsa-miR-125a. To infer the pathways that regulate expression, we ranked TReQTLs by connectivity within the structure of biological process subtrees. One TReQTL SNP (rs3790904) in CEU maps to Lphn2 and is associated (nominal p-value = 8.1×10(-7)) with the targets of the X-linked breast cancer suppressor Foxp3. The structure of the biological process subtree and a gene interaction network of the TReQTL revealed that tumor necrosis factor, NF-kappaB and variants in G-protein coupled receptors signaling may play a central role as communicators in Foxp3 functional regulation. The potential pleiotropic effect of the Foxp3 TReQTLs was gleaned from integrating mRNA-Seq data and SNP-set enrichment into the analysis.

Published
2012

38. Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity

Author

Fu, S, Yang, L, Li, P, Hofmann, O, Dicker, L, Hide, W, Lin, X, Watkins, SM, Ivanov, AR, Hotamisligil, GS, Fu, S, Yang, L, Li, P, Hofmann, O, Dicker, L, Hide, W, Lin, X, Watkins, SM, Ivanov, AR, and Hotamisligil, GS

Abstract

The endoplasmic reticulum (ER) is the main site of protein and lipid synthesis, membrane biogenesis, xenobiotic detoxification and cellular calcium storage, and perturbation of ER homeostasis leads to stress and the activation of the unfolded protein response. Chronic activation of ER stress has been shown to have an important role in the development of insulin resistance and diabetes in obesity. However, the mechanisms that lead to chronic ER stress in a metabolic context in general, and in obesity in particular, are not understood. Here we comparatively examined the proteomic and lipidomic landscape of hepatic ER purified from lean and obese mice to explore the mechanisms of chronic ER stress in obesity. We found suppression of protein but stimulation of lipid synthesis in the obese ER without significant alterations in chaperone content. Alterations in ER fatty acid and lipid composition result in the inhibition of sarco/endoplasmic reticulum calcium ATPase (SERCA) activity and ER stress. Correcting the obesity-induced alteration of ER phospholipid composition or hepatic Serca overexpression in vivo both reduced chronic ER stress and improved glucose homeostasis. Hence, we established that abnormal lipid and calcium metabolism are important contributors to hepatic ER stress in obesity.

Published
2011

39. Capture of MicroRNA-Bound mRNAs Identifies the Tumor Suppressor miR-34a as a Regulator of Growth Factor Signaling

Author

McManus, MT, Lal, A, Thomas, MP, Altschuler, G, Navarro, F, O'Day, E, Li, XL, Concepcion, C, Han, Y-C, Thiery, J, Rajani, DK, Deutsch, A, Hofmann, O, Ventura, A, Hide, W, Lieberman, J, McManus, MT, Lal, A, Thomas, MP, Altschuler, G, Navarro, F, O'Day, E, Li, XL, Concepcion, C, Han, Y-C, Thiery, J, Rajani, DK, Deutsch, A, Hofmann, O, Ventura, A, Hide, W, and Lieberman, J

Abstract

A simple biochemical method to isolate mRNAs pulled down with a transfected, biotinylated microRNA was used to identify direct target genes of miR-34a, a tumor suppressor gene. The method reidentified most of the known miR-34a regulated genes expressed in K562 and HCT116 cancer cell lines. Transcripts for 982 genes were enriched in the pull-down with miR-34a in both cell lines. Despite this large number, validation experiments suggested that ~90% of the genes identified in both cell lines can be directly regulated by miR-34a. Thus miR-34a is capable of regulating hundreds of genes. The transcripts pulled down with miR-34a were highly enriched for their roles in growth factor signaling and cell cycle progression. These genes form a dense network of interacting gene products that regulate multiple signal transduction pathways that orchestrate the proliferative response to external growth stimuli. Multiple candidate miR-34a-regulated genes participate in RAS-RAF-MAPK signaling. Ectopic miR-34a expression reduced basal ERK and AKT phosphorylation and enhanced sensitivity to serum growth factor withdrawal, while cells genetically deficient in miR-34a were less sensitive. Fourteen new direct targets of miR-34a were experimentally validated, including genes that participate in growth factor signaling (ARAF and PIK3R2) as well as genes that regulate cell cycle progression at various phases of the cell cycle (cyclins D3 and G2, MCM2 and MCM5, PLK1 and SMAD4). Thus miR-34a tempers the proliferative and pro-survival effect of growth factor stimulation by interfering with growth factor signal transduction and downstream pathways required for cell division.

Published
2011

40. ISA software suite: supporting standards-compliant experimental annotation and enabling curation at the community level

Author

Rocca-Serra, P, Brandizi, M, Maguire, E, Sklyar, N, Taylor, C, Begley, K, Field, D, Harris, S, Hide, W, Hofmann, O, Neumann, S, Sterk, P, Tong, W, Sansone, S-A, Rocca-Serra, P, Brandizi, M, Maguire, E, Sklyar, N, Taylor, C, Begley, K, Field, D, Harris, S, Hide, W, Hofmann, O, Neumann, S, Sterk, P, Tong, W, and Sansone, S-A

Abstract

UNLABELLED: The first open source software suite for experimentalists and curators that (i) assists in the annotation and local management of experimental metadata from high-throughput studies employing one or a combination of omics and other technologies; (ii) empowers users to uptake community-defined checklists and ontologies; and (iii) facilitates submission to international public repositories. AVAILABILITY AND IMPLEMENTATION: Software, documentation, case studies and implementations at http://www.isa-tools.org.

Published
2010

41. The H-Invitational Database (H-InvDB), a comprehensive annotation resource for human genes and transcripts.

Author

Yamasaki, C., Murakami, K., Fujii, Y., Sato, Y., Harada, E., Takeda, J-I, Taniya, T., Sakate, R., Kikugawa, S., Shimada, M., Tanino, M., Koyanagi, K.O., Barrero, R.A., Gough, C., Chun, H-W, Habara, T., Hanaoka, H., Hayakawa, Y., Hilton, P.B., Kaneko, Y., Kanno, M., Kawahara, Y., Kawamura, T., Matsuya, A., Nagata, N., Nishikata, K., Noda, A.O., Nurimoto, S., Saichi, N., Sakai, H., Sanbonmatsu, R., Shiba, R., Suzuki, M., Takabayashi, K., Takahashi, A., Tamura, T., Tanaka, M., Tanaka, S., Todokoro, F., Yamaguchi, K., Yamamoto, N., Okido, T., Mashima, J., Hashizume, A., Jin, L., Lee, K-B, Lin, Y-C, Nozaki, A., Sakai, K., Tada, M., Miyazaki, S., Makino, T., Ohyanagi, H., Osato, N., Tanaka, N., Suzuki, Y., Ikeo, K., Saitou, N., Sugawara, H., O'Donovan, C., Kulikova, T., Whitfield, E., Halligan, B., Shimoyama, M., Twigger, S., Yura, K., Kimura, K., Yasuda, T., Nishikawa, T., Akiyama, Y., Motono, C., Mukai, Y., Nagasaki, H., Suwa, M., Horton, P., Kikuno, R., Ohara, O., Lancet, D., Eveno, E., Graudens, E., Imbeaud, S., Debily, M.A., Hayashizaki, Y., Amid, C., Han, M., Osanger, A., Endo, T., Thomas, M.A., Hirakawa, M., Makalowski, W., Nakao, M., Kim, N-S, Yoo, H-S, De Souza, S.J., Bonaldo, M., Niimura, Y., Kuryshev, V., Schupp, I., Wiemann, S., Bellgard, M., Shionyu, M., Jia, L., Thierry-Mieg, D., Thierry-Mieg, J., Wagner, L., Zhang, Q., Go, M., Minoshima, S., Ohtsubo, M., Hanada, K., Tonellato, P., Isogai, T., Zhang, J., Lenhard, B., Kim, S., Chen, Z., Hinz, U., Estreicher, A., Nakai, K., Makalowska, I., Hide, W., Tiffin, N., Wilming, L., Chakraborty, R., Soares, M.B., Chiusano, M.L., Auffray, C., Yamaguchi-Kabata, Y., Itoh, T., Hishiki, T., Fukuchi, S., Nishikawa, K., Sugano, S., Nomura, N., Tateno, Y., Imanishi, T., Gojobori, T., Yamasaki, C., Murakami, K., Fujii, Y., Sato, Y., Harada, E., Takeda, J-I, Taniya, T., Sakate, R., Kikugawa, S., Shimada, M., Tanino, M., Koyanagi, K.O., Barrero, R.A., Gough, C., Chun, H-W, Habara, T., Hanaoka, H., Hayakawa, Y., Hilton, P.B., Kaneko, Y., Kanno, M., Kawahara, Y., Kawamura, T., Matsuya, A., Nagata, N., Nishikata, K., Noda, A.O., Nurimoto, S., Saichi, N., Sakai, H., Sanbonmatsu, R., Shiba, R., Suzuki, M., Takabayashi, K., Takahashi, A., Tamura, T., Tanaka, M., Tanaka, S., Todokoro, F., Yamaguchi, K., Yamamoto, N., Okido, T., Mashima, J., Hashizume, A., Jin, L., Lee, K-B, Lin, Y-C, Nozaki, A., Sakai, K., Tada, M., Miyazaki, S., Makino, T., Ohyanagi, H., Osato, N., Tanaka, N., Suzuki, Y., Ikeo, K., Saitou, N., Sugawara, H., O'Donovan, C., Kulikova, T., Whitfield, E., Halligan, B., Shimoyama, M., Twigger, S., Yura, K., Kimura, K., Yasuda, T., Nishikawa, T., Akiyama, Y., Motono, C., Mukai, Y., Nagasaki, H., Suwa, M., Horton, P., Kikuno, R., Ohara, O., Lancet, D., Eveno, E., Graudens, E., Imbeaud, S., Debily, M.A., Hayashizaki, Y., Amid, C., Han, M., Osanger, A., Endo, T., Thomas, M.A., Hirakawa, M., Makalowski, W., Nakao, M., Kim, N-S, Yoo, H-S, De Souza, S.J., Bonaldo, M., Niimura, Y., Kuryshev, V., Schupp, I., Wiemann, S., Bellgard, M., Shionyu, M., Jia, L., Thierry-Mieg, D., Thierry-Mieg, J., Wagner, L., Zhang, Q., Go, M., Minoshima, S., Ohtsubo, M., Hanada, K., Tonellato, P., Isogai, T., Zhang, J., Lenhard, B., Kim, S., Chen, Z., Hinz, U., Estreicher, A., Nakai, K., Makalowska, I., Hide, W., Tiffin, N., Wilming, L., Chakraborty, R., Soares, M.B., Chiusano, M.L., Auffray, C., Yamaguchi-Kabata, Y., Itoh, T., Hishiki, T., Fukuchi, S., Nishikawa, K., Sugano, S., Nomura, N., Tateno, Y., Imanishi, T., and Gojobori, T.

Abstract

Here we report the new features and improvements in our latest release of the H-Invitational Database (H-InvDB; http://www.h-invitational.jp/), a comprehensive annotation resource for human genes and transcripts. H-InvDB, originally developed as an integrated database of the human transcriptome based on extensive annotation of large sets of full-length cDNA (FLcDNA) clones, now provides annotation for 120 558 human mRNAs extracted from the International Nucleotide Sequence Databases (INSD), in addition to 54 978 human FLcDNAs, in the latest release H-InvDB_4.6. We mapped those human transcripts onto the human genome sequences (NCBI build 36.1) and determined 34 699 human gene clusters, which could define 34 057 (98.1%) protein-coding and 642 (1.9%) non-protein-coding loci; 858 (2.5%) transcribed loci overlapped with predicted pseudogenes. For all these transcripts and genes, we provide comprehensive annotation including gene structures, gene functions, alternative splicing variants, functional non-protein-coding RNAs, functional domains, predicted sub cellular localizations, metabolic pathways, predictions of protein 3D structure, mapping of SNPs and microsatellite repeat motifs, co-localization with orphan diseases, gene expression profiles, orthologous genes, protein-protein interactions (PPI) and annotation for gene families. The current H-InvDB annotation resources consist of two main views: Transcript view and Locus view and eight sub-databases: the DiseaseInfo Viewer, H-ANGEL, the Clustering Viewer, G-integra, the TOPO Viewer, Evola, the PPI view and the Gene family/group.

Published
2008

42. Simplified ontologies allowing comparison of developmental mammalian gene expression

Author

Kruger, A, Hofmann, O, Carninci, P, Hayashizaki, Y, Hide, W, Kruger, A, Hofmann, O, Carninci, P, Hayashizaki, Y, and Hide, W

Abstract

Model organisms represent an important resource for understanding the fundamental aspects of mammalian biology. Mapping of biological phenomena between model organisms is complex and if it is to be meaningful, a simplified representation can be a powerful means for comparison. The Developmental eVOC ontologies presented here are simplified orthogonal ontologies describing the temporal and spatial distribution of developmental human and mouse anatomy. We demonstrate the ontologies by identifying genes showing a bias for developmental brain expression in human and mouse.

Published
2007

43. Computational selection and prioritization of candidate genes for Fetal Alcohol Syndrome

Author

Lombard, Z, Tiffin, N, Hofmann, O, Bajic, VB, Hide, W, Ramsay, M, Lombard, Z, Tiffin, N, Hofmann, O, Bajic, VB, Hide, W, and Ramsay, M

Abstract

BACKGROUND: Fetal alcohol syndrome (FAS) is a serious global health problem and is observed at high frequencies in certain South African communities. Although in utero alcohol exposure is the primary trigger, there is evidence for genetic- and other susceptibility factors in FAS development. No genome-wide association or linkage studies have been performed for FAS, making computational selection and -prioritization of candidate disease genes an attractive approach. RESULTS: 10174 Candidate genes were initially selected from the whole genome using a previously described method, which selects candidate genes according to their expression in disease-affected tissues. Hereafter candidates were prioritized for experimental investigation by investigating criteria pertinent to FAS and binary filtering. 29 Criteria were assessed by mining various database sources to populate criteria-specific gene lists. Candidate genes were then prioritized for experimental investigation using a binary system that assessed the criteria gene lists against the candidate list, and candidate genes were scored accordingly. A group of 87 genes was prioritized as candidates and for future experimental validation. The validity of the binary prioritization method was assessed by investigating the protein-protein interactions, functional enrichment and common promoter element binding sites of the top-ranked genes. CONCLUSION: This analysis highlighted a list of strong candidate genes from the TGF-beta, MAPK and Hedgehog signalling pathways, which are all integral to fetal development and potential targets for alcohol's teratogenic effect. We conclude that this novel bioinformatics approach effectively prioritizes credible candidate genes for further experimental analysis.

Published
2007

44. Computational disease gene identification: a concert of methods prioritizes type 2 diabetes and obesity candidate genes

Author

Tiffin, N., Adie, E., Turner, F., Brunner, H.G., Driel, M.A. van, Oti, M.O., Lopez-Bigas, N., Ouzounis, C.A., Perez-Iratxeta, C., Andrade-Navarro, M.A., Adeyemo, A., Patti, M.E., Semple, C.A., Hide, W., Tiffin, N., Adie, E., Turner, F., Brunner, H.G., Driel, M.A. van, Oti, M.O., Lopez-Bigas, N., Ouzounis, C.A., Perez-Iratxeta, C., Andrade-Navarro, M.A., Adeyemo, A., Patti, M.E., Semple, C.A., and Hide, W.

Abstract

Contains fulltext : 36016.pdf (publisher's version ) (Open Access), Genome-wide experimental methods to identify disease genes, such as linkage analysis and association studies, generate increasingly large candidate gene sets for which comprehensive empirical analysis is impractical. Computational methods employ data from a variety of sources to identify the most likely candidate disease genes from these gene sets. Here, we review seven independent computational disease gene prioritization methods, and then apply them in concert to the analysis of 9556 positional candidate genes for type 2 diabetes (T2D) and the related trait obesity. We generate and analyse a list of nine primary candidate genes for T2D genes and five for obesity. Two genes, LPL and BCKDHA, are common to these two sets. We also present a set of secondary candidates for T2D (94 genes) and for obesity (116 genes) with 58 genes in common to both diseases. UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16757574

Published
2006

45. The LIFEdb database in 2006

Author

Mehrle, A, Rosenfelder, H, Schupp, I, del Val, C, Arlt, D, Hahne, F, Bechtel, S, Simpson, J, Hofmann, O, Hide, W, Glatting, K-H, Huber, W, Pepperkok, R, Poustka, A, Wiemann, S, Mehrle, A, Rosenfelder, H, Schupp, I, del Val, C, Arlt, D, Hahne, F, Bechtel, S, Simpson, J, Hofmann, O, Hide, W, Glatting, K-H, Huber, W, Pepperkok, R, Poustka, A, and Wiemann, S

Abstract

LIFEdb (http://www.LIFEdb.de) integrates data from large-scale functional genomics assays and manual cDNA annotation with bioinformatics gene expression and protein analysis. New features of LIFEdb include (i) an updated user interface with enhanced query capabilities, (ii) a configurable output table and the option to download search results in XML, (iii) the integration of data from cell-based screening assays addressing the influence of protein-overexpression on cell proliferation and (iv) the display of the relative expression ('Electronic Northern') of the genes under investigation using curated gene expression ontology information. LIFEdb enables researchers to systematically select and characterize genes and proteins of interest, and presents data and information via its user-friendly web-based interface.

Published
2006

46. Mice and men:: Their promoter properties

Author

Blake, J, Hancock, J, Pavan, B, Stubbs, L, Bajic, VB, Tan, SL, Christoffels, A, Schonbach, C, Lipovich, L, Yang, L, Hofmann, O, Kruger, A, Hide, W, Kai, C, Kawai, J, Hume, DA, Carninci, P, Hayashizaki, Y, Blake, J, Hancock, J, Pavan, B, Stubbs, L, Bajic, VB, Tan, SL, Christoffels, A, Schonbach, C, Lipovich, L, Yang, L, Hofmann, O, Kruger, A, Hide, W, Kai, C, Kawai, J, Hume, DA, Carninci, P, and Hayashizaki, Y

Abstract

Using the two largest collections of Mus musculus and Homo sapiens transcription start sites (TSSs) determined based on CAGE tags, ditags, full-length cDNAs, and other transcript data, we describe the compositional landscape surrounding TSSs with the aim of gaining better insight into the properties of mammalian promoters. We classified TSSs into four types based on compositional properties of regions immediately surrounding them. These properties highlighted distinctive features in the extended core promoters that helped us delineate boundaries of the transcription initiation domain space for both species. The TSS types were analyzed for associations with initiating dinucleotides, CpG islands, TATA boxes, and an extensive collection of statistically significant cis-elements in mouse and human. We found that different TSS types show preferences for different sets of initiating dinucleotides and cis-elements. Through Gene Ontology and eVOC categories and tissue expression libraries we linked TSS characteristics to expression. Moreover, we show a link of TSS characteristics to very specific genomic organization in an example of immune-response-related genes (GO:0006955). Our results shed light on the global properties of the two transcriptomes not revealed before and therefore provide the framework for better understanding of the transcriptional mechanisms in the two species, as well as a framework for development of new and more efficient promoter- and gene-finding tools.

Published
2006

47. Quantitating the Multiplicity of Infection with Human Immunodeficiency Virus Type 1 Subtype C Reveals a Non-Poisson Distribution of Transmitted Variants

Author

Abrahams, M.-R., primary, Anderson, J. A., additional, Giorgi, E. E., additional, Seoighe, C., additional, Mlisana, K., additional, Ping, L.-H., additional, Athreya, G. S., additional, Treurnicht, F. K., additional, Keele, B. F., additional, Wood, N., additional, Salazar-Gonzalez, J. F., additional, Bhattacharya, T., additional, Chu, H., additional, Hoffman, I., additional, Galvin, S., additional, Mapanje, C., additional, Kazembe, P., additional, Thebus, R., additional, Fiscus, S., additional, Hide, W., additional, Cohen, M. S., additional, Karim, S. Abdool, additional, Haynes, B. F., additional, Shaw, G. M., additional, Hahn, B. H., additional, Korber, B. T., additional, Swanstrom, R., additional, and Williamson, C., additional

Published
2009
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