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Your search keyword '"Shoa L CLARKE"' showing total 13 results
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13 results on '"Shoa L CLARKE"'

1. The enhancer landscape during early neocortical development reveals patterns of dense regulation and co-option.

Author

Aaron M Wenger, Shoa L Clarke, James H Notwell, Tisha Chung, Geetu Tuteja, Harendra Guturu, Bruce T Schaar, and Gill Bejerano

Subjects
Genetics, QH426-470
Abstract

Genetic studies have identified a core set of transcription factors and target genes that control the development of the neocortex, the region of the human brain responsible for higher cognition. The specific regulatory interactions between these factors, many key upstream and downstream genes, and the enhancers that mediate all these interactions remain mostly uncharacterized. We perform p300 ChIP-seq to identify over 6,600 candidate enhancers active in the dorsal cerebral wall of embryonic day 14.5 (E14.5) mice. Over 95% of the peaks we measure are conserved to human. Eight of ten (80%) candidates tested using mouse transgenesis drive activity in restricted laminar patterns within the neocortex. GREAT based computational analysis reveals highly significant correlation with genes expressed at E14.5 in key areas for neocortex development, and allows the grouping of enhancers by known biological functions and pathways for further studies. We find that multiple genes are flanked by dozens of candidate enhancers each, including well-known key neocortical genes as well as suspected and novel genes. Nearly a quarter of our candidate enhancers are conserved well beyond mammals. Human and zebrafish regions orthologous to our candidate enhancers are shown to most often function in other aspects of central nervous system development. Finally, we find strong evidence that specific interspersed repeat families have contributed potentially key developmental enhancers via co-option. Our analysis expands the methodologies available for extracting the richness of information found in genome-wide functional maps.

Published
2013
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2. Human developmental enhancers conserved between deuterostomes and protostomes.

Author

Shoa L Clarke, Julia E VanderMeer, Aaron M Wenger, Bruce T Schaar, Nadav Ahituv, and Gill Bejerano

Subjects
Genetics, QH426-470
Abstract

The identification of homologies, whether morphological, molecular, or genetic, is fundamental to our understanding of common biological principles. Homologies bridging the great divide between deuterostomes and protostomes have served as the basis for current models of animal evolution and development. It is now appreciated that these two clades share a common developmental toolkit consisting of conserved transcription factors and signaling pathways. These patterning genes sometimes show common expression patterns and genetic interactions, suggesting the existence of similar or even conserved regulatory apparatus. However, previous studies have found no regulatory sequence conserved between deuterostomes and protostomes. Here we describe the first such enhancers, which we call bilaterian conserved regulatory elements (Bicores). Bicores show conservation of sequence and gene synteny. Sequence conservation of Bicores reflects conserved patterns of transcription factor binding sites. We predict that Bicores act as response elements to signaling pathways, and we show that Bicores are developmental enhancers that drive expression of transcriptional repressors in the vertebrate central nervous system. Although the small number of identified Bicores suggests extensive rewiring of cis-regulation between the protostome and deuterostome clades, additional Bicores may be revealed as our understanding of cis-regulatory logic and sample of bilaterian genomes continue to grow.

Published
2012
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4. Genetic interactions drive heterogeneity in causal variant effect sizes for gene expression and complex traits

Author

Roshni A. Patel, Shaila A. Musharoff, Jeffrey P. Spence, Harold Pimentel, Catherine Tcheandjieu, Hakhamanesh Mostafavi, Nasa Sinnott-Armstrong, Shoa L. Clarke, Courtney J. Smith, Peter P. Durda, Kent D. Taylor, Russell Tracy, Yongmei Liu, W. Craig Johnson, Francois Aguet, Kristin G. Ardlie, Stacey Gabriel, Josh Smith, Deborah A. Nickerson, Stephen S. Rich, Jerome I. Rotter, Philip S. Tsao, Themistocles L. Assimes, and Jonathan K. Pritchard

Subjects
Multifactorial Inheritance, Genetics, Gene Expression, Humans, Cholesterol, LDL, Polymorphism, Single Nucleotide, White People, Article, Genetics (clinical), Genome-Wide Association Study
Abstract

Despite the growing number of genome-wide association studies (GWASs), it remains unclear to what extent gene-by-gene and gene-by-environment interactions influence complex traits in humans. The magnitude of genetic interactions in complex traits has been difficult to quantify because GWASs are generally underpowered to detect individual interactions of small effect. Here, we develop a method to test for genetic interactions that aggregates information across all trait-associated loci. Specifically, we test whether SNPs in regions of European ancestry shared between European American and admixed African American individuals have the same causal effect sizes. We hypothesize that in African Americans, the presence of genetic interactions will drive the causal effect sizes of SNPs in regions of European ancestry to be more similar to those of SNPs in regions of African ancestry. We apply our method to two traits: gene expression in 296 African Americans and 482 European Americans in the Multi-Ethnic Study of Atherosclerosis (MESA) and low-density lipoprotein cholesterol (LDL-C) in 74K African Americans and 296K European Americans in the Million Veteran Program (MVP). We find significant evidence for genetic interactions in our analysis of gene expression; for LDL-C, we observe a similar point estimate, although this is not significant, most likely due to lower statistical power. These results suggest that gene-by-gene or gene-by-environment interactions modify the effect sizes of causal variants in human complex traits.

Published
2022
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5. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Author

Stavroula Kanoni, Sarah E. Graham, Yuxuan Wang, Ida Surakka, Shweta Ramdas, Xiang Zhu, Shoa L. Clarke, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W. Winkler, Adam E. Locke, Eirini Marouli, Greg J. M. Zajac, Kuan-Han H. Wu, Ioanna Ntalla, Qin Hui, Derek Klarin, Austin T. Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F. Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M. Brumpton, Humaira Rasheed, Aki S. Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A. Rosenthal, Todd Lingren, QiPing Feng, Iftikhar J. Kullo, Akira Narita, Jun Takayama, Hilary C. Martin, Karen A. Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E. Miller, Archie Campbell, Kuang Lin, Iona Y. Millwood, Asif Rasheed, George Hindy, Jessica D. Faul, Wei Zhao, David R. Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R. Brown, Weihua Zhang, Ketian Yu, Ellen M. Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian’an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Andrew R. Wood, Yingji Ji, Zishan Gao, Simon Haworth, Noha A. Yousri, Ruth E. Mitchell, Jin Fang Chai, Mette Aadahl, Anne A. Bjerregaard, Jie Yao, Ani Manichaikul, Chii-Min Hwu, Yi-Jen Hung, Helen R. Warren, Julia Ramirez, Jette Bork-Jensen, Line L. Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Pala Mauro, Floris Matteo, Aaron F. McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T. Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Claudia Lamina, Lukas Forer, Markus Scholz, Tessel E. Galesloot, Jonathan P. Bradfield, Sanni E. Ruotsalainen, EWarwick Daw, Joseph M. Zmuda, Jonathan S. Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A. Brody, Miguel Vazquez-Moreno, Mary F. Feitosa, Mary K. Wojczynski, Zhe Wang, Michael H. Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W. Benjamins, Jorgen Engmann, Noah L. Tsao, Anurag Verma, Roderick C. Slieker, Ken Sin Lo, Nuno R. Zilhao, Phuong Le, Marcus E. Kleber, Graciela E. Delgado, Shaofeng Huo, Daisuke D. Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L. Leonard, Jonathan Marten, Mirjam Frank, Börge Schmidt, Laura J. Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Suraj S. Nongmaithem, Swati Bayyana, Heather M. Stringham, Marguerite R. Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R. H. J. Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A. Lange, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N. Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C. Warner, Ya Xing Wang, Wen B. Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A. Kentistou, Bernhard Banas, Giuseppe Giovanni Nardone, Karina Meidtner, Lawrence F. Bielak, Jennifer A. Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J. van der Most, Niina Pitkänen, Brian E. Cade, Sander W. van der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Amy R. Bentley, Ayo P. Doumatey, Adebowale A. Adeyemo, Jong Young Lee, Eva R. B. Petersen, Aneta A. Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W. Rayner, Carol A. Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O. Obura, Jessica van Setten, Xiaoyin Li, Jingjing Liang, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D. Jackson, Alexander P. Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Joshua C. Bis, Lenore J. Launer, Huaixing Li, Mike A. Nalls, Olli T. Raitakari, Sahoko Ichihara, Sarah H. Wild, Christopher P. Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S. Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Dominique de Kleijn, Gert J. de Borst, Eung Kweon Kim, Hieab H. H. Adams, M. Arfan Ikram, Xiaofeng Zhu, Folkert W. Asselbergs, Adriaan O. Kraaijeveld, Joline W. J. Beulens, Xiao-Ou Shu, Loukianos S. Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W. Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E. Pennell, Trevor A. Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M. Heid, Klaus J. Stark, Martina E. Zimmermann, Henry Völzke, Georg Homuth, Michele K. Evans, Alan B. Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E. Hoefer, Susan Redline, Katja Pahkala, Albertine J. Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Sharon L. R. Kardia, Patricia A. Peyser, Norihiro Kato, Matthias B. Schulze, Giorgia Girotto, Carsten A. Böger, Bettina Jung, Peter K. Joshi, David A. Bennett, Philip L. De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J. Caulfield, Patricia B. Munroe, Xiuqing Guo, Marina Ciullo, Jost B. Jonas, Nilesh J. Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié-Luna, Carlos A. Aguilar-Salinas, Linda S. Adair, Sonny Augustin Bechayda, H. Janaka de Silva, Ananda R. Wickremasinghe, Ronald M. Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke Iden Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G. Wilson, Lars Lind, Chew-Kiat Heng, Amanda E. Nelson, Yvonne M. Golightly, James F. Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J. Scott, D. C. Rao, Donna K. Arnett, Steven C. Hunt, Mark Walker, Heikki A. Koistinen, Giriraj R. Chandak, Josep M. Mercader, Maria C. Costanzo, Dongkeun Jang, Noël P. Burtt, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, EShyong Tai, Rob M. van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F. Reilly, Amy Jayne McKnight, Frank Kee, Karl-Heinz Jöckel, Mark I. McCarthy, Colin N. A. Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M. van Duijn, Zi-Bing Jin, Jia Qu, Haretsugu Hishigaki, Xu Lin, Winfried März, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M.‘t Hart, Petra J. M. Elders, Scott M. Damrauer, Meena Kumari, Mika Kivimaki, Pim van der Harst, Tim D. Spector, Ruth J. F. Loos, Michael A. Province, Esteban J. Parra, Miguel Cruz, Bruce M. Psaty, Ivan Brandslund, Peter P. Pramstaller, Charles N. Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F. A. Grant, Lambertus A. L. M. Kiemeney, Jacqueline de Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W. Franks, Allan Linneberg, J. Wouter Jukema, Amit V. Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Cucca Francesco, Dennis O. Mook-Kanamori, Ko Willems van Dijk, Hugh Watkins, David P. Strachan, Niels Grarup, Peter Sever, Neil Poulter, Lee-Ming Chuang, Jerome I. Rotter, Thomas M. Dantoft, Fredrik Karpe, Matt J. Neville, Nicholas J. Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T. Hattersley, Nancy L. Pedersen, Patrik K. E. Magnusson, Dorret I. Boomsma, Allegonda H. M. Willemsen, LAdrienne Cupples, Joyce B. J. van Meurs, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J. Wareham, Claudia Langenberg, Eleftheria Zeggini, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C. Chambers, Jaspal S. Kooner, Paul S. de Vries, Alanna C. Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E. North, Martha Daviglus, Peter Kraft, Nicholas G. Martin, John B. Whitfield, Shahid Abbas, Danish Saleheen, Robin G. Walters, Michael V. Holmes, Corri Black, Blair H. Smith, Aris Baras, Anne E. Justice, Julie E. Buring, Paul M. Ridker, Daniel I. Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A. van Heel, Richard C. Trembath, Wei-Qi Wei, Gail P. Jarvik, Bahram Namjou, M. Geoffrey Hayes, Marylyn D. Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Thorsteinsdottir, Kari Stefansson, Jifeng Zhang, YEugene Chen, Yuk-Lam Ho, Julie A. Lynch, Daniel J. Rader, Philip S. Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J. O’Donnell, John M. Gaziano, Peter W. F. Wilson, Timothy M. Frayling, Joel N. Hirschhorn, Sekar Kathiresan, Karen L. Mohlke, Yan V. Sun, Andrew P. Morris, Michael Boehnke, Christopher D. Brown, Pradeep Natarajan, Panos Deloukas, Cristen J. Willer, Themistocles L. Assimes, Gina M. Peloso, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Medicum, Institute for Molecular Medicine Finland, Complex Disease Genetics, Samuli Olli Ripatti / Principal Investigator, HUSLAB, Epigenetics of Complex Diseases and Traits, Department of Medicine, Helsinki University Hospital Area, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Faculty Common Matters (Faculty of Social Sciences), Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, Tampere University, Primary Health Care, Clinical Medicine, Department of Clinical Chemistry, TAYS Heart Centre, Department of Clinical Physiology and Nuclear Medicine, Epidemiology and Data Science, APH - Aging & Later Life, ACS - Diabetes & metabolism, ACS - Heart failure & arrhythmias, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, General practice, APH - Digital Health, Lee Kong Chian School of Medicine (LKCMedicine), Peloso, Gina M [0000-0002-5355-8636], Apollo - University of Cambridge Repository, Epidemiology, Department of Marketing Management, Erasmus MC other, Radiology & Nuclear Medicine, Kanoni, Stavroula, Graham, Sarah E, Wang, Yuxuan, Surakka, Ida, Ramdas, Shweta, Zhu, Xiang, Clarke, Shoa L, Bhatti, Konain Fatima, Vedantam, Sailaja, Winkler, Thomas W, Locke, Adam E, Marouli, Eirini, Zajac, Greg J M, Wu, Kuan-Han H, Ntalla, Ioanna, Hui, Qin, Klarin, Derek, Hilliard, Austin T, Wang, Zeyuan, Xue, Chao, Thorleifsson, Gudmar, Helgadottir, Anna, Gudbjartsson, Daniel F, Holm, Hilma, Olafsson, Isleifur, Hwang, Mi Yeong, Han, Sohee, Akiyama, Masato, Sakaue, Saori, Terao, Chikashi, Kanai, Masahiro, Zhou, Wei, Brumpton, Ben M, Rasheed, Humaira, Havulinna, Aki S, Veturi, Yogasudha, Pacheco, Jennifer Allen, Rosenthal, Elisabeth A, Lingren, Todd, Feng, Qiping, Kullo, Iftikhar J, Narita, Akira, Takayama, Jun, Martin, Hilary C, Hunt, Karen A, Trivedi, Bhavi, Haessler, Jeffrey, Giulianini, Franco, Bradford, Yuki, Miller, Jason E, Campbell, Archie, Lin, Kuang, Millwood, Iona Y, Rasheed, Asif, Hindy, George, Faul, Jessica D, Zhao, Wei, Weir, David R, Turman, Constance, Huang, Hongyan, Graff, Mariaelisa, Choudhury, Ananyo, Sengupta, Dhriti, Mahajan, Anubha, Brown, Michael R, Zhang, Weihua, Yu, Ketian, Schmidt, Ellen M, Pandit, Anita, Gustafsson, Stefan, Yin, Xianyong, Luan, Jian'An, Zhao, Jing-Hua, Matsuda, Fumihiko, Jang, Hye-Mi, Yoon, Kyungheon, Medina-Gomez, Carolina, Pitsillides, Achillea, Hottenga, Jouke Jan, Wood, Andrew R, Ji, Yingji, Gao, Zishan, Haworth, Simon, Yousri, Noha A, Mitchell, Ruth E, Chai, Jin Fang, Aadahl, Mette, Bjerregaard, Anne A, Yao, Jie, Manichaikul, Ani, Hwu, Chii-Min, Hung, Yi-Jen, Warren, Helen R, Ramirez, Julia, Bork-Jensen, Jette, Kårhus, Line L, Goel, Anuj, Sabater-Lleal, Maria, Noordam, Raymond, Mauro, Pala, Matteo, Flori, Mcdaid, Aaron F, Marques-Vidal, Pedro, Wielscher, Matthia, Trompet, Stella, Sattar, Naveed, Møllehave, Line T, Munz, Matthia, Zeng, Lingyao, Huang, Jianfeng, Yang, Bin, Poveda, Alaitz, Kurbasic, Azra, Lamina, Claudia, Forer, Luka, Scholz, Marku, Galesloot, Tessel E, Bradfield, Jonathan P, Ruotsalainen, Sanni E, Daw, Ewarwick, Zmuda, Joseph M, Mitchell, Jonathan S, Fuchsberger, Christian, Christensen, Henry, Brody, Jennifer A, Vazquez-Moreno, Miguel, Feitosa, Mary F, Wojczynski, Mary K, Wang, Zhe, Preuss, Michael H, Mangino, Massimo, Christofidou, Paraskevi, Verweij, Niek, Benjamins, Jan W, Engmann, Jorgen, Tsao, Noah L, Verma, Anurag, Slieker, Roderick C, Lo, Ken Sin, Zilhao, Nuno R, Le, Phuong, Kleber, Marcus E, Delgado, Graciela E, Huo, Shaofeng, Ikeda, Daisuke D, Iha, Hiroyuki, Yang, Jian, Liu, Jun, Demirkan, Ayşe, Leonard, Hampton L, Marten, Jonathan, Frank, Mirjam, Schmidt, Börge, Smyth, Laura J, Cañadas-Garre, Marisa, Wang, Chaolong, Nakatochi, Masahiro, Wong, Andrew, Hutri-Kähönen, Nina, Sim, Xueling, Xia, Rui, Huerta-Chagoya, Alicia, Fernandez-Lopez, Juan Carlo, Lyssenko, Valeriya, Nongmaithem, Suraj S, Bayyana, Swati, Stringham, Heather M, Irvin, Marguerite R, Oldmeadow, Christopher, Kim, Han-Na, Ryu, Seungho, Timmers, Paul R H J, Arbeeva, Liubov, Dorajoo, Rajkumar, Lange, Leslie A, Prasad, Gauri, Lorés-Motta, Laura, Pauper, Marc, Long, Jirong, Li, Xiaohui, Theusch, Elizabeth, Takeuchi, Fumihiko, Spracklen, Cassandra N, Loukola, Anu, Bollepalli, Sailalitha, Warner, Sophie C, Wang, Ya Xing, Wei, Wen B, Nutile, Teresa, Ruggiero, Daniela, Sung, Yun Ju, Chen, Shufeng, Liu, Fangchao, Yang, Jingyun, Kentistou, Katherine A, Banas, Bernhard, Nardone, Giuseppe Giovanni, Meidtner, Karina, Bielak, Lawrence F, Smith, Jennifer A, Hebbar, Prashantha, Farmaki, Aliki-Eleni, Hofer, Edith, Lin, Maoxuan, Concas, Maria Pina, Vaccargiu, Simona, van der Most, Peter J, Pitkänen, Niina, Cade, Brian E, van der Laan, Sander W, Chitrala, Kumaraswamy Naidu, Weiss, Stefan, Bentley, Amy R, Doumatey, Ayo P, Adeyemo, Adebowale A, Lee, Jong Young, Petersen, Eva R B, Nielsen, Aneta A, Choi, Hyeok Sun, Nethander, Maria, Freitag-Wolf, Sandra, Southam, Lorraine, Rayner, Nigel W, Wang, Carol A, Lin, Shih-Yi, Wang, Jun-Sing, Couture, Christian, Lyytikäinen, Leo-Pekka, Nikus, Kjell, Cuellar-Partida, Gabriel, Vestergaard, Henrik, Hidalgo, Bertha, Giannakopoulou, Olga, Cai, Qiuyin, Obura, Morgan O, van Setten, Jessica, Li, Xiaoyin, Liang, Jingjing, Tang, Hua, Terzikhan, Natalie, Shin, Jae Hun, Jackson, Rebecca D, Reiner, Alexander P, Martin, Lisa Warsinger, Chen, Zhengming, Li, Liming, Kawaguchi, Takahisa, Thiery, Joachim, Bis, Joshua C, Launer, Lenore J, Li, Huaixing, Nalls, Mike A, Raitakari, Olli T, Ichihara, Sahoko, Wild, Sarah H, Nelson, Christopher P, Campbell, Harry, Jäger, Susanne, Nabika, Toru, Al-Mulla, Fahd, Niinikoski, Harri, Braund, Peter S, Kolcic, Ivana, Kovacs, Peter, Giardoglou, Tota, Katsuya, Tomohiro, de Kleijn, Dominique, de Borst, Gert J, Kim, Eung Kweon, Adams, Hieab H H, Ikram, M Arfan, Zhu, Xiaofeng, Asselbergs, Folkert W, Kraaijeveld, Adriaan O, Beulens, Joline W J, Shu, Xiao-Ou, Rallidis, Loukianos S, Pedersen, Oluf, Hansen, Torben, Mitchell, Paul, Hewitt, Alex W, Kähönen, Mika, Pérusse, Loui, Bouchard, Claude, Tönjes, Anke, Chen, Yii-Der Ida, Pennell, Craig E, Mori, Trevor A, Lieb, Wolfgang, Franke, Andre, Ohlsson, Clae, Mellström, Dan, Cho, Yoon Shin, Lee, Hyejin, Yuan, Jian-Min, Koh, Woon-Puay, Rhee, Sang Youl, Woo, Jeong-Taek, Heid, Iris M, Stark, Klaus J, Zimmermann, Martina E, Völzke, Henry, Homuth, Georg, Evans, Michele K, Zonderman, Alan B, Polasek, Ozren, Pasterkamp, Gerard, Hoefer, Imo E, Redline, Susan, Pahkala, Katja, Oldehinkel, Albertine J, Snieder, Harold, Biino, Ginevra, Schmidt, Reinhold, Schmidt, Helena, Bandinelli, Stefania, Dedoussis, George, Thanaraj, Thangavel Alphonse, Kardia, Sharon L R, Peyser, Patricia A, Kato, Norihiro, Schulze, Matthias B, Girotto, Giorgia, Böger, Carsten A, Jung, Bettina, Joshi, Peter K, Bennett, David A, De Jager, Philip L, Lu, Xiangfeng, Mamakou, Vasiliki, Brown, Morri, Caulfield, Mark J, Munroe, Patricia B, Guo, Xiuqing, Ciullo, Marina, Jonas, Jost B, Samani, Nilesh J, Kaprio, Jaakko, Pajukanta, Päivi, Tusié-Luna, Teresa, Aguilar-Salinas, Carlos A, Adair, Linda S, Bechayda, Sonny Augustin, de Silva, H Janaka, Wickremasinghe, Ananda R, Krauss, Ronald M, Wu, Jer-Yuarn, Zheng, Wei, Hollander, Anneke Iden, Bharadwaj, Dwaipayan, Correa, Adolfo, Wilson, James G, Lind, Lar, Heng, Chew-Kiat, Nelson, Amanda E, Golightly, Yvonne M, Wilson, James F, Penninx, Brenda, Kim, Hyung-Lae, Attia, John, Scott, Rodney J, Rao, D C, Arnett, Donna K, Hunt, Steven C, Walker, Mark, Koistinen, Heikki A, Chandak, Giriraj R, Mercader, Josep M, Costanzo, Maria C, Jang, Dongkeun, Burtt, Noël P, Villalpando, Clicerio Gonzalez, Orozco, Lorena, Fornage, Myriam, Tai, Eshyong, van Dam, Rob M, Lehtimäki, Terho, Chaturvedi, Nish, Yokota, Mitsuhiro, Liu, Jianjun, Reilly, Dermot F, Mcknight, Amy Jayne, Kee, Frank, Jöckel, Karl-Heinz, Mccarthy, Mark I, Palmer, Colin N A, Vitart, Veronique, Hayward, Caroline, Simonsick, Eleanor, van Duijn, Cornelia M, Jin, Zi-Bing, Qu, Jia, Hishigaki, Haretsugu, Lin, Xu, März, Winfried, Gudnason, Vilmundur, Tardif, Jean-Claude, Lettre, Guillaume, Hart, Leen M 't, Elders, Petra J M, Damrauer, Scott M, Kumari, Meena, Kivimaki, Mika, van der Harst, Pim, Spector, Tim D, Loos, Ruth J F, Province, Michael A, Parra, Esteban J, Cruz, Miguel, Psaty, Bruce M, Brandslund, Ivan, Pramstaller, Peter P, Rotimi, Charles N, Christensen, Kaare, Ripatti, Samuli, Widén, Elisabeth, Hakonarson, Hakon, Grant, Struan F A, Kiemeney, Lambertus A L M, de Graaf, Jacqueline, Loeffler, Marku, Kronenberg, Florian, Gu, Dongfeng, Erdmann, Jeanette, Schunkert, Heribert, Franks, Paul W, Linneberg, Allan, Jukema, J Wouter, Khera, Amit V, Männikkö, Minna, Jarvelin, Marjo-Riitta, Kutalik, Zoltan, Francesco, Cucca, Mook-Kanamori, Dennis O, van Dijk, Ko Willem, Watkins, Hugh, Strachan, David P, Grarup, Niel, Sever, Peter, Poulter, Neil, Chuang, Lee-Ming, Rotter, Jerome I, Dantoft, Thomas M, Karpe, Fredrik, Neville, Matt J, Timpson, Nicholas J, Cheng, Ching-Yu, Wong, Tien-Yin, Khor, Chiea Chuen, Li, Hengtong, Sabanayagam, Charumathi, Peters, Annette, Gieger, Christian, Hattersley, Andrew T, Pedersen, Nancy L, Magnusson, Patrik K E, Boomsma, Dorret I, Willemsen, Allegonda H M, Cupples, Ladrienne, van Meurs, Joyce B J, Ghanbari, Mohsen, Gordon-Larsen, Penny, Huang, Wei, Kim, Young Jin, Tabara, Yasuharu, Wareham, Nicholas J, Langenberg, Claudia, Zeggini, Eleftheria, Kuusisto, Johanna, Laakso, Markku, Ingelsson, Erik, Abecasis, Goncalo, Chambers, John C, Kooner, Jaspal S, de Vries, Paul S, Morrison, Alanna C, Hazelhurst, Scott, Ramsay, Michèle, North, Kari E, Daviglus, Martha, Kraft, Peter, Martin, Nicholas G, Whitfield, John B, Abbas, Shahid, Saleheen, Danish, Walters, Robin G, Holmes, Michael V, Black, Corri, Smith, Blair H, Baras, Ari, Justice, Anne E, Buring, Julie E, Ridker, Paul M, Chasman, Daniel I, Kooperberg, Charle, Tamiya, Gen, Yamamoto, Masayuki, van Heel, David A, Trembath, Richard C, Wei, Wei-Qi, Jarvik, Gail P, Namjou, Bahram, Hayes, M Geoffrey, Ritchie, Marylyn D, Jousilahti, Pekka, Salomaa, Veikko, Hveem, Kristian, Åsvold, Bjørn Olav, Kubo, Michiaki, Kamatani, Yoichiro, Okada, Yukinori, Murakami, Yoshinori, Kim, Bong-Jo, Thorsteinsdottir, Unnur, Stefansson, Kari, Zhang, Jifeng, Chen, Yeugene, Ho, Yuk-Lam, Lynch, Julie A, Rader, Daniel J, Tsao, Philip S, Chang, Kyong-Mi, Cho, Kelly, O'Donnell, Christopher J, Gaziano, John M, Wilson, Peter W F, Frayling, Timothy M, Hirschhorn, Joel N, Kathiresan, Sekar, Mohlke, Karen L, Sun, Yan V, Morris, Andrew P, Boehnke, Michael, Brown, Christopher D, Natarajan, Pradeep, Deloukas, Pano, Willer, Cristen J, Assimes, Themistocles L, and Peloso, Gina M

Subjects
Genome-wide association study, Medizin, Polymorphism, Single Nucleotide, Humans, Genome-Wide Association Study, Genetic Predisposition to Disease, Sex Characteristics, Phenotype, Lipids/genetics, Genetic Pleiotropy, Cholesterol, GWAS, Genetics, Lipids, Genetic, SDG 3 - Good Health and Well-being, Medicine [Science], 112 Statistics and probability, Medicinsk genetik, Genome-wide Association Study, Gwas, 1184 Genetics, developmental biology, physiology, 3126 Surgery, anesthesiology, intensive care, radiology, 3142 Public health care science, environmental and occupational health, 3141 Health care science, FOS: Biological sciences, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 3111 Biomedicine, Medical Genetics
Abstract

Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry metaanalysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk., United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Heart Lung & Blood Institute (NHLBI) R01HL127564 R01HL142711, Wellcome Trust 201543/B/16/Z 202802/Z/16/Z, European Commission HEALTH-F2-2013-601456 608765 786833, TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation NNF15CC0018486, American Diabetes Association 1-19-ICTS-068, Academy of Finland 312062 Finnish Foundation for Cardiovascular Research, Sigrid Juselius Foundation, Finnish innovation fund Sitra (EW) Finska Lakaresallskapet, American Heart Association 15POST24470131 17POST33650016, University of Bristol NIHR Biomedical Research Centre BRC-1215-2001, MRC & WT 217065/Z/19/Z, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) MC_UU_00011, CRUK Integrative Cancer Epidemiology Programme C18281/A19169, Medical Research Council UK (MRC) MC_UU_00011/1, UK National Institute for Health Research Academic Clinical Fellowship, American Heart Association 18CDA34110116, Miguel Servet contract from the ISCIII Spanish Health Institute CP17/00142, European Social Fund (ESF), Westlake Education Foundation, British Heart Foundation FS/14/66/3129 Z01HG200362 R01HL142302 R01HL105756

Published
2022
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6. The need for polygenic score reporting standards in evidence-based practice: lipid genetics use case

Author

Hannah Wand, Shoa L. Clarke, and Joshua W. Knowles

Subjects
0301 basic medicine, Multifactorial Inheritance, Evidence-based practice, precision medicine, reporting standards, Endocrinology, Diabetes and Metabolism, Clinical Decision-Making, GENETICS AND MOLECULAR BIOLOGY: Edited by Robert A. Hegele, Technical standard, MEDLINE, 030204 cardiovascular system & hematology, Risk Assessment, 03 medical and health sciences, translational medicine, 0302 clinical medicine, Resource (project management), Genetics, Humans, polygenic score, Generalizability theory, Genetic Testing, Molecular Biology, Dyslipidemias, Nutrition and Dietetics, Clinical study design, Reproducibility of Results, Cell Biology, Lipids, Data sharing, 030104 developmental biology, Risk analysis (engineering), Evidence-Based Practice, lipids (amino acids, peptides, and proteins), evidence-based medicine, Cardiology and Cardiovascular Medicine, Psychology, Risk assessment
Abstract

Purpose of review Polygenic scores (PGS) are used to quantify the genetic predisposition for heritable traits, with hypothesized utility for personalized risk assessments. Lipid PGS are primed for clinical translation, but evidence-based practice changes will require rigorous PGS standards to ensure reproducibility and generalizability. Here we review applicable reporting and technical standards for dyslipidemia PGS translation along phases of the ACCE (Analytical validity, Clinical validity, Clinical utility, Ethical considerations) framework for evaluating genetic tests. Recent findings New guidance suggests existing standards for study designs incorporating the ACCE framework are applicable to PGS and should be adopted. One recent example is the Clinical Genomics Resource (ClinGen) and Polygenic Score Catalog's PRS reporting standards, which define minimal requirements for describing rationale for score development, study population definitions and data parameters, risk model development and application, risk model evaluation, and translational considerations, such as generalizability beyond the target population studied. Summary Lipid PGS are likely to be integrated into clinical practice in the future. Clinicians will need to be prepared to determine if and when lipid PGS is useful and valid. This decision-making will depend on the quality of evidence for the clinical use of PGS. Establishing reporting standards for PGS will help facilitate data sharing and transparency for critical evaluation, ultimately benefiting the efficiency of evidence-based practice.

Published
2021
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7. Associations of Genetically Predicted Lp(a) (Lipoprotein [a]) Levels With Cardiovascular Traits in Individuals of European and African Ancestry

Author

Themistocles L. Assimes, Ozan Dikilitas, Maya S. Safarova, Mariza de Andrade, Amy S. Shah, Iftikhar J. Kullo, Gail P. Jarvik, Bahram Namjou-Khales, Shoa L. Clarke, Benjamin A. Satterfield, Wei-Qi Wei, Elisabeth A. Rosenthal, QiPing Feng, Teri A. Manolio, Xiang Zhu, Anne E. Justice, Ning Shang, Catherine Tcheandjieu, Eric B. Larson, Elaine M. Urbina, Lisa Bastarache, and Scott J. Hebbring

Subjects
Male, 0301 basic medicine, A lipoprotein, Black People, 030204 cardiovascular system & hematology, Biology, Article, White People, 03 medical and health sciences, Quantitative Trait, Heritable, 0302 clinical medicine, Humans, Genetic Predisposition to Disease, Aged, Aged, 80 and over, Genetics, Mendelian Randomization Analysis, General Medicine, Middle Aged, United Kingdom, 030104 developmental biology, Cardiovascular Diseases, Female, Lipoprotein(a), Lipoprotein
Abstract

Background: Lp(a) (lipoprotein [a]) levels are higher in individuals of African ancestry (AA) than in individuals of European ancestry (EA). We examined associations of genetically predicted Lp(a) levels with (1) atherosclerotic cardiovascular disease subtypes: coronary heart disease, cerebrovascular disease, peripheral artery disease, and abdominal aortic aneurysm and (2) nonatherosclerotic cardiovascular disease phenotypes, stratified by ancestry. Methods: We performed (1) Mendelian randomization analyses for previously reported cardiovascular associations and (2) Mendelian randomization–phenome-wide association analyses for novel associations. Analyses were stratified by ancestry in electronic Medical Records and Genomics, United Kingdom Biobank, and Million Veteran Program cohorts separately and in a combined cohort of 804 507 EA and 103 580 AA participants. Results: In Mendelian randomization analyses using the combined cohort, a 1-SD genetic increase in Lp(a) level was associated with atherosclerotic cardiovascular disease subtypes in EA—odds ratio and 95% CI for coronary heart disease 1.28 (1.16–1.41); cerebrovascular disease 1.14 (1.07–1.21); peripheral artery disease 1.22 (1.11–1.34); abdominal aortic aneurysm 1.28 (1.17–1.40); in AA, the effect estimate was lower than in EA and nonsignificant for coronary heart disease 1.11 (0.99–1.24) and cerebrovascular disease 1.06 (0.99–1.14) but similar for peripheral artery disease 1.16 (1.01–1.33) and abdominal aortic aneurysm 1.34 (1.11–1.62). In EA, a 1-SD genetic increase in Lp(a) level was associated with aortic valve disorders 1.34 (1.10–1.62), mitral valve disorders 1.18 (1.09–1.27), congestive heart failure 1.12 (1.05–1.19), and chronic kidney disease 1.07 (1.01–1.14). In AA, no significant associations were noted for aortic valve disorders 1.08 (0.94–1.25), mitral valve disorders 1.02 (0.89–1.16), congestive heart failure 1.02 (0.95–1.10), or chronic kidney disease 1.05 (0.99–1.12). Mendelian randomization–phenome-wide association analyses identified novel associations in EA with arterial thromboembolic disease, nonaortic aneurysmal disease, atrial fibrillation, cardiac conduction disorders, and hypertension. Conclusions: Many cardiovascular associations of genetically increased Lp(a) that were significant in EA were not significant in AA. Lp(a) was associated with atherosclerotic cardiovascular disease in four major arterial beds in EA but only with peripheral artery disease and abdominal aortic aneurysm in AA. Additionally, novel cardiovascular associations were detected in EA.

Published
2021
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8. PRISM offers a comprehensive genomic approach to transcription factor function prediction

Author

Gill Bejerano, Bruce T. Schaar, Aaron M. Wenger, Shoa L. Clarke, Harendra Guturu, Jenny Chen, and Cory Y. McLean

Subjects
Resource, False discovery rate, Computational biology, Regulatory Sequences, Nucleic Acid, Biology, Mice, Genetics, Animals, Humans, Binding site, Enhancer, Gene, Transcription factor, Genetics (clinical), Binding Sites, Genome, Base Sequence, Computational Biology, DNA-Binding Proteins, DNA binding site, Human genome, TRANSFAC, Algorithms, Software, Protein Binding, Transcription Factors
Abstract

The human genome encodes 1500–2000 different transcription factors (TFs). ChIP-seq is revealing the global binding profiles of a fraction of TFs in a fraction of their biological contexts. These data show that the majority of TFs bind directly next to a large number of context-relevant target genes, that most binding is distal, and that binding is context specific. Because of the effort and cost involved, ChIP-seq is seldom used in search of novel TF function. Such exploration is instead done using expression perturbation and genetic screens. Here we propose a comprehensive computational framework for transcription factor function prediction. We curate 332 high-quality nonredundant TF binding motifs that represent all major DNA binding domains, and improve cross-species conserved binding site prediction to obtain 3.3 million conserved, mostly distal, binding site predictions. We combine these with 2.4 million facts about all human and mouse gene functions, in a novel statistical framework, in search of enrichments of particular motifs next to groups of target genes of particular functions. Rigorous parameter tuning and a harsh null are used to minimize false positives. Our novel PRISM (predicting regulatory information from single motifs) approach obtains 2543 TF function predictions in a large variety of contexts, at a false discovery rate of 16%. The predictions are highly enriched for validated TF roles, and 45 of 67 (67%) tested binding site regions in five different contexts act as enhancers in functionally matched cells.

Published
2013
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9. Erosion of Conserved Binding Sites in Personal Genomes Points to Medical Histories

Author

Shoa L. Clarke, Harendra Guturu, Gill Bejerano, and Sandeep Chinchali

Subjects
0301 basic medicine, Genomics, Genome-wide association study, Disease, Biology, Linkage Disequilibrium, 03 medical and health sciences, Cellular and Molecular Neuroscience, Genetics, HLA-DQ beta-Chains, Humans, Expressivity (genetics), Precision Medicine, Molecular Biology, lcsh:QH301-705.5, Ecology, Evolution, Behavior and Systematics, Narcolepsy, Comparative genomics, Binding Sites, Models, Statistical, Models, Genetic, Ecology, Genome, Human, Penetrance, 3. Good health, DNA binding site, 030104 developmental biology, Computational Theory and Mathematics, lcsh:Biology (General), Modeling and Simulation, Mutation, Human genome, Research Article
Abstract

Although many human diseases have a genetic component involving many loci, the majority of studies are statistically underpowered to isolate the many contributing variants, raising the question of the existence of alternate processes to identify disease mutations. To address this question, we collect ancestral transcription factor binding sites disrupted by an individual’s variants and then look for their most significant congregation next to a group of functionally related genes. Strikingly, when the method is applied to five different full human genomes, the top enriched function for each is invariably reflective of their very different medical histories. For example, our method implicates “abnormal cardiac output” for a patient with a longstanding family history of heart disease, “decreased circulating sodium level” for an individual with hypertension, and other biologically appealing links for medical histories spanning narcolepsy to axonal neuropathy. Our results suggest that erosion of gene regulation by mutation load significantly contributes to observed heritable phenotypes that manifest in the medical history. The test we developed exposes a hitherto hidden layer of personal variants that promise to shed new light on human disease penetrance, expressivity and the sensitivity with which we can detect them., Author Summary A central goal of personal genomics is to interpret an individual’s genome to identify variants that confer disease risk, an aim that has far-reaching implications for personalized, precision medicine. Here, we leverage next generation sequencing, health records, and functional genome annotations to develop statistical methods that predict disease risk from a single genome. Motivated by the fact that about 90% of genome-wide association study disease-associated variants lie in the non-coding genome, we identify personal variants that mutate conserved transcription factor binding sites. To identify if such non-coding personal variants collectively dysregulate a key biological process, we employ the enrichment analysis tool GREAT to identify if a person’s noncoding mutations are over-represented in the regulatory domains of genes involved in a common biological pathway. Notably, in five unrelated genomes we analyzed, the most statistically significant, seemingly dysregulated pathway is indicative of that person’s medical history, ranging from neuropathy to heart disease. Statistical analysis confirms that associations from our predicted pathway to an individual’s medical record are rigorous and significant in the context of the un-phenotyped, race-matched 1,000 Genomes cohort. As such, we present a novel method that leverages the contribution of multifactorial non-coding variation to predict disease risk in individual genomes.

Published
2016

10. Coding exons function as tissue-specific enhancers of nearby genes

Author

Shoa L. Clarke, Loan Nguyen, Ramon Y. Birnbaum, Orly Agamy, Fiorella Gurrieri, Zachary Pappalardo, Gill Bejerano, Mee J. Kim, E. Josephine Clowney, Aaron M. Wenger, Jingjing Zhao, Charles E. Schwartz, David B. Everman, Stavros Lomvardas, Ohad S. Birk, Nadav Ahituv, and Takayuki Yamanaka

Subjects
Cytoplasmic Dyneins, Male, Chromatin Immunoprecipitation, coding exons, Limb Deformities, Congenital, Mice, Transgenic, Enhancer RNAs, Biology, Settore MED/03 - GENETICA MEDICA, Mice, chemistry.chemical_compound, Exon, Genetics, Animals, Humans, Promoter Regions, Genetic, Enhancer, EP300, Gene, In Situ Hybridization, Fluorescence, Zebrafish, Genetics (clinical), Chromosome Aberrations, Homeodomain Proteins, Regulation of gene expression, Research, Extremities, Exons, Enhancer Elements, Genetic, Gene Expression Regulation, chemistry, Essential gene, Female, DNA
Abstract

Enhancers are essential gene regulatory elements whose alteration can lead to morphological differences between species, developmental abnormalities, and human disease. Current strategies to identify enhancers focus primarily on noncoding sequences and tend to exclude protein coding sequences. Here, we analyzed 25 available ChIP-seq data sets that identify enhancers in an unbiased manner (H3K4me1, H3K27ac, and EP300) for peaks that overlap exons. We find that, on average, 7% of all ChIP-seq peaks overlap coding exons (after excluding for peaks that overlap with first exons). By using mouse and zebrafish enhancer assays, we demonstrate that several of these exonic enhancer (eExons) candidates can function as enhancers of their neighboring genes and that the exonic sequence is necessary for enhancer activity. Using ChIP, 3C, and DNA FISH, we further show that one of these exonic limb enhancers, Dync1i1 exon 15, has active enhancer marks and physically interacts with Dlx5/6 promoter regions 900 kb away. In addition, its removal by chromosomal abnormalities in humans could cause split hand and foot malformation 1 (SHFM1), a disorder associated with DLX5/6. These results demonstrate that DNA sequences can have a dual function, operating as coding exons in one tissue and enhancers of nearby gene(s) in another tissue, suggesting that phenotypes resulting from coding mutations could be caused not only by protein alteration but also by disrupting the regulation of another gene.

Published
2012
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11. GREAT improves functional interpretation of cis-regulatory regions

Author

Cory Y. McLean, Bruce T. Schaar, Craig B. Lowe, Michael Hiller, Gill Bejerano, Dave Bristor, Shoa L. Clarke, and Aaron M. Wenger

Subjects
Chromatin Immunoprecipitation, Serum Response Factor, Biomedical Engineering, Bioengineering, Genomics, ATAC-seq, Computational biology, Biology, Applied Microbiology and Biotechnology, Human accelerated regions, Article, Jurkat Cells, Mice, Databases, Genetic, Animals, Data Mining, Humans, Regulatory Elements, Transcriptional, ChIA-PET, Epigenomics, Genetics, Comparative genomics, Genome, Massive parallel sequencing, ChIP-sequencing, Molecular Medicine, E1A-Associated p300 Protein, Software, Protein Binding, Biotechnology
Abstract

We developed the Genomic Regions Enrichment of Annotations Tool (GREAT) to analyze the functional significance of cis-regulatory regions identified by localized measurements of DNA binding events across an entire genome. Whereas previous methods took into account only binding proximal to genes, GREAT is able to properly incorporate distal binding sites and control for false positives using a binomial test over the input genomic regions. GREAT incorporates annotations from 20 ontologies and is available as a web application. Applying GREAT to data sets from chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-seq) of multiple transcription-associated factors, including SRF, NRSF, GABP, Stat3 and p300 in different developmental contexts, we recover many functions of these factors that are missed by existing gene-based tools, and we generate testable hypotheses. The utility of GREAT is not limited to ChIP-seq, as it could also be applied to open chromatin, localized epigenomic markers and similar functional data sets, as well as comparative genomics sets.

Published
2010
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12. The enhancer landscape during early neocortical development reveals patterns of dense regulation and co-option

Author

Geetu Tuteja, Tisha Chung, Shoa L. Clarke, Bruce T. Schaar, Aaron M. Wenger, Gill Bejerano, Harendra Guturu, and James H. Notwell

Subjects
Cancer Research, lcsh:QH426-470, Interspersed repeat, Neocortex, Computational biology, Regulatory Sequences, Nucleic Acid, Biology, Conserved sequence, Evolution, Molecular, Mice, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Animals, Humans, Promoter Regions, Genetic, Enhancer, Molecular Biology, Gene, Transcription factor, Zebrafish, Conserved Sequence, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, Oligonucleotide Array Sequence Analysis, 030304 developmental biology, 0303 health sciences, Base Sequence, Gene Expression Regulation, Developmental, biology.organism_classification, lcsh:Genetics, Enhancer Elements, Genetic, medicine.anatomical_structure, Regulatory sequence, 030217 neurology & neurosurgery, Transcription Factors, Research Article
Abstract

Genetic studies have identified a core set of transcription factors and target genes that control the development of the neocortex, the region of the human brain responsible for higher cognition. The specific regulatory interactions between these factors, many key upstream and downstream genes, and the enhancers that mediate all these interactions remain mostly uncharacterized. We perform p300 ChIP-seq to identify over 6,600 candidate enhancers active in the dorsal cerebral wall of embryonic day 14.5 (E14.5) mice. Over 95% of the peaks we measure are conserved to human. Eight of ten (80%) candidates tested using mouse transgenesis drive activity in restricted laminar patterns within the neocortex. GREAT based computational analysis reveals highly significant correlation with genes expressed at E14.5 in key areas for neocortex development, and allows the grouping of enhancers by known biological functions and pathways for further studies. We find that multiple genes are flanked by dozens of candidate enhancers each, including well-known key neocortical genes as well as suspected and novel genes. Nearly a quarter of our candidate enhancers are conserved well beyond mammals. Human and zebrafish regions orthologous to our candidate enhancers are shown to most often function in other aspects of central nervous system development. Finally, we find strong evidence that specific interspersed repeat families have contributed potentially key developmental enhancers via co-option. Our analysis expands the methodologies available for extracting the richness of information found in genome-wide functional maps., Author Summary Sequencing based technologies provide global snapshots of transcriptional regulation. These data promise insights into gene regulation, disease susceptibility and organismal evolution. They also provide a methodological challenge in distilling specific hypotheses from large masses of data. Most work to date has focused on deriving broad biochemical insights. Here we obtain the active enhancer landscape of the dorsal cerebral wall during early neocortical development. We show that our set likely contains enhancers from both the developing neocortex, the ventricular, subventricular and intermediate zones, and develop methods to separate this mass into subsets of interest in particular contexts. We discover novel enhancers next to key neocortex development genes. We show that some known key and novel genes are regulated by dozens of enhancers each, and find known and novel enriched binding sites for key transcription factors in our set. Nearly all newly discovered enhancers are conserved in human. A quarter of loci are shared with non-mammalian vertebrates. We show that the human and zebrafish orthologs of our enhancers mostly drive expression in related nervous system contexts. We also show that particular interspersed repeats were preferentially co-opted into potentially key neocortex development enhancers.

Published
2013

13. Control of Pelvic Girdle Development by Genes of the Pbx Family and Emx2

Author

Gill Bejerano, Giuseppina Di Giacomo, Licia Selleri, Elisabetta Ferretti, Karen Handschuh, Laura Quintana, Vincenzo Zappavigna, Aaron M. Wenger, Terence D. Capellini, Giulia Vaccari, Shoa L. Clarke, James Sharpe, and Sebastian Fantini

Subjects
Male, Mesoderm, Mutant, Biology, Article, Somatopleuric mesenchyme, Pelvis, Mice, hemic and lymphatic diseases, Proto-Oncogene Proteins, medicine, Limb development, Animals, Paired Box Transcription Factors, Hox gene, Enhancer, Gene, In Situ Hybridization, Genetics, Homeodomain Proteins, Pelvic girdle, fungi, Pre-B-Cell Leukemia Transcription Factor 1, Computational Biology, Gene Expression Regulation, Developmental, emx2, pbx, hox, limb development, medicine.anatomical_structure, Female, T-Box Domain Proteins, Developmental Biology, Transcription Factors
Abstract

Genes expressed in the somatopleuric mesoderm, the embryonic domain giving rise to the vertebrate pelvis, appear important for pelvic girdle formation. Among such genes, Pbx family members and Emx2 were found to genetically interact in hindlimb and pectoral girdle formation. Here, we generated compound mutant embryos carrying combinations of mutated alleles for Pbx1, Pbx2, and Pbx3, as well as Pbx1 and Emx2, to examine potential genetic interactions during pelvic development. Indeed, Pbx genes share overlapping functions and Pbx1 and Emx2 genetically interact in pelvic formation. We show that, in compound Pbx1;Pbx2 and Pbx1;Emx2 mutants, pelvic mesenchymal condensation is markedly perturbed, indicative of an upstream control by these homeoproteins. We establish that expression of Tbx15, Prrx1, and Pax1, among other genes involved in the specification and development of select pelvic structures, is altered in our compound mutants. Lastly, we identify potential Pbx1-Emx2–regulated enhancers for Tbx15, Prrx1, and Pax1, using bioinformatics analyses. Developmental Dynamics 240:1173–1189, 2011. © 2011 Wiley-Liss, Inc.

Published
2011

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