Nature Genetics Contents: October 2014 pp 1043 - 1151

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At EA | Quintiles, our experienced scientists leverage innovative bioinformatics and methodologies to give you the genomic information you need to succeed. genomicknowhow.com Subscribe   Facebook   RSS   Recommend to library   Twitter   Advertisement The Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Nature Genetics, and Nature Reviews Cancer present: NUCLEAR REPROGRAMMING AND THE CANCER GENOME 2014 October 31- November 2, 2014 Ramada Plaza, Guangzhou, China  Click here for more information or to register for this conference today!   Editorial Top Growing quality   p1043 doi:10.1038/ng.3115 Brazil's success in applying a systems approach to agricultural productivity has been rapidly followed by an expansion in postgraduate training with particular strength in agronomy, plant molecular biology and biotechnology. Research publications with international impact will be a key to sustaining and exporting these successes. Obituary Top David H. Dressler 1941-2014   p1044 Huntington Potter doi:10.1038/ng.3099 News and Views Top Tetrad analysis in the mouse   pp1045 - 1046 Danny E Miller & R Scott Hawley doi:10.1038/ng.3104 Meiotic tetrad analysis is a powerful tool for analyzing all four products of a single meiosis. A new method for tetrad analysis in mammals provides valuable insights into the mechanisms that mediate the exchange of DNA sequences between homologs during meiosis and their influence on the evolution of recombination hotspots. See also: Article by Cole et al. Reaching a CNV milestone   pp1046 - 1048 Arthur L Beaudet doi:10.1038/ng.3106 A new study compares the copy number variants (CNVs) in 29,085 children with developmental delay to those in 19,584 healthy controls, providing a valuable compilation of such data. The phenotypic variability and wide range of penetrance for these variants present societal challenges regarding how these findings might be incorporated into newborn screening, early intervention and, perhaps, carrier testing and prenatal diagnosis. See also: Article by Coe et al. NLRC4 gets out of control   pp1048 - 1049 Hanif Javanmard Khameneh & Alessandra Mortellaro doi:10.1038/ng.3100 The NLRC4 inflammasome mediates the rapid release of proinflammatory cytokines in response to various microbial stimuli, but its role in the pathology of human diseases remains unknown. Two new studies now report gain-of-function mutations in the NLRC4 gene that cosegregate with distinct autoinflammatory syndromes in affected families. See also: Letter by Romberg et al. | Letter by Canna et al. Genetics JOBS of the week Postdoctoral Fellowship in Imaging Genetics Stanford Functional Imaging in Neuropsychiatric Disorders Laboratory Postdoctoral Researcher - Molecular & Medical Genetics Oregon Health & Science University (OHSU) Assistant Professor in Population Genetics University of Colorado Postdoc in Genomics and Translational Aspects of Oral Cancer Washington University School of Medicine Post-doctoral Fellow in statistical genomics and imaging analysis at Tulane University Tulane University - Biomedical Engineering More Science jobs from Genetics EVENT Malaria Experimental Genetics 15.03.15 Bangkok, Thailand More science events from Research Highlights Top Ebola genomes track virus evolution in real-time epidemic | Chromatin looping and globin expression | Mutational landscape of chromophobe renal cell carcinoma | Single-cell genomics in the brain | Hummingbird taste perception Analysis Top An integrated genomics approach identifies drivers of proliferation in luminal-subtype human breast cancer   pp1051 - 1059 Michael L Gatza, Grace O Silva, Joel S Parker, Cheng Fan & Charles M Perou doi:10.1038/ng.3073 Charles Perou and colleagues apply a panel of 52 published gene expression signatures of human breast tumors to expression data from The Cancer Genome Project to identify new proliferation drivers. They find genomic regions that are uniquely amplified in highly proliferative luminal breast tumors, including some that are correlated with poor prognosis. Brief Communication Top Recurrent point mutations in the kinetochore gene KNSTRN in cutaneous squamous cell carcinoma   pp1060 - 1062 Carolyn S Lee, Aparna Bhaduri, Angela Mah, Whitney L Johnson, Alexander Ungewickell, Cody J Aros, Christie B Nguyen, Eon J Rios, Zurab Siprashvili, Aaron Straight, Jinah Kim, Sumaira Z Aasi & Paul A Khavari doi:10.1038/ng.3091 Paul Khavari and colleagues identify recurrent mutations concentrated at an ultraviolet signature hotspot in the KNSTRN gene in 19% of cutaneous squamous cell carcinomas. KNSTRN encodes a kinetochore protein. Articles Top Refining analyses of copy number variation identifies specific genes associated with developmental delay   pp1063 - 1071 Bradley P Coe, Kali Witherspoon, Jill A Rosenfeld, Bregje W M van Bon, Anneke T Vulto-van Silfhout, Paolo Bosco, Kathryn L Friend, Carl Baker, Serafino Buono, Lisenka E L M Vissers, Janneke H Schuurs-Hoeijmakers, Alex Hoischen, Rolph Pfundt, Nik Krumm, Gemma L Carvill, Deana Li, David Amaral, Natasha Brown, Paul J Lockhart, Ingrid E Scheffer, Antonino Alberti, Marie Shaw, Rosa Pettinato, Raymond Tervo, Nicole de Leeuw, Margot R F Reijnders, Beth S Torchia, Hilde Peeters, Elizabeth Thompson, Brian J O'Roak, Marco Fichera, Jayne Y Hehir-Kwa, Jay Shendure, Heather C Mefford, Eric Haan, Jozef Gécz, Bert B A de Vries, Corrado Romano & Evan E Eichler doi:10.1038/ng.3092 Evan Eichler and colleagues report an expanded copy number variation (CNV) morbidity map of developmental delay, with additional resequencing of candidate genes in regions implicated by large CNVs. They identify several new disease-associated CNVs and show how their combined approach facilitates discovery of new developmental syndromes and disease genes. See also: News and Views by Beaudet Mouse tetrad analysis provides insights into recombination mechanisms and hotspot evolutionary dynamics   pp1072 - 1080 Francesca Cole, Frédéric Baudat, Corinne Grey, Scott Keeney, Bernard de Massy & Maria Jasin doi:10.1038/ng.3068 Scott Keeney, Bernard de Massy, Maria Jasin and colleagues report a method to perform tetrad analysis (analysis of all four chromatids from a single meiosis) in mouse and analyzed two recombination hotspots in mouse oocytes and spermatocytes. They show that gene conversion frequently spares the binding site of the hotspot-specifying protein PRDM9. See also: News and Views by Miller & Hawley A worldwide survey of genome sequence variation provides insight into the evolutionary history of the honeybee Apis mellifera   pp1081 - 1088 Andreas Wallberg, Fan Han, Gustaf Wellhagen, Bjørn Dahle, Masakado Kawata, Nizar Haddad, Zilá Luz Paulino Simões, Mike H Allsopp, Irfan Kandemir, Pilar De la Rúa, Christian W Pirk & Matthew T Webster doi:10.1038/ng.3077 Matthew Webster and colleagues report whole-genome sequencing of 140 honeybees from 14 worldwide populations. Their analyses provide insights into the evolutionary history and genetic basis of local adaptation in honeybees. Population genomics of Populus trichocarpa identifies signatures of selection and adaptive trait associations   pp1089 - 1096 Luke M Evans, Gancho T Slavov, Eli Rodgers-Melnick, Joel Martin, Priya Ranjan, Wellington Muchero, Amy M Brunner, Wendy Schackwitz, Lee Gunter, Jin-Gui Chen, Gerald A Tuskan & Stephen P DiFazio doi:10.1038/ng.3075 Stephen DiFazio and colleagues report the genome sequences and population genomic analyses of 544 black cottonwood trees (Populus trichocarpa) along the Northwest coast of North America. They find evidence for climate-driven selection on adaptive traits, including genes related to drought, photoperiod and stress. Letters Top Genetic landscape of esophageal squamous cell carcinoma   pp1097 - 1102 Yi-Bo Gao, Zhao-Li Chen, Jia-Gen Li, Xue-Da Hu, Xue-Jiao Shi, Zeng-Miao Sun, Fan Zhang, Zi-Ran Zhao, Zi-Tong Li, Zi-Yuan Liu, Yu-Da Zhao, Jian Sun, Cheng-Cheng Zhou, Ran Yao, Su-Ya Wang, Pan Wang, Nan Sun, Bai-Hua Zhang, Jing-Si Dong, Yue Yu, Mei Luo, Xiao-Li Feng, Su-Sheng Shi, Fang Zhou, Feng-Wei Tan, Bin Qiu, Ning Li, Kang Shao, Li-Jian Zhang, Lan-Jun Zhang, Qi Xue, Shu-Geng Gao & Jie He doi:10.1038/ng.3076 Jie He and colleagues report exome sequencing of 113 tumor-normal pairs of esophageal squamous cell carcinoma. They highlight mutations in genes involved in cell cycle and apoptosis regulation, histone modifier genes and genes encoding members of the Hippo and Notch pathways. A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer   pp1103 - 1109 Ali Amin Al Olama, Zsofia Kote-Jarai, Sonja I Berndt, David V Conti, Fredrick Schumacher, Ying Han, Sara Benlloch, Dennis J Hazelett, Zhaoming Wang, Ed Saunders, Daniel Leongamornlert, Sara Lindstrom, Sara Jugurnauth-Little, Tokhir Dadaev, Malgorzata Tymrakiewicz, Daniel O Stram, Kristin Rand, Peggy Wan, Alex Stram, Xin Sheng, Loreall C Pooler, Karen Park, Lucy Xia, Jonathan Tyrer, Laurence N Kolonel, Loic Le Marchand, Robert N Hoover, Mitchell J Machiela, Merideth Yeager, Laurie Burdette, Charles C Chung, Amy Hutchinson, Kai Yu, Chee Goh, Mahbubl Ahmed, Koveela Govindasami, Michelle Guy, Teuvo L J Tammela, Anssi Auvinen, Tiina Wahlfors, Johanna Schleutker, Tapio Visakorpi, Katri A Leinonen, Jianfeng Xu, Markus Aly, Jenny Donovan, Ruth C Travis, Tim J Key, Afshan Siddiq, Federico Canzian, Kay-Tee Khaw, Atsushi Takahashi, Michiaki Kubo, Paul Pharoah, Nora Pashayan, Maren Weischer, Borge G Nordestgaard, Sune F Nielsen, Peter Klarskov, Martin Andreas Røder, Peter Iversen, Stephen N Thibodeau, Shannon K McDonnell, Daniel J Schaid, Janet L Stanford, Suzanne Kolb, Sarah Holt, Beatrice Knudsen, Antonio Hurtado Coll, Susan M Gapstur, W Ryan Diver, Victoria L Stevens, Christiane Maier, Manuel Luedeke, Kathleen Herkommer, Antje E Rinckleb, Sara S Strom, Curtis Pettaway, Edward D Yeboah, Yao Tettey, Richard B Biritwum, Andrew A Adjei, Evelyn Tay, Ann Truelove, Shelley Niwa, Anand P Chokkalingam, Lisa Cannon-Albright, Cezary Cybulski, Dominika Wokołorczyk, Wojciech Kluźniak, Jong Park, Thomas Sellers, Hui-Yi Lin, William B Isaacs, Alan W Partin, Hermann Brenner, Aida Karina Dieffenbach, Christa Stegmaier, Constance Chen, Edward L Giovannucci, Jing Ma, Meir Stampfer, Kathryn L Penney, Lorelei Mucci, Esther M John, Sue A Ingles, Rick A Kittles, Adam B Murphy, Hardev Pandha, Agnieszka Michael, Andrzej M Kierzek, William Blot, Lisa B Signorello, Wei Zheng, Demetrius Albanes, Jarmo Virtamo, Stephanie Weinstein, Barbara Nemesure, John Carpten, Cristina Leske, Suh-Yuh Wu, Anselm Hennis, Adam S Kibel, Benjamin A Rybicki, Christine Neslund-Dudas, Ann W Hsing, Lisa Chu, Phyllis J Goodman, Eric A Klein, S Lilly Zheng, Jyotsna Batra, Judith Clements, Amanda Spurdle, Manuel R Teixeira, Paula Paulo, Sofia Maia, Chavdar Slavov, Radka Kaneva, Vanio Mitev, John S Witte, Graham Casey, Elizabeth M Gillanders, Daniella Seminara, Elio Riboli, Freddie C Hamdy, Gerhard A Coetzee, Qiyuan Li, Matthew L Freedman, David J Hunter, Kenneth Muir, Henrik Gronberg, David E Neal, Melissa Southey, Graham G Giles, Gianluca Severi, The Breast and Prostate Cancer Cohort Consortium (BPC3), The PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, The COGS (Collaborative Oncological Gene-environment Study) Consortium, The GAME-ON/ELLIPSE Consortium, Michael B Cook, Hidewaki Nakagawa, Fredrik Wiklund, Peter Kraft, Stephen J Chanock, Brian E Henderson, Douglas F Easton, Rosalind A Eeles & Christopher A Haiman doi:10.1038/ng.3094 Rosalind Eeles, Christopher Haiman and colleagues report genome-wide association and meta-analyses of prostate cancer in populations of European, African, Japanese and Latino ancestry. They identify 23 new susceptibility loci, including one associated with early-onset prostate cancer. Genome-wide association study identifies three susceptibility loci for laryngeal squamous cell carcinoma in the Chinese population   pp1110 - 1114 Qingyi Wei, Dianke Yu, Mingbo Liu, Mengyun Wang, Miaoqing Zhao, Ming Liu, Weihua Jia, Hongxia Ma, Jugao Fang, Wei Xu, Kexing Chen, Zhengang Xu, Jialing Wang, Linli Tian, Hua Yuan, Jiang Chang, Zhibin Hu, Lixun Wei, Ying Huang, Yaling Han, Jie Liu, Demin Han, Hongbing Shen, Shiming Yang, Hong Zheng, Qinghai Ji, Duanshu Li, Wen Tan, Chen Wu & Dongxin Lin doi:10.1038/ng.3090 Dongxin Lin and colleagues report a genome-wide association study for laryngeal squamous cell carcinoma (LSCC) in Chinese populations. They identify three loci newly associated with LSCC. Common variants near ABCA1 and in PMM2 are associated with primary open-angle glaucoma   pp1115 - 1119 Yuhong Chen, Ying Lin, Eranga N Vithana, Liyun Jia, Xianbo Zuo, Tien Yin Wong, Li Jia Chen, Xianjun Zhu, Pancy O S Tam, Bo Gong, Shaohong Qian, Zheng Li, Xiaoqi Liu, Baskaran Mani, Qian Luo, Celeste Guzman, Christopher K S Leung, Xiaobo Li, Wenjun Cao, Quanyao Yang, Clement C Y Tham, Yilian Cheng, Xuejun Zhang, Ningli Wang, Tin Aung, Chiea Chuen Khor, Chi Pui Pang, Xinghuai Sun & Zhenglin Yang doi:10.1038/ng.3078 Zhenglin Yang, Xinghuai Sun and colleagues report the results of a genome-wide association study of primary open-angle glaucoma in East Asians. They show that common variants near ABCA1 and in PPM2 are associated with increased risk of this disease. Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma   pp1120 - 1125 Puya Gharahkhani, Kathryn P Burdon, Rhys Fogarty, Shiwani Sharma, Alex W Hewitt, Sarah Martin, Matthew H Law, Katie Cremin, Jessica N Cooke Bailey, Stephanie J Loomis, Louis R Pasquale, Jonathan L Haines, Michael A Hauser, Ananth C Viswanathan, Peter McGuffin, Fotis Topouzis, Paul J Foster, Stuart L Graham, Robert J Casson, Mark Chehade, Andrew J White, Tiger Zhou, Emmanuelle Souzeau, John Landers, Jude T Fitzgerald, Sonja Klebe, Jonathan B Ruddle, Ivan Goldberg, Paul R Healey, Wellcome Trust Case Control Consortium 2, NEIGHBORHOOD Consortium, Richard A Mills, Jie Jin Wang, Grant W Montgomery, Nicholas G Martin, Graham Radford-Smith, David C Whiteman, Matthew A Brown, Janey L Wiggs, David A Mackey, Paul Mitchell, Stuart MacGregor & Jamie E Craig doi:10.1038/ng.3079 Jamie Craig, Puya Gharahkhani and colleagues report results of a genome-wide association study of primary open-angle glaucoma. They identify common variants near ABCA1, AFAP1 and GMDS that are associated with risk of this disease. Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma   pp1126 - 1130 Pirro G Hysi, Ching-Yu Cheng, Henriët Springelkamp, Stuart Macgregor, Jessica N Cooke Bailey, Robert Wojciechowski, Veronique Vitart, Abhishek Nag, Alex W Hewitt, René Höhn, Cristina Venturini, Alireza Mirshahi, Wishal D Ramdas, Gudmar Thorleifsson, Eranga Vithana, Chiea-Chuen Khor, Arni B Stefansson, Jiemin Liao, Jonathan L Haines, Najaf Amin, Ya Xing Wang, Philipp S Wild, Ayse B Ozel, Jun Z Li, Brian W Fleck, Tanja Zeller, Sandra E Staffieri, Yik-Ying Teo, Gabriel Cuellar-Partida, Xiaoyan Luo, R Rand Allingham, Julia E Richards, Andrea Senft, Lennart C Karssen, Yingfeng Zheng, Céline Bellenguez, Liang Xu, Adriana I Iglesias, James F Wilson, Jae H Kang, Elisabeth M van Leeuwen, Vesteinn Jonsson, Unnur Thorsteinsdottir, Dominiek D G Despriet, Sarah Ennis, Sayoko E Moroi, Nicholas G Martin, Nomdo M Jansonius, Seyhan Yazar, E-Shyong Tai, Philippe Amouyel, James Kirwan, Leonieke M E van Koolwijk, Michael A Hauser, Fridbert Jonasson, Paul Leo, Stephanie J Loomis, Rhys Fogarty, Fernando Rivadeneira, Lisa Kearns, Karl J Lackner, Paulus T V M de Jong, Claire L Simpson, Craig E Pennell, Ben A Oostra, André G Uitterlinden, Seang-Mei Saw, Andrew J Lotery, Joan E Bailey-Wilson, Albert Hofman, Johannes R Vingerling, Cécilia Maubaret, Norbert Pfeiffer, Roger C W Wolfs, Hans G Lemij, Terri L Young, Louis R Pasquale, Cécile Delcourt, Timothy D Spector, Caroline C W Klaver, Kerrin S Small, Kathryn P Burdon, Kari Stefansson, Tien-Yin Wong, BMES GWAS Group, NEIGHBORHOOD Consortium, Wellcome Trust Case Control Consortium 2, Ananth Viswanathan, David A Mackey, Jamie E Craig, Janey L Wiggs, Cornelia M van Duijn, Christopher J Hammond & Tin Aung doi:10.1038/ng.3087 Tin Aung, Christopher Hammond and colleagues report the results of a large genome-wide association study of intraocular pressure. They identify four new loci associated with this trait and show that three of these loci are associated with risk of primary open-angle glaucoma. HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants   pp1131 - 1134 Graham A Heap, Michael N Weedon, Claire M Bewshea, Abhey Singh, Mian Chen, Jack B Satchwell, Julian P Vivian, Kenji So, Patrick C Dubois, Jane M Andrews, Vito Annese, Peter Bampton, Martin Barnardo, Sally Bell, Andy Cole, Susan J Connor, Tom Creed, Fraser R Cummings, Mauro D'Amato, Tawfique K Daneshmend, Richard N Fedorak, Timothy H Florin, Daniel R Gaya, Emma Greig, Jonas Halfvarson, Alisa Hart, Peter M Irving, Gareth Jones, Amir Karban, Ian C Lawrance, James C Lee, Charlie Lees, Raffi Lev-Tzion, James O Lindsay, John Mansfield, Joel Mawdsley, Zia Mazhar, Miles Parkes, Kirstie Parnell, Timothy R Orchard, Graham Radford-Smith, Richard K Russell, David Reffitt, Jack Satsangi, Mark S Silverberg, Giacomo C Sturniolo, Mark Tremelling, Epameinondas V Tsianos, David A van Heel, Alissa Walsh, Gill Watermeyer, Rinse K Weersma, Sebastian Zeissig, Jamie Rossjohn, Arthur L Holden, International Serious Adverse Events Consortium, IBD Pharmacogenetics Study Group & Tariq Ahmad doi:10.1038/ng.3093 Graham Heap, Tariq Ahmad and colleagues show that common variants in the HLA-DQA1-HLA-DRB1 region confer susceptibility to thiopurine-induced pancreatitis in individuals undergoing treatment for inflammatory bowel diseases. These findings could help identify patients at risk of developing this serious adverse reaction to thiopurine therapy. Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation   pp1135 - 1139 Neil Romberg, Khatoun Al Moussawi, Carol Nelson-Williams, Amy L Stiegler, Erin Loring, Murim Choi, John Overton, Eric Meffre, Mustafa K Khokha, Anita J Huttner, Brian West, Nikolai A Podoltsev, Titus J Boggon, Barbara I Kazmierczak & Richard P Lifton doi:10.1038/ng.3066 Richard Lifton, Barbara Kazmierczak and colleagues report the identification of a new enterocolitic and autoinflammatory syndrome, which they find is caused by de novo gain-of-function mutations affecting the inflammasome protein NLRC4. Cells with mutant NLRC4 produce elevated levels of cleaved caspase-1, which leads to cell death by pyroptosis. See also: News and Views by Khameneh & Mortellaro An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome   pp1140 - 1146 Scott W Canna, Adriana A de Jesus, Sushanth Gouni, Stephen R Brooks, Bernadette Marrero, Yin Liu, Michael A DiMattia, Kristien J M Zaal, Gina A Montealegre Sanchez, Hanna Kim, Dawn Chapelle, Nicole Plass, Yan Huang, Alejandro V Villarino, Angelique Biancotto, Thomas A Fleisher, Joseph A Duncan, John J O'Shea, Susanne Benseler, Alexei Grom, Zuoming Deng, Ronald M Laxer & Raphaela Goldbach-Mansky doi:10.1038/ng.3089 Scott Canna and colleagues report the identification of a de novo mutation in a conserved region of NLRC4 by whole-exome sequencing of an individual presenting with macrophage activation syndrome. Functional studies confirm that the mutation leads to constitutive inflammasome activation. See also: News and Views by Khameneh & Mortellaro The Scc2-Scc4 complex acts in sister chromatid cohesion and transcriptional regulation by maintaining nucleosome-free regions   pp1147 - 1151 Lidia Lopez-Serra, Gavin Kelly, Harshil Patel, Aengus Stewart & Frank Uhlmann doi:10.1038/ng.3080 Frank Uhlmann and colleagues show that the yeast Scc2-Scc4 cohesin loader complex is recruited to nucleosome-free regions in the promoters of highly expressed genes by the RSC chromatin remodeling complex and acts to maintain the nucleosome-free status of its binding sites. These findings suggest that human disorders caused by disruption of cohesin or RSC complex function, such as Cornelia de Lange and Coffin-Siris syndromes, could arise from related changes in the nucleosome landscape. 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