Nature Genetics Contents: August 2015 pp 849- 962

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Learn more.  Subscribe   Facebook   RSS   Recommend to library   Twitter   Advertisement Mouse Molecular Genetics (16-19 September 2015)  The 28th annual Mouse Molecular Genetics meeting will feature the latest developments in genetics, genomics, engineering of the mouse genome, systems analysis, and imaging of dynamic molecular and physiological processes. Abstract Deadline: 23 July | Registration Deadline: 7 August   Advertisement Web Focus: Genetics and Gastrointestinal Diseases Genetics and genomics are beginning to strongly influence the care of patients with GI conditions. This web focus brings together seminal articles exploring new genomic findings in clinical practice that have been published in Genetics in Medicine, The American Journal of Gastroenterology and Clinical and Translational Gastroenterology. Access the focus online.      Advertisement A new open access journal dedicated to publishing the most important scientific advances in all aspects of genomics and its application in the practice of medicine. Part of the Nature Partner Journals series, the journal is published in partnership with the Center of Excellence in Genomic Medicine Research. Open for submissions   Editorial Top Marshaling the Variome   p849 doi:10.1038/ng.3377 From the Human Genome Organization (HUGO) onward, there has been a desire to get together to talk about using our shared genomic heritage to improve human health and development. We now have all the organizations we need and should collaborate on multiple practical demonstrations of the usefulness of genomic knowledge—be it human, animal or plant—for human health. Obituary Top Richard Graham Hay Cotton 1940-2015   p850 Tim Smith & Graham Taylor doi:10.1038/ng.3369 News and Views Top Pediatric cancer genomics, a play rather than a portrait   pp851 - 852 Vijay Ramaswamy & Michael D Taylor doi:10.1038/ng.3366 Relapsed neuroblastoma is common, frequently lethal and poorly studied and poses a major treatment challenge. Two new studies shed light on the genomic landscape of recurrent neuroblastoma and demonstrate profound differences between the disease at diagnosis and relapse. See also: Article by Eleveld et al. | Article by Schramm et al. Counting copy number and calories   pp852 - 853 Stefan White doi:10.1038/ng.3365 Copy number variation (CNV) at several genomic loci has been associated with different human traits and diseases, but in many cases the findings could not be replicated. A new study provides insights into the degree of variation present at the amylase locus and calls into question a previous association between amylase copy number and body mass index. See also: Letter by Usher et al. Running spell-check to identify regulatory variants   pp853 - 855 Martin Kircher & Jay Shendure doi:10.1038/ng.3364 A major challenge in human genetics is pinpointing which non-coding genetic variants affect gene expression and disease risk. A new study in this issue describes a broadly applicable approach for this task that explicitly models cell type-specific regulatory motifs and generates variant effect predictions that are more accurate and interpretable than those of alternative tools. See also: Technical Report by Lee et al. Genetics JOBS of the week NIH-Funded Postdoctoral Position on Imaging Genetics of Dystonia Icahn School of Medicine at Mount Sinai Postdoctoral Research Scientist in Disease Gene Regulation Wellcome Trust Centre for Human Genetics Senior Scientist – Gene Editing The Cystic Fibrosis Foundation Bioinformatics / Computational Genomics Postdoctoral Researcher UT Health Science Center More Science jobs from Genetics EVENT Nature Genetics and the Wellcome Trust Present: The Genomics of Common Diseases 2015 02.09.15 Cambridge, UK More science events from Analysis Top The support of human genetic evidence for approved drug indications   pp856 - 860 Matthew R Nelson, Hannah Tipney, Jeffery L Painter, Judong Shen, Paola Nicoletti, Yufeng Shen, Aris Floratos, Pak Chung Sham, Mulin Jun Li, Junwen Wang, Lon R Cardon, John C Whittaker & Philippe Sanseau doi:10.1038/ng.3314 Matthew Nelson and colleagues investigate how well genetic evidence for disease susceptibility predicts drug mechanisms. They find a correlation between gene products that are successful drug targets and genetic loci associated with the disease treated by the drug and predict that selecting genetically supported targets could increase the success rate of drugs in clinical development. Brief Communication Top Consistent in-frame internal tandem duplications of BCOR characterize clear cell sarcoma of the kidney   pp861 - 863 Hitomi Ueno-Yokohata, Hajime Okita, Keiko Nakasato, Shingo Akimoto, Jun-ichi Hata, Tsugumichi Koshinaga, Masahiro Fukuzawa & Nobutaka Kiyokawa doi:10.1038/ng.3338 Hajime Okita and colleagues show that clear-cell sarcoma of the kidney (CCSK) is characterized by recurrent in-frame, internal tandem duplications in BCOR. They detected BCOR alterations in all 20 CCSK tumors analyzed but not in any other pediatric renal tumors, suggesting a specific role for these in-frame duplications in driving CCSK oncogenesis. Articles Top Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations   pp864 - 871 Thomas F Eleveld, Derek A Oldridge, Virginie Bernard, Jan Koster, Leo Colmet Daage, Sharon J Diskin, Linda Schild, Nadia Bessoltane Bentahar, Angela Bellini, Mathieu Chicard, Eve Lapouble, Valérie Combaret, Patricia Legoix-Né, Jean Michon, Trevor J Pugh, Lori S Hart, JulieAnn Rader, Edward F Attiyeh, Jun S Wei, Shile Zhang, Arlene Naranjo, Julie M Gastier-Foster, Michael D Hogarty, Shahab Asgharzadeh, Malcolm A Smith, Jaime M Guidry Auvil, Thomas B K Watkins, Danny A Zwijnenburg, Marli E Ebus, Peter van Sluis, Anne Hakkert, Esther van Wezel, C Ellen van der Schoot, Ellen M Westerhout, Johannes H Schulte, Godelieve A Tytgat, M Emmy M Dolman, Isabelle Janoueix-Lerosey, Daniela S Gerhard, Huib N Caron, Olivier Delattre, Javed Khan, Rogier Versteeg, Gudrun Schleiermacher, Jan J Molenaar & John M Maris doi:10.1038/ng.3333 John Maris, Jan Molenaar, Gudrun Schleiermacher and colleagues performed whole-genome sequencing of 23 paired diagnostic and relapsed neuroblastomas, showing enrichment for mutations in the RAS-MAPK signaling pathway. These mutations render neuroblastoma cell lines susceptible to MEK inhibition. See also: News and Views by Ramaswamy & Taylor Mutational dynamics between primary and relapse neuroblastomas   pp872 - 877 Alexander Schramm, Johannes Köster, Yassen Assenov, Kristina Althoff, Martin Peifer, Ellen Mahlow, Andrea Odersky, Daniela Beisser, Corinna Ernst, Anton G Henssen, Harald Stephan, Christopher Schröder, Lukas Heukamp, Anne Engesser, Yvonne Kahlert, Jessica Theissen, Barbara Hero, Frederik Roels, Janine Altmüller, Peter Nürnberg, Kathy Astrahantseff, Christian Gloeckner, Katleen De Preter, Christoph Plass, Sangkyun Lee, Holger N Lode, Kai-Oliver Henrich, Moritz Gartlgruber, Frank Speleman, Peter Schmezer, Frank Westermann, Sven Rahmann, Matthias Fischer, Angelika Eggert & Johannes H Schulte doi:10.1038/ng.3349 Alexander Schramm, Johannes Schulte and colleagues characterize 16 paired samples from patients with neuroblastoma at diagnosis and relapse using whole-exome sequencing, mRNA expression profiling, array CGH and DNA methylation analysis. Their data show the frequency, identity and evolution of genetic alterations in neuroblastoma. See also: News and Views by Ramaswamy & Taylor An in vivo screen identifies ependymoma oncogenes and tumor-suppressor genes   pp878 - 887 Kumarasamypet M Mohankumar, David S Currle, Elsie White, Nidal Boulos, Jason Dapper, Christopher Eden, Birgit Nimmervoll, Radhika Thiruvenkatam, Michele Connelly, Tanya A Kranenburg, Geoffrey Neale, Scott Olsen, Yong-Dong Wang, David Finkelstein, Karen Wright, Kirti Gupta, David W Ellison, Arzu Onar Thomas & Richard J Gilbertson doi:10.1038/ng.3323 Richard Gilbertson and colleagues report an in vivo screen of 84 candidate oncogenes and 39 candidate tumor-suppressor genes in ependymoma mouse models. The validated targets are involved in vesicle trafficking, DNA modification and cholesterol biosynthesis. Genome-wide significant risk associations for mucinous ovarian carcinoma   pp888 - 897 the Ovarian Cancer Association Consortium doi:10.1038/ng.3336 Simon Gayther and colleagues report 3 new risk variants for mucinous ovarian carcinoma (MOC) on the basis of an analysis of 1,644 MOC cases and 21,693 controls. They confirm an eQTL association between the HOXD9 promoter and risk SNPs at 2q31.1 using chromosome conformation capture analysis and show that HOXD9 overexpression associates with neoplastic transformation. Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk   pp898 - 905 Xinli Hu, Aaron J Deutsch, Tobias L Lenz, Suna Onengut-Gumuscu, Buhm Han, Wei-Min Chen, Joanna M M Howson, John A Todd, Paul I W de Bakker, Stephen S Rich & Soumya Raychaudhuri doi:10.1038/ng.3353 Soumya Raychaudhuri and colleagues present a detailed analysis of the association between the HLA region and type 1 diabetes risk. They find that variants at three amino acid positions in HLA-DQβ1 and HLA-DRβ1 account for a large fraction of the association signal, acting through a combination of additive and interaction effects. Letters Top Loss-of-function variants in ATM confer risk of gastric cancer   pp906 - 910 Hannes Helgason, Thorunn Rafnar, Halla S Olafsdottir, Jon G Jonasson, Asgeir Sigurdsson, Simon N Stacey, Adalbjorg Jonasdottir, Laufey Tryggvadottir, Kristin Alexiusdottir, Asgeir Haraldsson, Louise le Roux, Julius Gudmundsson, Hrefna Johannsdottir, Asmundur Oddsson, Arnaldur Gylfason, Olafur T Magnusson, Gisli Masson, Thorvaldur Jonsson, Halla Skuladottir, Daniel F Gudbjartsson, Unnur Thorsteinsdottir, Patrick Sulem & Kari Stefansson doi:10.1038/ng.3342 Hannes Helgason, Kari Stefansson and colleagues report an association study of gastric cancer susceptibility based on whole-genome sequencing in the Icelandic population. They find that loss-of-function variants in ATM confer risk of gastric cancer. Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer   pp911 - 916 Erica J Childs, Evelina Mocci, Daniele Campa, Paige M Bracci, Steven Gallinger, Michael Goggins, Donghui Li, Rachel E Neale, Sara H Olson, Ghislaine Scelo, Laufey T Amundadottir, William R Bamlet, Maarten F Bijlsma, Amanda Blackford, Michael Borges, Paul Brennan, Hermann Brenner, H Bas Bueno-de-Mesquita, Federico Canzian, Gabriele Capurso, Giulia M Cavestro, Kari G Chaffee, Stephen J Chanock, Sean P Cleary, Michelle Cotterchio, Lenka Foretova, Charles Fuchs, Niccola Funel, Maria Gazouli, Manal Hassan, Joseph M Herman, Ivana Holcatova, Elizabeth A Holly, Robert N Hoover, Rayjean J Hung, Vladimir Janout, Timothy J Key, Juozas Kupcinskas, Robert C Kurtz, Stefano Landi, Lingeng Lu, Ewa Malecka-Panas, Andrea Mambrini, Beatrice Mohelnikova-Duchonova, John P Neoptolemos, Ann L Oberg, Irene Orlow, Claudio Pasquali, Raffaele Pezzilli, Cosmeri Rizzato, Amethyst Saldia, Aldo Scarpa, Rachael Z Stolzenberg-Solomon, Oliver Strobel, Francesca Tavano, Yogesh K Vashist, Pavel Vodicka, Brian M Wolpin, Herbert Yu, Gloria M Petersen, Harvey A Risch & Alison P Klein doi:10.1038/ng.3341 Alison Klein and colleagues report a genome-wide meta-analysis to identify loci associated with pancreatic cancer risk. They identify associated variants at 17q25.1, 3q29, 7p13 and 2p13.3. Rare A2ML1 variants confer susceptibility to otitis media   pp917 - 920 Regie Lyn P Santos-Cortez, Charlotte M Chiong, Ma Rina T Reyes-Quintos, Ma Leah C Tantoco, Xin Wang, Anushree Acharya, Izoduwa Abbe, Arnaud P Giese, Joshua D Smith, E Kaitlynn Allen, Biao Li, Eva Maria Cutiongco-de la Paz, Marieflor Cristy Garcia, Erasmo Gonzalo D V Llanes, Patrick John Labra, Teresa Luisa I Gloria-Cruz, Abner L Chan, Gao T Wang, Kathleen A Daly, Jay Shendure, Michael J Bamshad, Deborah A Nickerson, Janak A Patel, Saima Riazuddin, Michele M Sale, University of Washington Center for Mendelian Genomics, Tasnee Chonmaitree, Zubair M Ahmed, Generoso T Abes & Suzanne M Leal doi:10.1038/ng.3347 Regie Lyn Santos-Cortez and colleagues identify a duplication variant within A2ML1 that cosegregates with otitis media in an indigenous Filipino pedigree. They also identify seven additional A2ML1 variants in otitis-prone children. Structural forms of the human amylase locus and their relationships to SNPs, haplotypes and obesity   pp921 - 925 Christina L Usher, Robert E Handsaker, Tõnu Esko, Marcus A Tuke, Michael N Weedon, Alex R Hastie, Han Cao, Jennifer E Moon, Seva Kashin, Christian Fuchsberger, Andres Metspalu, Carlos N Pato, Michele T Pato, Mark I McCarthy, Michael Boehnke, David M Altshuler, Timothy M Frayling, Joel N Hirschhorn & Steven A McCarroll doi:10.1038/ng.3340 Steven McCarroll, Joel Hirschhorn and colleagues identify eight common structural forms of the human amylase locus. They measured amylase gene copy number in ~3,500 individuals and detected no association with BMI and obesity. See also: News and Views by White Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder   pp926 - 932 Alexander J Abrams, Robert B Hufnagel, Adriana Rebelo, Claudia Zanna, Neville Patel, Michael A Gonzalez, Ion J Campeanu, Laurie B Griffin, Saskia Groenewald, Alleene V Strickland, Feifei Tao, Fiorella Speziani, Lisa Abreu, Rebecca Schüle, Leonardo Caporali, Chiara La Morgia, Alessandra Maresca, Rocco Liguori, Raffaele Lodi, Zubair M Ahmed, Kristen L Sund, Xinjian Wang, Laura A Krueger, Yanyan Peng, Carlos E Prada, Cynthia A Prows, Elizabeth K Schorry, Anthony Antonellis, Holly H Zimmerman, Omar A Abdul-Rahman, Yaping Yang, Susan M Downes, Jeffery Prince, Flavia Fontanesi, Antonio Barrientos, Andrea H Németh, Valerio Carelli, Taosheng Huang, Stephan Zuchner & Julia E Dallman doi:10.1038/ng.3354 Stephan Zuchner, Taosheng Huang and colleagues show that recessive mutations in SLC25A46 cause optic atrophy with additional neurological symptoms. They further show that SLC25A46 encodes a modified mitochondrial solute transporter linked to mitochondrial dynamics. Keratin-dependent regulation of Aire and gene expression in skin tumor keratinocytes   pp933 - 938 Ryan P Hobbs, Daryle J DePianto, Justin T Jacob, Minerva C Han, Byung-Min Chung, Adriana S Batazzi, Brian G Poll, Yajuan Guo, Jingnan Han, SuFey Ong, Wenxin Zheng, Janis M Taube, Daniela Čiháková, Fengyi Wan & Pierre A Coulombe doi:10.1038/ng.3355 Pierre Coulombe and colleagues show that the autoimmune regulator Aire is induced in tumor keratinocytes in a keratin 17 (K17)-dependent manner and promotes skin tumorigenesis in mice. They further show that K17 and Aire colocalize in the nucleus and bind a subset of proinflammatory genes, providing a molecular explanation for the K17-dependent amplification of inflammatory responses in diseased epithelia. GmHs1-1, encoding a calcineurin-like protein, controls hard-seededness in soybean   pp939 - 943 Lianjun Sun, Zhenyan Miao, Chunmei Cai, Dajian Zhang, Meixia Zhao, Yanyan Wu, Xueling Zhang, Stephen A Swarm, Liwen Zhou, Zhanyuan J Zhang, Randall L Nelson & Jianxin Ma doi:10.1038/ng.3339 Jianxin Ma and colleagues report the identification of a gene variant selected for during the domestication of soybean that causes permeable seed coats, in contrast to the hard seed coats of its wild ancestors. The identified gene, GmHs1-1, is predicted to encode a calcineurin-like metallophosphatase, although its cellular function remains unknown. Copy number variation at the GL7 locus contributes to grain size diversity in rice   pp944 - 948 Yuexing Wang, Guosheng Xiong, Jiang Hu, Liang Jiang, Hong Yu, Jie Xu, Yunxia Fang, Longjun Zeng, Erbo Xu, Jing Xu, Weijun Ye, Xiangbing Meng, Ruifang Liu, Hongqi Chen, Yanhui Jing, Yonghong Wang, Xudong Zhu, Jiayang Li & Qian Qian doi:10.1038/ng.3346 Jiayang Li, Xudong Zhu, Qian Qian and colleagues report cloning of the Grain Length on Chromosome 7 (GL7) locus in rice and identify a copy number variant that increases grain length and improves grain quality. They demonstrate how interactions with other grain length-related genes may be used to improve breeding. The OsSPL16-GW7 regulatory module determines grain shape and simultaneously improves rice yield and grain quality   pp949 - 954 Shaokui Wang, Shan Li, Qian Liu, Kun Wu, Jianqing Zhang, Shuansuo Wang, Yi Wang, Xiangbin Chen, Yi Zhang, Caixia Gao, Feng Wang, Haixiang Huang & Xiangdong Fu doi:10.1038/ng.3352 Xiangdong Fu and colleagues show that variation in GW7 influences rice grain shape and yield. They further show that GW7 expression is directly regulated by OsSPL16, a transcription factor encoded by the grain-width locus GW8. Technical Report Top A method to predict the impact of regulatory variants from DNA sequence   pp955 - 961 Dongwon Lee, David U Gorkin, Maggie Baker, Benjamin J Strober, Alessandro L Asoni, Andrew S McCallion & Michael A Beer doi:10.1038/ng.3331 Michael Beer and colleagues report a metric based on a regulatory region annotation method, gkm-SVM, and use this to predict the effects of regulatory variants from sequencing and DNase I-hypersensitive site data. They apply their method to autoimmune disease GWAS data and report several new predictions for causal SNPs. See also: News and Views by Kircher & Shendure Corrigenda Top Corrigendum: Transcriptional regulator PRDM12 is essential for human pain perception   p962 Ya-Chun Chen, Michaela Auer-Grumbach, Shinya Matsukawa, Manuela Zitzelsberger, Andreas C Themistocleous, Tim M Strom, Chrysanthi Samara, Adrian W Moore, Lily Ting-Yin Cho, Gareth T Young, Caecilia Weiss, Maria Schabhüttl, Rolf Stucka, Annina B Schmid, Yesim Parman, Luitgard Graul-Neumann, Wolfram Heinritz, Eberhard Passarge, Rosemarie M Watson, Jens Michael Hertz, Ute Moog, Manuela Baumgartner, Enza Maria Valente, Diego Pereira, Carlos M Restrepo, Istvan Katona, Marina Dusl, Claudia Stendel, Thomas Wieland, Fay Stafford, Frank Reimann, Katja von Au, Christian Finke, Patrick J Willems, Michael S Nahorski, Samiha S Shaikh, Ofélia P Carvalho, Adeline K Nicholas, Gulshan Karbani, Maeve A McAleer, Maria Roberta Cilio, John C McHugh, Sinead M Murphy, Alan D Irvine, Uffe Birk Jensen, Reinhard Windhager, Joachim Weis, Carsten Bergmann, Bernd Rautenstrauss, Jonathan Baets, Peter De Jonghe, Mary M Reilly, Regina Kropatsch, Ingo Kurth, Roman Chrast, Tatsuo Michiue, David L H Bennett, C Geoffrey Woods & Jan Senderek doi:10.1038/ng0815-962b Corrigendum: Statistical colocalization of genetic risk variants for related autoimmune diseases in the context of common controls   p962 Mary D Fortune, Hui Guo, Oliver Burren, Ellen Schofield, Neil M Walker, Maria Ban, Stephen J Sawcer, John Bowes, Jane Worthington, Anne Barton, Steve Eyre, John A Todd & Chris Wallace doi:10.1038/ng0815-962c Erratum Top Erratum: The draft genome of the grass carp (Ctenopharyngodon idellus) provides insights into its evolution and vegetarian adaptation   p962 Yaping Wang, Ying Lu, Yong Zhang, Zemin Ning, Yan Li, Qiang Zhao, Hengyun Lu, Rong Huang, Xiaoqin Xia, Qi Feng, Xufang Liang, Kunyan Liu, Lei Zhang, Tingting Lu, Tao Huang, Danlin Fan, Qijun Weng, Chuanrang Zhu, Yiqi Lu, Wenjun Li, Ziruo Wen, Congcong Zhou, Qilin Tian, Xiaojun Kang, Mijuan Shi, Wanting Zhang, Songhun Jang, Fukuan Du, Shan He, Lanjie Liao, Yongming Li, Bin Gui, Huihui He, Zhen Ning, Cheng Yang, Libo He, Lifei Luo, Rui Yang, Qiong Luo, Xiaochun Liu, Shuisheng Li, Wen Huang, Ling Xiao, Haoran Lin, Bin Han & Zuoyan Zhu doi:10.1038/ng0815-962a Top Natureevents is a fully searchable, multi-disciplinary database designed to maximise exposure for events organisers. 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