Nature Genetics Contents: October 2015 pp 1101 - 1219

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Advertisement Accelerating Neuroscience Research  A major challenge in neuroscience research and drug discovery is the lack of easy access to relevant animal models for use in screening drug candidates.  The Advanced Neuroscience Mouse Model Portfolio provides simplified access to models and services for the study of neuronal disease and signaling. Learn about extensive phenotyping data, and aging services to help accelerate research outcomes.  Learn More  TABLE OF CONTENTS October 2015 Volume 47, Issue 10 Editorial News and Views Analysis Articles Letters Technical Report Subscribe   Facebook   RSS   Recommend to library   Twitter   Advertisement Unlock the Potential of CRISPR Cas9 Gene Editing, at Pharma IQ's CRISPR Summit, Europe's #1 event for addressing CRISPR's application challenges. Are you currently working with CRISPR technology and encountering delivery challenges? If so, this is a MUST attend event for you! Join key industry leaders addressing the challenges preventing you from making the most of CRISPR.   Advertisement Nature Plants: Call for Papers Nature Plants launched in January and covers all aspects of plants be it their evolution, genetics, development or metabolism, their interactions with the environment, or their societal significance. The journal welcomes high quality submissions and encourages you and your colleagues to consider submitting your next research paper to the journal.  Submit your next research paper to the journal.     Editorial Top Data and preprints   p1101 doi:10.1038/ng.3418 Journal requirements for data deposition and encouragement of deposition of preprints in a community preprint server are stated policy. Because many authors put data in a public repository only upon publication and many still ask about the status of preprints, here is a further statement of our position. News and Views Top Gene signatures from pancreatic cancer tumor and stromal cells predict disease outcome   pp1102 - 1103 Filippos Kottakis & Nabeel Bardeesy doi:10.1038/ng.3408 Pancreatic cancers consist of a heterogeneous amalgam of assorted cell types, making it challenging to develop a classification system that groups these tumors according to common molecular features. A new study tackles this important issue using bioinformatics approaches to decipher gene expression signatures derived specifically from either tumor cells or nonmalignant stromal cells that predict patient outcome and may inform personalized treatments. See also: Article by Moffitt et al. Adeno-associated virus finds its disease   pp1104 - 1105 David W Russell & Markus Grompe doi:10.1038/ng.3407 Adeno-associated virus (AAV) vectors have been widely adopted for use in gene therapy. A new study raises concerns regarding this approach, reporting that chromosomal insertions of AAV serotype 2 seem to activate proto-oncogenes in human hepatocellular carcinoma. See also: Letter by Nault et al. PRC1 proteins orchestrate three-dimensional genome architecture   pp1105 - 1106 Giacomo Cavalli doi:10.1038/ng.3411 The three-dimensional organization of the genome has an important role in orchestrating gene expression, but its regulation is poorly understood. Now, a new study uncovers a major role for Polycomb components of the PRC1 complex in organizing physical networks of genes that are co-repressed to maintain pluripotency. See also: Letter by Schoenfelder et al. Genetics JOBS of the week Assistant / Associate Faculty Position in Quantitative Genetics and Statistical Genomics Cornell University Assistant Professor, Stem Cell Genomics University of California, Santa Cruz Environmental, Genomics & Systems Biology (EGSB) Division Director Lawrence Berkeley National Laboratory (LBNL) Assistant / Associate Faculty Position in Quantitative Genetics and Statistical Genomics Cornell University AIHS Translational Chair in Child Health Genomics University of Calgary and the Alberta Children’s Hospital Research Institute (ACHRI) More Science jobs from Genetics EVENT Plant Genetics and Breeding Technologies II 01.02.16 Vienna, Austria More science events from Analysis Top Class II HLA interactions modulate genetic risk for multiple sclerosis   pp1107 - 1113 the International Multiple Sclerosis Genetics Consortium doi:10.1038/ng.3395 Gil McVean and colleagues report a meta-analysis of Immunochip studies including over 17,000 multiple sclerosis cases and 30,000 controls, with imputation of classical HLA alleles. They find two interactions involving class II HLA alleles but no evidence for significant epistatic interactions or interactions between HLA and non-HLA risk variants. Watch an audio-visual summary of the paper here Genetic variance estimation with imputed variants finds negligible missing heritability for human height and body mass index   pp1114 - 1120 Jian Yang, Andrew Bakshi, Zhihong Zhu, Gibran Hemani, Anna A E Vinkhuyzen, Sang Hong Lee, Matthew R Robinson, John R B Perry, Ilja M Nolte, Jana V van Vliet-Ostaptchouk, Harold Snieder, The LifeLines Cohort Study, Tonu Esko, Lili Milani, Reedik Mägi, Andres Metspalu, Anders Hamsten, Patrik K E Magnusson, Nancy L Pedersen, Erik Ingelsson, Nicole Soranzo, Matthew C Keller, Naomi R Wray, Michael E Goddard & Peter M Visscher doi:10.1038/ng.3390 Jian Yang and colleagues present a method, GREML-LDMS, to estimate heritability for complex human traits using whole-genome sequencing data or imputation with the 1000 Genomes Project reference panel. Using the heritability estimates from GREML-LDMS, they find that there is negligible missing heritability for human height and BMI. Advertisement Discover a Better PCR-Free Library Prep  The Accel-NGS 2S PCR-Free DNA Library Kit from Swift Biosciences provides greater genome coverage than other commercial kits. Samples as low as 10 ng can be prepared PCR-free to increase library complexity, improve sample coverage, and reveal difficult to read sequences in your NGS samples. Download our application note to learn more.   Articles Top A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease   pp1121 - 1130 the CARDIoGRAMplusC4D Consortium doi:10.1038/ng.3396 Hugh Watkins, Sekar Kathiresan, Ruth McPherson, Martin Farrall and colleagues report the results of a large genome-wide association meta-analysis of coronary artery disease based on 1000 Genomes imputation. They identify ten new risk loci and show that susceptibility to this disease is largely determined by common SNPs with small effect sizes. Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies   pp1131 - 1140 Joseph Saliba, Cécile Saint-Martin, Antonio Di Stefano, Gaëlle Lenglet, Caroline Marty, Boris Keren, Florence Pasquier, Véronique Della Valle, Lise Secardin, Gwendoline Leroy, Emna Mahfoudhi, Sarah Grosjean, Nathalie Droin, M'boyba Diop, Philippe Dessen, Sabine Charrier, Alberta Palazzo, Jane Merlevede, Jean-Côme Meniane, Christine Delaunay-Darivon, Pascal Fuseau, Françoise Isnard, Nicole Casadevall, Eric Solary, Najet Debili, Olivier A Bernard, Hana Raslova, Albert Najman, William Vainchenker, Christine Bellanné-Chantelot & Isabelle Plo doi:10.1038/ng.3380 Isabelle Plo, Christine Bellanné-Chantelot, William Vainchenker and colleagues report a 700-kb germline duplication including the ATG2B and GSKIP genes in four related families with myeloid malignancy predisposition. Using induced pluripotent stem cells and primary cells, they demonstrate that ATG2B and GSKIP enhance hematopoietic progenitor differentiation. Evidence of long-term gene flow and selection during domestication from analyses of Eurasian wild and domestic pig genomes   pp1141 - 1148 Laurent A F Frantz, Joshua G Schraiber, Ole Madsen, Hendrik-Jan Megens, Alex Cagan, Mirte Bosse, Yogesh Paudel, Richard P M A Crooijmans, Greger Larson & Martien A M Groenen doi:10.1038/ng.3394 Laurent Frantz and colleagues report an analysis of 103 whole genomes from European and Asian wild boars and domestic pigs. They find evidence in support of a complex domestication model with gene flow from wild populations counteracted by recurrent artificial selection for traits important for domestication. Broad H3K4me3 is associated with increased transcription elongation and enhancer activity at tumor-suppressor genes   pp1149 - 1157 Kaifu Chen, Zhong Chen, Dayong Wu, Lili Zhang, Xueqiu Lin, Jianzhong Su, Benjamin Rodriguez, Yuanxin Xi, Zheng Xia, Xi Chen, Xiaobing Shi, Qianben Wang & Wei Li doi:10.1038/ng.3385 Wei Li, Qianben Wang and colleagues analyze genome-wide epigenetic patterns in tumor and normal tissues and find that broad H3K4me3 peaks are associated with increased transcription elongation and are enriched at tumor-suppressor genes. They demonstrate that this epigenetic mark may be used to identify new candidate tumor-suppressor genes. Absence of canonical marks of active chromatin in developmentally regulated genes   pp1158 - 1167 Sílvia Pérez-Lluch, Enrique Blanco, Hagen Tilgner, Joao Curado, Marina Ruiz-Romero, Montserrat Corominas & Roderic Guigó doi:10.1038/ng.3381 Roderic Guigó, Montserrat Corominas and colleagues find that histone marks associated with active chromatin are absent from genes with high expression during specific developmental stages in both Drosophila melanogaster and Caenorhabditis elegans. They observe similar patterns for genes with high levels of transcriptional variation across mammalian tissues and cell types. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma   pp1168 - 1178 Richard A Moffitt, Raoud Marayati, Elizabeth L Flate, Keith E Volmar, S Gabriela Herrera Loeza, Katherine A Hoadley, Naim U Rashid, Lindsay A Williams, Samuel C Eaton, Alexander H Chung, Jadwiga K Smyla, Judy M Anderson, Hong Jin Kim, David J Bentrem, Mark S Talamonti, Christine A Iacobuzio-Donahue, Michael A Hollingsworth & Jen Jen Yeh doi:10.1038/ng.3398 Jen Jen Yeh and colleagues apply statistical methods to separate tumor, stroma and normal tissue gene expression signatures from pancreatic ductal adenocarcinoma expression profiling data sets. They identify and validate two tumor-specific and two stroma-specific subtypes, which are associated with different clinical outcomes. See also: News and Views by Kottakis & Bardeesy Advertisement Droplet Digital™ PCR (ddPCR™) is leading the way More than 250 peer-reviewed publications have taken advantage of Droplet Digital PCR's unmatched ability to detect rare nucleic acid species. From tracking cancer biomarkers to quantifying rare mutations, gene editing events, and miniscule viral loads, Droplet Digital PCR has led to more discoveries than any other digital PCR platform. Visit our ddPCR page for application guides, publication lists, and webinars that explore the world of ddPCR. Learn more   Letters Top Polycomb repressive complex PRC1 spatially constrains the mouse embryonic stem cell genome   pp1179 - 1186 Stefan Schoenfelder, Robert Sugar, Andrew Dimond, Biola-Maria Javierre, Harry Armstrong, Borbala Mifsud, Emilia Dimitrova, Louise Matheson, Filipe Tavares-Cadete, Mayra Furlan-Magaril, Anne Segonds-Pichon, Wiktor Jurkowski, Steven W Wingett, Kristina Tabbada, Simon Andrews, Bram Herman, Emily LeProust, Cameron S Osborne, Haruhiko Koseki, Peter Fraser, Nicholas M Luscombe & Sarah Elderkin doi:10.1038/ng.3393 Sarah Elderkin and colleagues show that PRC1 acts as a master regulator of genome architecture in mouse embryonic stem cells by organizing genes in three-dimensional interaction networks. They find that the strongest spatial network is composed of the four Hox clusters and key early developmental transcription factor genes, and they propose that selective release of genes from this spatial network underlies cell fate specification during embryonic development. See also: News and Views by Cavalli Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas   pp1187 - 1193 Jean-Charles Nault, Shalini Datta, Sandrine Imbeaud, Andrea Franconi, Maxime Mallet, Gabrielle Couchy, Eric Letouzé, Camilla Pilati, Benjamin Verret, Jean-Frédéric Blanc, Charles Balabaud, Julien Calderaro, Alexis Laurent, Mélanie Letexier, Paulette Bioulac-Sage, Fabien Calvo & Jessica Zucman-Rossi doi:10.1038/ng.3389 Jessica Zucman-Rossi and colleagues identify clonal integrations of adeno-associated virus type 2 (AAV2) in hepatocellular carcinomas. These AAV2 integrations occurred within known cancer driver genes, suggesting a pathogenic role of AAV2 in these patients. See also: News and Views by Russell & Grompe Exome sequencing of desmoplastic melanoma identifies recurrent NFKBIE promoter mutations and diverse activating mutations in the MAPK pathway   pp1194 - 1199 A Hunter Shain, Maria Garrido, Thomas Botton, Eric Talevich, Iwei Yeh, J Zachary Sanborn, Jongsuk Chung, Nicholas J Wang, Hojabr Kakavand, Graham J Mann, John F Thompson, Thomas Wiesner, Ritu Roy, Adam B Olshen, Alexander Gagnon, Joe W Gray, Nam Huh, Joe S Hur, Klaus J Busam, Richard A Scolyer, Raymond J Cho, Rajmohan Murali & Boris C Bastian doi:10.1038/ng.3382 Boris Bastian and colleagues report the results of exome sequencing of desmoplastic melanoma. They identify recurrent NFKBIE promoter mutations and diverse mutations leading to activation of the MAPK pathway. SMARCA4 inactivation defines a group of undifferentiated thoracic malignancies transcriptionally related to BAF-deficient sarcomas   pp1200 - 1205 Francois Le Loarer, Sarah Watson, Gaelle Pierron, Vincent Thomas de Montpreville, Stelly Ballet, Nelly Firmin, Aurelie Auguste, Daniel Pissaloux, Sandrine Boyault, Sandrine Paindavoine, Pierre Joseph Dechelotte, Benjamin Besse, Jean Michel Vignaud, Marie Brevet, Elie Fadel, Wilfrid Richer, Isabelle Treilleux, Julien Masliah-Planchon, Mojgan Devouassoux-Shisheboran, Gerard Zalcman, Yves Allory, Franck Bourdeaut, Francoise Thivolet-Bejui, Dominique Ranchere-Vince, Nicolas Girard, Sylvie Lantuejoul, Francoise Galateau-Sallé, Jean Michel Coindre, Alexandra Leary, Olivier Delattre, Jean Yves Blay & Franck Tirode doi:10.1038/ng.3399 Francois Le Loarer, Franck Tirode and colleagues identify a new class of undifferentiated thoracic sarcomas characterized by inactivation of SMARCA4, which encodes an ATPase subunit of BAF chromatin-remodeling complexes. They further show that these tumors exhibit transcriptional profiles similar to those of other BAF-deficient malignancies. Genetic association analyses highlight biological pathways underlying mitral valve prolapse   pp1206 - 1211 Christian Dina, Nabila Bouatia-Naji, Nathan Tucker, Francesca N Delling, Katelynn Toomer, Ronen Durst, Maelle Perrocheau, Leticia Fernandez-Friera, Jorge Solis, PROMESA investigators, Thierry Le Tourneau, Ming-Huei Chen, Vincent Probst, Yohan Bosse, Philippe Pibarot, Diana Zelenika, Mark Lathrop, Serge Hercberg, Ronan Roussel, Emelia J Benjamin, Fabrice Bonnet, Su Hao Lo, Elena Dolmatova, Floriane Simonet, Simon Lecointe, Florence Kyndt, Richard Redon, Hervé Le Marec, Philippe Froguel, Patrick T Ellinor, Ramachandran S Vasan, Patrick Bruneval, Roger R Markwald, Russell A Norris, David J Milan, Susan A Slaugenhaupt, Robert A Levine, Jean-Jacques Schott, Albert A Hagege, MVP-France, Xavier Jeunemaitre & Leducq Transatlantic MITRAL Network doi:10.1038/ng.3383 Christian Dina, Nabila Bouatia-Naji, Xavier Jeunemaitre and colleagues from the Leducq Transatlantic MITRAL Network report the results of a genome-wide association study of nonsyndromic mitral valve prolapse. They identify six susceptibility loci and provide functional evidence implicating LMCD1 and TNS1 as genes influencing mitral valve development. Technical Report Top In situ single-cell analysis identifies heterogeneity for PIK3CA mutation and HER2 amplification in HER2-positive breast cancer   pp1212 - 1219 Michalina Janiszewska, Lin Liu, Vanessa Almendro, Yanan Kuang, Cloud Paweletz, Rita A Sakr, Britta Weigelt, Ariella B Hanker, Sarat Chandarlapaty, Tari A King, Jorge S Reis-Filho, Carlos L Arteaga, So Yeon Park, Franziska Michor & Kornelia Polyak doi:10.1038/ng.3391 Kornelia Polyak, Franziska Michor and colleagues report a novel method, STAR-FISH, for combined in situ single-cell analysis of point mutations and copy number alterations in archived tissue samples. They apply STAR-FISH to clinically relevant PIK3CA mutations and HER2 amplifications and observe associations between intratumoral diversity and clinical outcome. 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