Nature Genetics Contents: February 2014 pp 93-212

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Advertisement RNA-Sequencing from FFPE Samples   NOW you can achieve comparable RNA-Sequencing data from FFPE samples. In this technote, EA|Quintiles unveils new methods to address the challenges of molecular analysis from FFPE samples. Read about this protocol and our comparison of results from FFPE vs. matched fresh-frozen tissue. 919-405-2248 * 866-293-6094  TABLE OF CONTENTS February 2014 Volume 46, Issue 2 Editorial News and Views Research Highlights Perspective Analysis Articles Letters Technical Reports Advertisement   New from Exiqon Services: microRNA and small RNA NGS - A complete sample-to-answer solution - Comprehensive analysis including biological interpretation - Experiments set up in close cooperation with our microRNA and NGS experts Learn more Subscribe   Facebook   RSS   Recommend to library   Twitter   Editorial Top Standards for clinical use of genetic variants   p93 doi:10.1038/ng.2893 The price of DNA sequencing has never been lower. However, there is little consensus as to when the identification of a genetic variant is clinically useful. Clinical geneticists carrying out systematic community reviews of evidence for the pathogenicity of variants collected in locus-specific and disease-specific databases are beginning to bridge the gap between research evidence and rules used to make clinical decisions. News and Views Top HOXB13, RFX6 and prostate cancer risk   pp94 - 95 Ian G Mills doi:10.1038/ng.2881 A new study shows that HOXB13 is preferentially recruited to the risk allele of a prostate cancer-associated SNP, enhancing the expression of RFX6, a driver of prostate cancer cell migration and predictor of disease progression. The work illustrates how a single risk locus contributes both to prostate cancer incidence and, through functional follow-up, to disease progression. See also: Article by Huang et al. A cistrome roadmap for understanding pancreatic islet biology   pp95 - 96 Dana Avrahami & Klaus H Kaestner doi:10.1038/ng.2880 Although dozens of common variants have been associated with increased risk of type 2 diabetes (T2D), the mechanisms by which these variants increase disease susceptibility are largely unknown. A new study mapping the human pancreatic islet cistrome provides a roadmap for exploring the effects of these variants and suggests that altered enhancer function might be a common contributor to the genetic risk of T2D. See also: Article by Pasquali et al. A RAG driver on the road to pediatric ALL   pp96 - 98 Roland P Kuiper & Esmé Waanders doi:10.1038/ng.2879 Genomic aberrations affecting genes in B cell differentiation are hallmarks of B-precursor acute lymphoblastic leukemia (ALL). A new whole-genome sequencing study of ETV6-RUNX1-positive ALL has now identified RAG-mediated recombination, which specifically targets genes and regulatory elements active during B cell differentiation, as the underlying mechanism. See also: Article by Papaemmanuil et al. Genetics JOBS of the week Independent Junior Research Group in Crop Plant Genetics Max Planck Institute for Plant Breeding Research Assistant Professor: Molecular biology / genetics of aquatic infectious diseases University of Maryland Faculty Positions in Genetics and Genomics University of Michigan Post-doctoral research fellow in transposon cancer genomics Memorial Sloan-Kettering Cancer Center Functional Genomics Lead Bioinformatics Core University of Oxford More Science jobs from Genetics EVENT Zebrafish Development and Genetics 10.08.14 Woods Hole, USA More science events from Research Highlights Top Gene expression in early development | A CRISPR method for genome-wide screening | Dynamic enhancer usage during development | Synthetic modeling of developmental enhancers | GADL1 variants and lithium response Perspective Top Advantages and pitfalls in the application of mixed-model association methods   pp100 - 106 Jian Yang, Noah A Zaitlen, Michael E Goddard, Peter M Visscher & Alkes L Price doi:10.1038/ng.2876 Alkes Price, Peter Visscher and colleagues provide recommendations on the application of mixed-linear-model association methods across a range of study designs. Analysis Top Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database   pp107 - 115 Bryony A Thompson, Amanda B Spurdle, John-Paul Plazzer, Marc S Greenblatt, Kiwamu Akagi, Fahd Al-Mulla, Bharati Bapat, Inge Bernstein, Gabriel Capellá, Johan T den Dunnen, Desiree du Sart, Aurelie Fabre, Michael P Farrell, Susan M Farrington, Ian M Frayling, Thierry Frebourg, David E Goldgar, Christopher D Heinen, Elke Holinski-Feder, Maija Kohonen-Corish, Kristina Lagerstedt Robinson, Suet Yi Leung, Alexandra Martins, Pal Moller, Monika Morak, Minna Nystrom, Paivi Peltomaki, Marta Pineda, Ming Qi, Rajkumar Ramesar, Lene Juel Rasmussen, Brigitte Royer-Pokora, Rodney J Scott, Rolf Sijmons, Sean V Tavtigian, Carli M Tops, Thomas Weber, Juul Wijnen, Michael O Woods, Finlay Macrae, Maurizio Genuardi & on behalf of InSiGHT doi:10.1038/ng.2854 Community microattribution review of the evidence for colon cancer risk conferred by constitutional variants in MLH1, MSH2, MSH6 and PMS2 has resulted in the reclassification of two-thirds of the variants reported in existing databases and led to clinical recommendations for the interpretation of 1,370 variants that do not result in obvious protein truncation. Articles Top RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia   pp116 - 125 Elli Papaemmanuil, Inmaculada Rapado, Yilong Li, Nicola E Potter, David C Wedge, Jose Tubio, Ludmil B Alexandrov, Peter Van Loo, Susanna L Cooke, John Marshall, Inigo Martincorena, Jonathan Hinton, Gunes Gundem, Frederik W van Delft, Serena Nik-Zainal, David R Jones, Manasa Ramakrishna, Ian Titley, Lucy Stebbings, Catherine Leroy, Andrew Menzies, John Gamble, Ben Robinson, Laura Mudie, Keiran Raine, Sarah O'Meara, Jon W Teague, Adam P Butler, Giovanni Cazzaniga, Andrea Biondi, Jan Zuna, Helena Kempski, Markus Muschen, Anthony M Ford, Michael R Stratton, Mel Greaves & Peter J Campbell doi:10.1038/ng.2874 Peter Campbell, Mel Greaves and colleagues use exome and whole-genome sequencing to characterize somatic mutations in childhood acute lymphoblastic leukemias with the ETV6-RUNX1 fusion gene. They find that RAG-mediated deletions are the dominant mutational process. See also: News and Views by Kuiper & Waanders A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding   pp126 - 135 Qilai Huang, Thomas Whitington, Ping Gao, Johan F Lindberg, Yuehong Yang, Jielin Sun, Marja-Riitta Väisänen, Robert Szulkin, Matti Annala, Jian Yan, Lars A Egevad, Kai Zhang, Ruizhu Lin, Arttu Jolma, Matti Nykter, Aki Manninen, Fredrik Wiklund, Markku H Vaarala, Tapio Visakorpi, Jianfeng Xu, Jussi Taipale & Gong-Hong Wei doi:10.1038/ng.2862 Gong-Hong Wei, Jussi Taipale and colleagues show that a prostate cancer risk allele at 6q22 enhances HOXB13 chromatin binding at this locus, leading to increased allele-specific expression of RFX6. They further show that RFX6 suppression reduces the proliferation, migration and invasion of prostate cancer cells and that RFX6 expression in clinical samples correlates with tumor progression and metastasis. See also: News and Views by Mills Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants   pp136 - 143 Lorenzo Pasquali, Kyle J Gaulton, Santiago A Rodríguez-Seguí, Loris Mularoni, Irene Miguel-Escalada, İldem Akerman, Juan J Tena, Ignasi Morán, Carlos Gómez-Marín, Martijn van de Bunt, Joan Ponsa-Cobas, Natalia Castro, Takao Nammo, Inês Cebola, Javier García-Hurtado, Miguel Angel Maestro, François Pattou, Lorenzo Piemonti, Thierry Berney, Anna L Gloyn, Philippe Ravassard, José Luis Gómez Skarmeta, Ferenc Müller, Mark I McCarthy & Jorge Ferrer doi:10.1038/ng.2870 Jorge Ferrer and colleagues have mapped regulatory SNP variants associated in GWAS with type 2 diabetes risk and glycemic traits to large clusters of enhancer elements regulating the transcriptional identity of pancreatic β cells via a highly connected transcription factor network. See also: News and Views by Avrahami & Kaestner Ionic leakage underlies a gain-of-function effect of dominant disease mutations affecting diverse P-type ATPases   pp144 - 151 Maki Kaneko, Bela S Desai & Boaz Cook doi:10.1038/ng.2850 Boaz Cook and colleagues show that dominant disease-causing mutations in genes encoding P-type ATPases result in a gain-of-function ionic leakage phenotype that is exacerbated at elevated temperatures. The authors propose that the mutations promote leakage by disrupting the tight coupling of ATPase activity and transmembrane gating control. Therapeutic modulation of eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models   pp152 - 160 Hyung-Jun Kim, Alya R Raphael, Eva S LaDow, Leeanne McGurk, Ross A Weber, John Q Trojanowski, Virginia M-Y Lee, Steven Finkbeiner, Aaron D Gitler & Nancy M Bonini doi:10.1038/ng.2853 Nancy Bonini and colleagues performed a genome-wide yeast screen for modifiers of TDP-43 toxicity and identified genes in RNA metabolism, including several RNA-binding proteins with connections to stress granules. They determined that therapeutic modulation of stress granule-associated eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models in flies and primary mammalian neurons. Letters Top Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas   pp161 - 165 Priscilla K Brastianos, Amaro Taylor-Weiner, Peter E Manley, Robert T Jones, Dora Dias-Santagata, Aaron R Thorner, Michael S Lawrence, Fausto J Rodriguez, Lindsay A Bernardo, Laura Schubert, Ashwini Sunkavalli, Nick Shillingford, Monica L Calicchio, Hart G W Lidov, Hala Taha, Maria Martinez-Lage, Mariarita Santi, Phillip B Storm, John Y K Lee, James N Palmer, Nithin D Adappa, R Michael Scott, Ian F Dunn, Edward R Laws Jr, Chip Stewart, Keith L Ligon, Mai P Hoang, Paul Van Hummelen, William C Hahn, David N Louis, Adam C Resnick, Mark W Kieran, Gad Getz & Sandro Santagata doi:10.1038/ng.2868 Sandro Santagata, Gad Getz and colleagues report the discovery of a recurrent mutation in the oncogene BRAF in papillary craniopharyngiomas that does not occur in the histologically related adamantinomatous form. Their results have the potential to aid in diagnosis and treatment of these intracranial tumors. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas   pp166 - 170 Teresa Palomero, Lucile Couronné, Hossein Khiabanian, Mi-Yeon Kim, Alberto Ambesi-Impiombato, Arianne Perez-Garcia, Zachary Carpenter, Francesco Abate, Maddalena Allegretta, J Erika Haydu, Xiaoyu Jiang, Izidore S Lossos, Concha Nicolas, Milagros Balbin, Christian Bastard, Govind Bhagat, Miguel A Piris, Elias Campo, Olivier A Bernard, Raul Rabadan & Adolfo A Ferrando doi:10.1038/ng.2873 Adolfo Ferrando and colleagues report the exome sequencing of peripheral T cell lymphomas. They identified recurrent mutations in RHOA, TET2, DNMT3A, IDH2, FYN, ATM, B2M and CD58. Somatic RHOA mutation in angioimmunoblastic T cell lymphoma   pp171 - 175 Mamiko Sakata-Yanagimoto, Terukazu Enami, Kenichi Yoshida, Yuichi Shiraishi, Ryohei Ishii, Yasuyuki Miyake, Hideharu Muto, Naoko Tsuyama, Aiko Sato-Otsubo, Yusuke Okuno, Seiji Sakata, Yuhei Kamada, Rie Nakamoto-Matsubara, Nguyen Bich Tran, Koji Izutsu, Yusuke Sato, Yasunori Ohta, Junichi Furuta, Seiichi Shimizu, Takuya Komeno, Yuji Sato, Takayoshi Ito, Masayuki Noguchi, Emiko Noguchi, Masashi Sanada, Kenichi Chiba, Hiroko Tanaka, Kazumi Suzukawa, Toru Nanmoku, Yuichi Hasegawa, Osamu Nureki, Satoru Miyano, Naoya Nakamura, Kengo Takeuchi, Seishi Ogawa & Shigeru Chiba doi:10.1038/ng.2872 Shigeru Chiba and colleagues report exome sequencing of angioimmunoblastic T cell lymphoma (AITL) and other peripheral T cell lymphomas and identify a recurrent somatic RHOA mutation encoding a p.Gly17Val alteration in 68% of AITL samples. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma   pp176 - 181 Jessica Okosun, Csaba Bödör, Jun Wang, Shamzah Araf, Cheng-Yuan Yang, Chenyi Pan, Sören Boller, Davide Cittaro, Monika Bozek, Sameena Iqbal, Janet Matthews, David Wrench, Jacek Marzec, Kiran Tawana, Nikolay Popov, Ciaran O'Riain, Derville O'Shea, Emanuela Carlotti, Andrew Davies, Charles H Lawrie, András Matolcsy, Maria Calaminici, Andrew Norton, Richard J Byers, Charles Mein, Elia Stupka, T Andrew Lister, Georg Lenz, Silvia Montoto, John G Gribben, Yuhong Fan, Rudolf Grosschedl, Claude Chelala & Jude Fitzgibbon doi:10.1038/ng.2856 Jessica Okosun, Csaba Bodor and colleagues performed whole-genome or whole-exome sequencing on 10 follicular lymphoma and transformed follicular lymphoma pairs, followed by deep sequencing of 28 target genes in an additional 122 cases. They identify recurrent mutations in linker histone genes and genes involved in JAK-STAT signaling, NF-κB signaling and B cell development. Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas   pp182 - 187 Arkadiusz Piotrowski, Jing Xie, Ying F Liu, Andrzej B Poplawski, Alicia R Gomes, Piotr Madanecki, Chuanhua Fu, Michael R Crowley, David K Crossman, Linlea Armstrong, Dusica Babovic-Vuksanovic, Amanda Bergner, Jaishri O Blakeley, Andrea L Blumenthal, Molly S Daniels, Howard Feit, Kathy Gardner, Stephanie Hurst, Christine Kobelka, Chung Lee, Rebecca Nagy, Katherine A Rauen, John M Slopis, Pim Suwannarat, Judith A Westman, Andrea Zanko, Bruce R Korf & Ludwine M Messiaen doi:10.1038/ng.2855 Ludwine Messiaen and colleagues report the identification of constitutional LZTR1 mutations in individuals with schwannomatosis, an autosomal dominant inherited disorder of multiple schwannomas. Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling   pp188 - 193 Clare V Logan, György Szabadkai, Jenny A Sharpe, David A Parry, Silvia Torelli, Anne-Marie Childs, Marjolein Kriek, Rahul Phadke, Colin A Johnson, Nicola Y Roberts, David T Bonthron, Karen A Pysden, Tamieka Whyte, Iulia Munteanu, A Reghan Foley, Gabrielle Wheway, Katarzyna Szymanska, Subaashini Natarajan, Zakia A Abdelhamed, Joanne E Morgan, Helen Roper, Gijs W E Santen, Erik H Niks, W Ludo van der Pol, Dick Lindhout, Anna Raffaello, Diego De Stefani, Johan T den Dunnen, Yu Sun, Ieke Ginjaar, Caroline A Sewry, Matthew Hurles, Rosario Rizzuto, UK10K Consortium, Michael R Duchen, Francesco Muntoni & Eamonn Sheridan doi:10.1038/ng.2851 Michael Duchen, Francesco Muntoni, Eamonn Sheridan and colleagues show that loss-of-function mutations in MICU1 cause a recessive disorder characterized by proximal myopathy, learning difficulties and progressive extrapyramidal motor deficits. The mutations alter mitochondrial calcium homeostasis, leading to mitochondrial damage and dysfunction. Antagonistic roles of ubiquitin ligase HEI10 and SUMO ligase RNF212 regulate meiotic recombination   pp194 - 199 Huanyu Qiao, H B D Prasada Rao, Ye Yang, Jared H Fong, Jeffrey M Cloutier, Dekker C Deacon, Kathryn E Nagel, Rebecca K Swartz, Edward Strong, J Kim Holloway, Paula E Cohen, John Schimenti, Jeremy Ward & Neil Hunter doi:10.1038/ng.2858 Neil Hunter and colleagues show that the HEI10 ubiquitin ligase regulates meiotic recombination by limiting the colocalization of RNF212 and MSH4-MSH5 to future crossover sites. At later stages, they find that HEI10 accumulates stably at designated crossover sites and facilitates clearance of RNF212 and MSH4-MSH5 complexes to promote the final steps of meiotic recombination. Technical Reports Top Meta-analysis of gene-level tests for rare variant association   pp200 - 204 Dajiang J Liu, Gina M Peloso, Xiaowei Zhan, Oddgeir L Holmen, Matthew Zawistowski, Shuang Feng, Majid Nikpay, Paul L Auer, Anuj Goel, He Zhang, Ulrike Peters, Martin Farrall, Marju Orho-Melander, Charles Kooperberg, Ruth McPherson, Hugh Watkins, Cristen J Willer, Kristian Hveem, Olle Melander, Sekar Kathiresan & Gonçalo R Abecasis doi:10.1038/ng.2852 Gonçalo Abecasis, Dajiang Liu and colleagues report a meta-analysis framework to identify rare variant associations based on gene-level tests and the use of shared summary statistics provided by individual studies. They demonstrate their approach on a meta-analysis of blood lipid levels including 18,699 individuals, drawn from across 7 studies and genotyped with exome arrays. Analysis of hundreds of cis-regulatory landscapes at high resolution in a single, high-throughput experiment   pp205 - 212 Jim R Hughes, Nigel Roberts, Simon McGowan, Deborah Hay, Eleni Giannoulatou, Magnus Lynch, Marco De Gobbi, Stephen Taylor, Richard Gibbons & Douglas R Higgs doi:10.1038/ng.2871 Douglas Higgs and colleagues report a high-throughput approach, called Capture-C, to analyze interactions between cis regulatory elements. Using Capture-C, the authors interrogated hundreds of specific interactions at high resolution in a single experiment. Top Advertisement Nature Reviews Neuroscience  FREE POSTER - BDNF function in health and disease This Poster summarizes the molecular functions of BDNF in the CNS and highlights its therapeutic potential for conditions such as Alzheimer's disease, Parkinson's disease, stroke and spinal cord injury. 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