Nature Genetics Contents: September 2015 pp 963 - 1099

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Powerful multiplexing and high throughput capabilities ensure that the MassARRAY System is not only scalable, but applicable to a wide range of testing needs.  Learn More Subscribe   Facebook   RSS   Recommend to library   Twitter   Advertisement Functional Genomics and Systems Biology: From Model Organisms to Human Health (28-30 October 2015)  This conference will bring together leading scientists from genomics, bioinformatics, proteomics and cellular networks to discuss our understanding of complex biological systems relevant to health and disease. Abstract & Bursary Deadline: 16 Sept Registration Deadline: 30 Sept   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: http://bit.ly/1ER59gQ   Editorial Top Whole genome?   p963 doi:10.1038/ng.3397 The reference human genome assembly is remarkable in its completeness and usefulness in research. However, the range of allelic variation in the human population is not well described by a haploid assembly with a profusion of alternative loci. Homozygous regions and the use of multiple sequencing technologies increasingly have roles in strategies for identifying regulatory and trait-associated variation. News and Views Top Linking germline and somatic variation in Ewing sarcoma   pp964 - 965 Nicholas C Gomez and Ian J Davis doi:10.1038/ng.3387 The identification of gene-regulatory polymorphisms that influence cancer susceptibility can identify key oncogenic pathways. A new study links a germline variant to Ewing sarcoma disease susceptibility and EWSR1-FLI1-mediated gene activation. See also: Letter by Grunewald et al. Genetic differential calculus   pp965 - 966 Richard Mott doi:10.1038/ng.3384 High-throughput analysis of the phenotypes of mouse genetic knockouts presents several challenges, such as systematic measurement biases that can vary with time. A report from the EUMODIC consortium presents data from 320 genetic knockouts generated using standardized phenotyping pipelines and new statistical analyses aimed at increasing reproducibility across centers. See also: Article by de Angelis et al. Building a staircase to precision medicine for biliary tract cancer   pp967 - 968 Nataliya Razumilava and Gregory J Gores doi:10.1038/ng.3386 A new study has conducted a comprehensive exome and transcriptome analysis of a large number of intrahepatic, perihilar and distal cholangiocarcinomas and gallbladder cancers in Japanese patients. This study identifies many new alterations, confirms genetic differences in these distinct subtypes of biliary tract cancer and demonstrates that approximately 40% of described genetic aberrations are potentially targetable. See also: Article by Nakamura et al. Generics JOBS of the week Two postdoc positions Yeast Genetics and Molecular Biology - Industrial Research Projects VIB Research Assistant Professor position in statistical / human genetics University of Montréal Postdoctoral Fellow, Chemical Genetics of Cell Division and Gene Expression Laboratory of Robert P. Fisher Icahn School of Medicine at Mount Sinai Tenure Track Faculty Position in Population Genetics at the Assistant Professor Level Nanyang Technological University (NTU) Advanced Research Assistant - Bespoke Gene Targeting Wellcome Trust Sanger Institute More Science jobs from Generics EVENT Heart Failure: Genetics, Genomics and Epigenetics 3rd April - 7th April 2016 Snowbird, USA More science events from Advertisement Droplet Digital™ PCR (ddPCR™) is leading the way  More than 200 peer-reviewed publications have benefited from Droplet Digital PCR's unmatched ability to detect rare nucleic acid species. From tracking cancer biomarkers to quantifying rare mutations, gene expression, 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.   Articles Top Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics   pp969 - 978 Martin Hrabě de Angelis, George Nicholson, Mohammed Selloum, Jacqueline K White, Hugh Morgan et al. doi:10.1038/ng.3360 Steve Brown and colleagues report an analysis of 20 phenotyping tests, including 413 data parameters, across 449 mutant mouse alleles. They identify widespread pleiotropy and assign putative functions to genes that lacked previous phenotypic annotation. See also: News and Views by Mott Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations   pp979 - 986 Jimmy Z Liu, Suzanne van Sommeren, Hailiang Huang, Siew C Ng, Rudi Alberts et al. doi:10.1038/ng.3359 Rinse Weersma, Carl Anderson and colleagues report the results of a trans-ancestry association study of inflammatory bowel disease. They implicate 38 new susceptibility loci, and show that the variance explained by each IBD risk locus is consistent across diverse ancestries, with a few notable exceptions. Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma   pp987 - 995 Matthew H Law, D Timothy Bishop, Jeffrey E Lee, Myriam Brossard, Nicholas G Martin et al. doi:10.1038/ng.3373 Matthew Law, Mark Iles and colleagues report the results of a large-scale genome-wide meta-analysis of cutaneous malignant melanoma. They confirm previously reported association signals and identify five new susceptibility loci, with associated variants mapping within putative melanocyte regulatory elements. Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas   pp996 - 1002 Michael Krauthammer, Yong Kong, Antonella Bacchiocchi, Perry Evans, Natapol Pornputtapong et al. doi:10.1038/ng.3361 Ruth Halaban, Michael Krauthammer and colleagues report exome sequencing of 213 melanomas and identify a distinct co-mutation pattern of NF1 with known RASopathy genes. They identify novel melanoma mutations in several RASopathy genes and suggest that mutations in these genes may enhance the pathogenicity of NF1 mutation. Genomic spectra of biliary tract cancer   pp1003 - 1010 Hiromi Nakamura, Yasuhito Arai, Yasushi Totoki, Tomoki Shirota, Asmaa Elzawahry et al. doi:10.1038/ng.3375 Tatsuhiro Shibata and colleagues molecularly characterize 260 biliary tract cancer samples by a combination of exome and transcriptome sequencing. They find genomic alterations that could potentially be therapeutic targets. Watch an audio-visual summary of the paper here See also: News and Views by Razumilava & Gores Genomic landscape of cutaneous T cell lymphoma   pp1011 - 1019 Jaehyuk Choi, Gerald Goh, Trent Walradt, Bok S Hong, Christopher G Bunick et al. doi:10.1038/ng.3356 Richard Lifton and colleagues report a genomic analysis of cutaneous T cell lymphoma (CTCL). Their results implicate several pathways in CTCL pathogenesis, including genes involved in T cell activation and apoptosis, NF-κB signaling, chromatin remodeling and DNA damage response. Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options   pp1020 - 1029 Ute Fischer, Michael Forster, Anna Rinaldi, Thomas Risch, Stéphanie Sungalee et al. doi:10.1038/ng.3362 Jean-Pierre Bourquin, Martin Stanulla and colleagues report whole genome, whole exome and transcriptome sequencing of TCF3-HLF fusion-positive acute lymphoblastic leukemia. Drug response profiling in patient-derived xenografts identified sensitivity to the BCL2-specific inhibitor ABT-199 (venetoclax) as a new option for treating this fatal disease. The transcriptomic landscape and directed chemical interrogation of MLL-rearranged acute myeloid leukemias   pp1030 - 1037 Vincent-Philippe Lavallée, Irène Baccelli, Jana Krosl, Brian Wilhelm, Frédéric Barabé et al. doi:10.1038/ng.3371 Guy Sauvageau, Josée Hébert and colleagues analyze exomes and transcriptomes in MLL-rearranged acute myeloid leukemias. They find frequent RAS pathway mutations, which sensitize leukemias to MEK and receptor tyrosine kinase inhibitors. Whole-genome sequencing provides new insights into the clonal architecture of Barrett's esophagus and esophageal adenocarcinoma   pp1038 - 1046 Caryn S Ross-Innes, Jennifer Becq, Andrew Warren, R Keira Cheetham, Helen Northen et al. doi:10.1038/ng.3357 Rebecca Fitzgerald and colleagues report whole-genome sequence analyses of 23 paired samples of Barrett's esophagus and esophageal adenocarcinoma. Their analyses of the clonal architecture of these lesions shows that copy number increases and heterogeneity persists during development of esophageal adenocarcinoma. Paired exome analysis of Barrett's esophagus and adenocarcinoma   pp1047 - 1055 Matthew D Stachler, Amaro Taylor-Weiner, Shouyong Peng, Aaron McKenna, Agoston T Agoston et al. doi:10.1038/ng.3343 Adam Bass, Gad Getz, Scott Carter and colleagues report the whole-exome sequences of 25 pairs of esophageal adenocarcinoma and Barrett's esophagus. They identify two pathways by which Barrett's esophagus can develop into esophageal adenocarcinoma. Letters Top Genomic analysis of mycosis fungoides and Sezary syndrome identifies recurrent alterations in TNFR2   pp1056 - 1060 Alexander Ungewickell, Aparna Bhaduri, Eon Rios, Jason Reuter, Carolyn S Lee et al. doi:10.1038/ng.3370 Paul Khavari and colleagues report genomic analyses of cutaneous T cell lymphomas. They identify recurrent point mutations and genomic gains of TNFRSF1B, encoding the tumor necrosis factor receptor TNFR2, in 18% of tumors and show that expression of a recurrent TNFR2 mutant in T cells leads to enhanced non-canonical NF-κB signaling that is sensitive to the proteasome inhibitor bortezomib. Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma   pp1061 - 1066 Lu Jiang, Zhao-Hui Gu, Zi-Xun Yan, Xia Zhao, Yin-Yin Xie et al. doi:10.1038/ng.3358 Zhu Chen, Sai-Juan Chen, Wei-Li Zhao and colleagues identify recurrent loss-of-function mutations in the RNA helicase gene DDX3X in 20% of subjects with natural killer/T-cell lymphoma (NKTCL) in their study. The results suggest that DDX3X acts as a tumor suppressor and that its inactivation leads to poor clinical outcome. An APOBEC3A hypermutation signature is distinguishable from the signature of background mutagenesis by APOBEC3B in human cancers   pp1067 - 1072 Kin Chan, Steven A Roberts, Leszek J Klimczak, Joan F Sterling, Natalie Saini et al. doi:10.1038/ng.3378 Dmitry Gordenin and colleagues use a yeast reporter strain to identify distinct mutagenic signatures for the cytosine deaminases APOBEC3A and APOBEC3B. They find that cancer samples with APOBEC3A-like mutation signatures have greater than tenfold more APOBEC signature mutations than those with APOBEC3B-like signatures. Watch an audio-visual summary of the paper here Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite   pp1073 - 1078 Thomas G P Grünewald, Virginie Bernard, Pascale Gilardi-Hebenstreit, Virginie Raynal, Didier Surdez et al. doi:10.1038/ng.3363 Olivier Delattre and colleagues show that a Ewing sarcoma susceptibility variant at 10q21.3 influences EGR2 expression by altering the activity of an enhancer bound by EWSR1-FLI1. They further show that EGR2 knockdown inhibits growth of Ewing sarcoma cells in vitro and induces complete regression of xenografts in vivo, establishing a critical role for EGR2 in Ewing sarcomagenesis. See also: News and Views by Gomez & Davis A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer   pp1079 - 1084 Folefac Aminkeng, Amit P Bhavsar, Henk Visscher, Shahrad R Rassekh, Yuling Li et al. doi:10.1038/ng.3374 Colin Ross and colleagues report the results of a genome-wide association study of anthracycline-induced cardiotoxicity in children treated for cancer. They identify a nonsynonymous coding variant in RARG associated with roughly fivefold higher risk of developing this severe adverse drug reaction. Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases   pp1085 - 1090 Tobias L Lenz, Aaron J Deutsch, Buhm Han, Xinli Hu, Yukinori Okada et al. doi:10.1038/ng.3379 Soumya Raychaudhuri, Paul de Bakker and colleagues test the non-additive disease contributions of classical HLA alleles to five common autoimmune diseases. In four of the five diseases, they observe highly significant non-additive dominance and interaction effects. Technical Report Top A gene-based association method for mapping traits using reference transcriptome data   pp1091 - 1098 Eric R Gamazon, Heather E Wheeler, Kaanan P Shah, Sahar V Mozaffari, Keston Aquino-Michaels et al. doi:10.1038/ng.3367 Hae Kyung Im and colleagues report a method for predicting gene expression perturbations from genotype data after training on reference transcriptome data sets. Association of predicted gene expression with disease traits identifies known and new candidate disease genes. Corrigenda Top Corrigendum: Exploring population size changes using SNP frequency spectra   p1099 Xiaoming Liu and Yun-Xin Fu doi:10.1038/ng0915-1099a Corrigendum: Transcriptional activation of retrotransposons alters the expression of adjacent genes in wheat   p1099 Khalil Kashkush, Moshe Feldman and Avraham A. Levy doi:10.1038/ng0915-1099b Top Advertisement Nature Insight: Origin and evolution of vertebrates Vertebrates have many special features - from large brains to unique tissues. But how they evolved from invertebrates is obscure. This Insight looks at the many theories to explain vertebrate origins, the fossil evidence, a new perspective on the origin of the head and a uniquely vertebrate feature called the neural crest. Access the Insight online   Natureevents is a fully searchable, multi-disciplinary database designed to maximise exposure for events organisers. The contents of the Natureevents Directory are now live. The digital version is available here. 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