Nature Genetics Contents: May 2015 pp 425 - 559

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Advertisement A*STAR Research - Highlighting the best of research at the Agency for Science, Technology and Research (A*STAR), Singapore's premier research organization Recent Highlights Infectious diseases: A gene for Salmonella resistance | Parasitology: Genes of carcinogenic liver fluke revealed | Schizophrenia: Teamwork uncovers genetic risk factors Download the A*STAR Research app now!  TABLE OF CONTENTS May 2015 Volume 47, Issue 5 Focus Editorial News and Views Research Highlights Articles Brief Communication Letters Technical Reports Advertisement Four million CpGs - we've got you covered. Diagenode's Premium RRBS kit uses a proprietary protocol for highest efficiency of bisulfite conversion and minimal bias with reduced amplification requirements. High resolution DNA methylation profiling at the single nucleotide level Superior coverage - 4 million CpGs Cost-efficient - Optimized for multiplexing up 6 samples/lane Learn more  Subscribe   Facebook   RSS   Recommend to library   Twitter   Advertisement The 2015 IMB Conference on DNA Repair and Genome Stability in a Chromatin Environment will explore local chromatin events and their implications for genome stability, such as the emerging roles of chromatin remodellers and posttranslational modifications in a variety of DNA repair and damage signalling pathways. Keynote speakers will be Susan Gasser and Titia Sixma.   Focus Top Focus on epilepsy Focus issue: May 2015 Volume 47, No 5 Contents Editorial Letters Article Brief Communication Data Descriptor Sponsor Editorial Top Focus on Genomes of Icelanders Letters from Iceland   p425 doi:10.1038/ng.3277 The largest-ever set of human genomes from a single population and the consequent insights into mutation, evolution, gene function and disease predisposition are reported in four linked papers. These results provide a strategy for the analysis of the full spectrum of genetic variation in any population and raise questions about how society should implement the knowledge gained. News and Views Top Loss of negative regulators amplifies RAS signaling   pp426 - 427 Rebecca Lock & Karen Cichowski doi:10.1038/ng.3299 A new study identifies SPRY4 as a tumor suppressor in acute myeloid leukemia and shows that loss of SPRY4 acts as an alternative mechanism to drive RAS signaling. In addition, a paradigm of cooperativity in which combined loss of multiple negative regulators of the RAS pathway supplants the need for RAS mutations is suggested. See also: Letter by Zhao et al. Keeping methylation at bay   pp427 - 428 Gavin Kelsey doi:10.1038/ng.3290 A hallmark of CpG islands is their unmethylated state, and determining how DNA methylation can invade these elements is therefore important for understanding developmental gene regulation and disease. A new study shows that FBXL10, a protein commonly altered by mutation in leukemia, is part of a mechanism that blocks methylation of CpG islands. See also: Article by Boulard et al. Genetics JOBS of the week Group Leader (M / F) - Epigenetics and Mouse Genetics European Molecular Biology Laboratory (EMBL) Full Professor (W3) in Human Genetics Medizinischen Fakultat Der RWTH Aachen Postdoctoral Position in Molecular Biology and Genetics South Dakota State University Research Associate: Cancer Genetics, Epigenetics and Biomarkers Baylor Research Institute Assistant / Associate Professor of Genetics and Complex Diseases Harvard T.H. Chan School of Public Health More Science jobs from Genetics EVENT Yeast Genetics & Genomics 21.07.15 Cold Spring Harbour, USA More science events from Research Highlights Top Dementia in a dish | BRAF pseudogene induces cancer | MicroRNAs dampen noisy expression | Fine-tuning of transcription factor binding | Bladder exstrophy risk variants Articles Top Focus on Genomes of Icelanders Large-scale whole-genome sequencing of the Icelandic population   pp435 - 444 Daniel F Gudbjartsson, Hannes Helgason, Sigurjon A Gudjonsson, Florian Zink, Asmundur Oddson, Arnaldur Gylfason, Soren Besenbacher, Gisli Magnusson, Bjarni V Halldorsson, Eirikur Hjartarson, Gunnar Th Sigurdsson, Simon N Stacey, Michael L Frigge, Hilma Holm, Jona Saemundsdottir, Hafdis Th Helgadottir, Hrefna Johannsdottir, Gunnlaugur Sigfusson, Gudmundur Thorgeirsson, Jon Th Sverrisson, Solveig Gretarsdottir, G Bragi Walters, Thorunn Rafnar, Bjarni Thjodleifsson, Einar S Bjornsson, Sigurdur Olafsson, Hildur Thorarinsdottir, Thora Steingrimsdottir, Thora S Gudmundsdottir, Asgeir Theodors, Jon G Jonasson, Asgeir Sigurdsson, Gyda Bjornsdottir, Jon J Jonsson, Olafur Thorarensen, Petur Ludvigsson, Hakon Gudbjartsson, Gudmundur I Eyjolfsson, Olof Sigurdardottir, Isleifur Olafsson, David O Arnar, Olafur Th Magnusson, Augustine Kong, Gisli Masson, Unnur Thorsteinsdottir, Agnar Helgason, Patrick Sulem & Kari Stefansson doi:10.1038/ng.3247 Kari Stefansson and colleagues report the whole-genome sequencing of 2,636 individuals from Iceland to a median of 20× coverage, providing a valuable genomic resource for this population isolate. They characterize patterns of genetic variation and population structure and demonstrate the usefulness of this resource for genetic discovery for several disease phenotypes. Brief Communication Top Focus on Genomes of Icelanders Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease   pp445 - 447 Stacy Steinberg, Hreinn Stefansson, Thorlakur Jonsson, Hrefna Johannsdottir, Andres Ingason, Hannes Helgason, Patrick Sulem, Olafur Th Magnusson, Sigurjon A Gudjonsson, Unnur Unnsteinsdottir, Augustine Kong, Seppo Helisalmi, Hilkka Soininen, James J Lah, DemGene, Dag Aarsland, Tormod Fladby, Ingun D Ulstein, Srdjan Djurovic, Sigrid B Sando, Linda R White, Gun-Peggy Knudsen, Lars T Westlye, Geir Selbæk, Ina Giegling, Harald Hampel, Mikko Hiltunen, Allan I Levey, Ole A Andreassen, Dan Rujescu, Palmi V Jonsson, Sigurbjorn Bjornsson, Jon Snaedal & Kari Stefansson doi:10.1038/ng.3246 Stacy Steinberg, Hreinn Stefansson, Thorlakur Jonsson and colleagues found that rare variants predicted to alter the function of ABCA7 are associated with risk of Alzheimer's disease. The association was found in Iceland and replicated in northern Europe and the United States. Letters Top Focus on Genomes of Icelanders Identification of a large set of rare complete human knockouts   pp448 - 452 Patrick Sulem, Hannes Helgason, Asmundur Oddson, Hreinn Stefansson, Sigurjon A Gudjonsson, Florian Zink, Eirikur Hjartarson, Gunnar Th Sigurdsson, Adalbjorg Jonasdottir, Aslaug Jonasdottir, Asgeir Sigurdsson, Olafur Th Magnusson, Augustine Kong, Agnar Helgason, Hilma Holm, Unnur Thorsteinsdottir, Gisli Masson, Daniel F Gudbjartsson & Kari Stefansson doi:10.1038/ng.3243 Patrick Sulem, Hannes Helgason and colleagues identify homozygous and compound heterozygous loss-of-function variants of minor allele frequency <2% in 7.7% of the genotyped Icelandic population. Under transmission of some of these variants from heterozygous parents provides evidence that they are actually deleterious. Focus on Genomes of Icelanders The Y-chromosome point mutation rate in humans   pp453 - 457 Agnar Helgason, Axel W Einarsson, Valdís B Guðmundsdóttir, Ásgeir Sigurðsson, Ellen D Gunnarsdóttir, Anuradha Jagadeesan, S Sunna Ebenesersdóttir, Augustine Kong & Kári Stefánsson doi:10.1038/ng.3171 Agnar Helgason and colleagues report the point mutation rate for the male-specific euchromatic sequence of the Y chromosome based on 753 Icelandic males. They find that the non-recombining portions of the Y chromosome mutate at a faster rate than palindromic regions, suggesting that gene conversion acts to correct mutations in palindromic sequences. Articles Top Mutational landscape and clonal architecture in grade II and III gliomas   pp458 - 468 Hiromichi Suzuki, Kosuke Aoki, Kenichi Chiba, Yusuke Sato, Yusuke Shiozawa, Yuichi Shiraishi, Teppei Shimamura, Atsushi Niida, Kazuya Motomura, Fumiharu Ohka, Takashi Yamamoto, Kuniaki Tanahashi, Melissa Ranjit, Toshihiko Wakabayashi, Tetsuichi Yoshizato, Keisuke Kataoka, Kenichi Yoshida, Yasunobu Nagata, Aiko Sato-Otsubo, Hiroko Tanaka, Masashi Sanada, Yutaka Kondo, Hideo Nakamura, Masahiro Mizoguchi, Tatsuya Abe, Yoshihiro Muragaki, Reiko Watanabe, Ichiro Ito, Satoru Miyano, Atsushi Natsume & Seishi Ogawa doi:10.1038/ng.3273 Seishi Ogawa, Atsushi Natsume and colleagues report analyses of large sets of sequence data of grade II and III gliomas. They find three distinct subtypes of grade II and III gliomas characterized by discrete mutation profiles and distinct clinical behaviors. Targeted disruption of DNMT1, DNMT3A and DNMT3B in human embryonic stem cells   pp469 - 478 Jing Liao, Rahul Karnik, Hongcang Gu, Michael J Ziller, Kendell Clement, Alexander M Tsankov, Veronika Akopian, Casey A Gifford, Julie Donaghey, Christina Galonska, Ramona Pop, Deepak Reyon, Shengdar Q Tsai, William Mallard, J Keith Joung, John L Rinn, Andreas Gnirke & Alexander Meissner doi:10.1038/ng.3258 Alexander Meissner and colleagues use CRISPR/Cas9 genome editing to inactivate the DNA methyltransferases DNMT1, DNMT3A and DNMT3B in human embryonic stem cells (ESCs). They find an essential role for DNMT1 in human ESCs and generate genome-wide maps of the DNA methylation changes that occur following inactivation of these enzymes. FBXL10 protects Polycomb-bound genes from hypermethylation   pp479 - 485 Mathieu Boulard, John R Edwards & Timothy H Bestor doi:10.1038/ng.3272 Timothy Bestor and colleagues disrupt the Fbxl10 gene in mice, which leads to dense de novo DNA methylation of promoters that are co-occupied by both FBXL10 and by Polycomb repressive complexes. They conclude that FBXL10 protects Polycomb-bound genes from hypermethylation. See also: News and Views by Kelsey Transposon mutagenesis identifies genetic drivers of BrafV600E melanoma   pp486 - 495 Michael B Mann, Michael A Black, Devin J Jones, Jerrold M Ward, Christopher Chin Kuan Yew, Justin Y Newberg, Adam J Dupuy, Alistair G Rust, Marcus W Bosenberg, Martin McMahon, Cristin G Print, Neal G Copeland & Nancy A Jenkins doi:10.1038/ng.3275 Nancy Jenkins, Neal Copeland and colleagues report the results of a Sleeping Beauty transposon mutagenesis screen in mice carrying a melanocyte-specific inducible BrafV600E allele. Analysis of transposon insertion sites identified candidate genetic drivers of melanoma. Muscle connective tissue controls development of the diaphragm and is a source of congenital diaphragmatic hernias   pp496 - 504 Allyson J Merrell, Benjamin J Ellis, Zachary D Fox, Jennifer A Lawson, Jeffrey A Weiss & Gabrielle Kardon doi:10.1038/ng.3250 Gabrielle Kardon and colleagues present a detailed study of diaphragm development in mice. They show that migration of connective tissue fibroblasts derived from the pleuroperitoneal folds controls diaphragm morphogenesis and that mosaic ablation of Gata4 in this cell population results in defects resembling human congenital diaphragmatic hernias. Letters Top Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets   pp505 - 511 Kornelius Schulze, Sandrine Imbeaud, Eric Letouzé, Ludmil B Alexandrov, Julien Calderaro, Sandra Rebouissou, Gabrielle Couchy, Clément Meiller, Jayendra Shinde, Frederic Soysouvanh, Anna-Line Calatayud, Roser Pinyol, Laura Pelletier, Charles Balabaud, Alexis Laurent, Jean-Frederic Blanc, Vincenzo Mazzaferro, Fabien Calvo, Augusto Villanueva, Jean-Charles Nault, Paulette Bioulac-Sage, Michael R Stratton, Josep M Llovet & Jessica Zucman-Rossi doi:10.1038/ng.3252 Jessica Zucman-Rossi and colleagues report exome sequences of 243 hepatocellular carcinomas. They identify mutational signatures associated with specific risk factors such as alcohol, tobacco and aflatoxin B1 and find genetic alterations potentially targetable by FDA-approved drugs in 28% of the tumors. Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening   pp512 - 517 Bridget D Stuart, Jungmin Choi, Samir Zaidi, Chao Xing, Brody Holohan, Rui Chen, Mihwa Choi, Pooja Dharwadkar, Fernando Torres, Carlos E Girod, Jonathan Weissler, John Fitzgerald, Corey Kershaw, Julia Klesney-Tait, Yolanda Mageto, Jerry W Shay, Weizhen Ji, Kaya Bilguvar, Shrikant Mane, Richard P Lifton & Christine Kim Garcia doi:10.1038/ng.3278 Christine Garcia and colleagues use exome sequencing to identify genetic risk factors for familial pulmonary fibrosis. They observe an excess of rare damaging variants in PARN and RTEL1 in probands with pulmonary fibrosis and show that these variants cosegregate with disease in the affected families. A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis   pp518 - 522 Karianne Fjeld, Frank Ulrich Weiss, Denise Lasher, Jonas Rosendahl, Jian-Min Chen, Bente B Johansson, Holger Kirsten, Claudia Ruffert, Emmanuelle Masson, Solrun J Steine, Peter Bugert, Miriam Cnop, Robert Grützmann, Julia Mayerle, Joachim Mössner, Monika Ringdal, Hans-Ulrich Schulz, Matthias Sendler, Peter Simon, Paweł Sztromwasser, Janniche Torsvik, Markus Scholz, Erling Tjora, Claude Férec, Heiko Witt, Markus M Lerch, Pål R Njølstad, Stefan Johansson & Anders Molven doi:10.1038/ng.3249 Anders Molven and colleagues show that a recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis. The hybrid allele is associated with approximately fivefold-higher risk of disease, and it encodes a protein with reduced lipolytic activity and prominent intracellular accumulation. Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration   pp523 - 527 James Curtis, Yang Luo, Helen L Zenner, Delphine Cuchet-Lourenço, Changxin Wu, Kitty Lo, Mailis Maes, Ali Alisaac, Emma Stebbings, Jimmy Z Liu, Liliya Kopanitsa, Olga Ignatyeva, Yanina Balabanova, Vladyslav Nikolayevskyy, Ingelore Baessmann, Thorsten Thye, Christian G Meyer, Peter Nürnberg, Rolf D Horstmann, Francis Drobniewski, Vincent Plagnol, Jeffrey C Barrett & Sergey Nejentsev doi:10.1038/ng.3248 Sergey Nejentsev and colleagues identify intronic variants in ASAP1 that associate with susceptibility to tuberculosis. They show that ASAP1 is downregulated in dendritic cells infected with Mycobacterium tuberculosis, impairing their migration and matrix degradation abilities. Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction   pp528 - 534 Naiara Akizu, Vincent Cantagrel, Maha S Zaki, Lihadh Al-Gazali, Xin Wang, Rasim Ozgur Rosti, Esra Dikoglu, Antoinette Bernabe Gelot, Basak Rosti, Keith K Vaux, Eric M Scott, Jennifer L Silhavy, Jana Schroth, Brett Copeland, Ashleigh E Schaffer, Philip L S M Gordts, Jeffrey D Esko, Matthew D Buschman, Seth J Field, Gennaro Napolitano, Ghada M Abdel-Salam, R Koksal Ozgul, Mahmut Samil Sagıroglu, Matloob Azam, Samira Ismail, Mona Aglan, Laila Selim, Iman G Mahmoud, Sawsan Abdel-Hadi, Amera El Badawy, Abdelrahim A Sadek, Faezeh Mojahedi, Hulya Kayserili, Amira Masri, Laila Bastaki, Samia Temtamy, Ulrich Müller, Isabelle Desguerre, Jean-Laurent Casanova, Ali Dursun, Murat Gunel, Stacey B Gabriel, Pascale de Lonlay & Joseph G Gleeson doi:10.1038/ng.3256 Joseph Gleeson and colleagues report that biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy marked by lysosome-autophagosome dysfunction. Their findings suggest a role for SNX14 in mediating lysosome-autophagosome fusion. Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia   pp535 - 538 Leila Noetzli, Richard W Lo, Alisa B Lee-Sherick, Michael Callaghan, Patrizia Noris, Anna Savoia, Madhvi Rajpurkar, Kenneth Jones, Katherine Gowan, Carlo L Balduini, Alessandro Pecci, Chiara Gnan, Daniela De Rocco, Michael Doubek, Ling Li, Lily Lu, Richard Leung, Carolina Landolt-Marticorena, Stephen Hunger, Paula Heller, Arthur Gutierrez-Hartmann, Liang Xiayuan, Fred G Pluthero, Jesse W Rowley, Andrew S Weyrich, Walter H A Kahr, Christopher C Porter & Jorge Di Paola doi:10.1038/ng.3253 Jorge Di Paola, Christopher Porter, Walter Kahr and colleagues report germline mutations in the transcriptional repressor gene ETV6 in three families with thrombocytopenia and elevated red blood cell volume. All three mutations affect the ability of ETV6 to repress transcription of a reporter construct, and the two protein-altering mutations affect megakaryocyte development. Cooperative loss of RAS feedback regulation drives myeloid leukemogenesis   pp539 - 543 Zhen Zhao, Chi-Chao Chen, Cory D Rillahan, Ronglai Shen, Thomas Kitzing, Megan E McNerney, Ernesto Diaz-Flores, Johannes Zuber, Kevin Shannon, Michelle M Le Beau, Mona S Spector, Scott C Kogan & Scott W Lowe doi:10.1038/ng.3251 Scott Lowe and colleagues investigate regulation of Ras signaling during leukemogenesis and show that negative regulators Spry4 and Nf1 prevent transformation to aggressive acute myeloid leukemia in mice. See also: News and Views by Lock & Cichowski Genetic conflict reflected in tissue-specific maps of genomic imprinting in human and mouse   pp544 - 549 Tomas Babak, Brian DeVeale, Emily K Tsang, Yiqi Zhou, Xin Li, Kevin S Smith, Kim R Kukurba, Rui Zhang, Jin Billy Li, Derek van der Kooy, Stephen B Montgomery & Hunter B Fraser doi:10.1038/ng.3274 Hunter Fraser and colleagues generate atlases of imprinted gene expression across many mouse and human tissues. They find that imprinted genes are enriched for co-expression in pairs of maternally and paternally expressed genes, consistent with an evolutionary signature of parental conflict. Technical Reports Top Testing for genetic associations in arbitrarily structured populations   pp550 - 554 Minsun Song, Wei Hao & John D Storey doi:10.1038/ng.3244 John Storey and colleagues report a statistical test for genetic association for use with data from structured populations. They demonstrate the use of this test on both simulated data and empirical data from the Northern Finland Birth Cohort, from which they identify significant loci not detected by other methods. Exploring population size changes using SNP frequency spectra   pp555 - 559 Xiaoming Liu & Yun-Xin Fu doi:10.1038/ng.3254 Xiaoming Liu and Yun-Xin Fu present a model-flexible method for inferring changes in population size over time on the basis of the composite likelihood of SNP frequencies. They apply the method to 1000 Genomes Project data to infer changes in human population size on the timescale of 10,000 to 200,000 years ago. 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