Nature Genetics Contents: January 2014 pp 1 - 92

TABLE OF CONTENTS January 2014 Volume 46, Issue 1 Editorial News and Views Research Highlights Brief Communication Articles Letters Subscribe   Facebook   RSS   Recommend to library   Twitter   Advertisement NatureJournals app for iPad The NatureJournals app for iPad now boasts over 25 Nature-branded titles. Subscribe to any journal in the app for $35.99* and gain access to world class research on the move. www.nature.com/content/app/anytitleoffer *Apple exchange rates apply. Limited time offer available on all journals except Scientific Reports. iPad is a trademark of Apple Inc.   Editorial Top Credit for code   p1 doi:10.1038/ng.2869 Moving toward fully transparent research publications, we suggest several approaches to share research that is instantiated in software written for computers and other laboratory machines. Review, replication, reuse and recognition are all incentives to provide code. News and Views Top A developmental program drives aggressive embryonal brain tumors   pp2 - 3 Tenley C Archer & Scott L Pomeroy doi:10.1038/ng.2857 Embryonal tumors with multilayered rosettes (ETMRs) are primitive neuroectodermal tumors arising in infants. A new study shows that these tumors are universally driven by fusion of the promoter of a gene with brain-specific expression, TTYH1, to C19MC, the largest human microRNA cluster, activating a fetal neural development program. See also: Letter by Kleinman et al. Enhancer mutations and phenotype modularity   pp3 - 4 Christopher T Gordon & Stanislas Lyonnet doi:10.1038/ng.2861 Only a few mutations in regulatory elements that cause human disease have been identified thus far. A new report identifies cis-regulatory mutations that abolish the activity of a developmental enhancer, thereby causing pancreatic agenesis. See also: Letter by Weedon et al. Genetic signature of bacterial pathogen adaptation during chronic pulmonary infections   pp5 - 6 Steve P Bernier, Matthew L Workentine & Michael G Surette doi:10.1038/ng.2859 To establish and maintain chronic infections, many pathogens adapt in response to selective pressures within the host, leaving unique genetic signatures. A new study uses whole-genome and population sequencing approaches to identify evidence of adaptive evolution in Burkholderia dolosa genomes isolated from chronic infections in patients with cystic fibrosis. See also: Letter by Lieberman et al. Genetics JOBS of the week Postdoctoral Research Position in Statistical Genetics and Genomics Harvard School of Public Health (HSPH) Computational Genetics and Genomics Vanderbilt University Medical Center Research Associate in Statistical Genetics Imperial College London Postdoctoral Fellowship, Genetics of Hematological Malignancies Memorial Sloan-Kettering Cancer Center Nuclear Control of Chloroplast Gene Expression Centre National de la Recherche Scientifique (French Science Academy) More Science jobs from Genetics EVENT Malaria Experimental Genetics 09.02.14 Cambridge, UK More science events from Research Highlights Top The cancer epigenome of mice and men | Isogenic iPSC-derived models of disease | OXA resistance from QTL to crystal structure | ELABELA, a peptide hormone for heart development | ARMC5 and adrenal hyperplasia Brief Communication Top High prevalence of MAP2K1 mutations in variant and IGHV4-34-expressing hairy-cell leukemias   pp8 - 10 Joshua J Waterfall, Evgeny Arons, Robert L Walker, Marbin Pineda, Laura Roth, J Keith Killian, Ogan D Abaan, Sean R Davis, Robert J Kreitman & Paul S Meltzer doi:10.1038/ng.2828 Paul Meltzer and colleagues report the results of an exome sequencing study of variant and IGHV4-34-expressing hairy-cell leukemias. They identify a high frequency of activating MAP2K1 mutations in these malignancies, suggesting potential therapeutic strategies. Articles Top Common and low-frequency variants associated with genome-wide recombination rate   pp11 - 16 Augustine Kong, Gudmar Thorleifsson, Michael L Frigge, Gisli Masson, Daniel F Gudbjartsson, Rasmus Villemoes, Erna Magnusdottir, Stefania B Olafsdottir, Unnur Thorsteinsdottir & Kari Stefansson doi:10.1038/ng.2833 Augustine Kong, Kari Stefansson and colleagues report the discovery of common and low-frequency variants associated with genome-wide recombination rates. Most of the newly discovered variants exhibit differential effects on male and female recombination rates, and several map to genes with known roles in recombination, including RAD21L and MSH4. Large conserved domains of low DNA methylation maintained by Dnmt3a   pp17 - 23 Mira Jeong, Deqiang Sun, Min Luo, Yun Huang, Grant A Challen, Benjamin Rodriguez, Xiaotian Zhang, Lukas Chavez, Hui Wang, Rebecca Hannah, Sang-Bae Kim, Liubin Yang, Myunggon Ko, Rui Chen, Berthold Göttgens, Ju-Seog Lee, Preethi Gunaratne, Lucy A Godley, Gretchen J Darlington, Anjana Rao, Wei Li & Margaret A Goodell doi:10.1038/ng.2836 Margaret Goodell and colleagues report genome-wide mapping of 5-methylcytosine and 5-hydroxymethylcytosine in purified mouse hematopoietic stem cells. They identify large regions of low methylation with borders marked by 5-hydroxymethylcytosine. These borders become eroded in the absence of DNA methyltransferase 3a. Transposon mutagenesis identifies genes driving hepatocellular carcinoma in a chronic hepatitis B mouse model   pp24 - 32 Emilie A Bard-Chapeau, Anh-Tuan Nguyen, Alistair G Rust, Ahmed Sayadi, Philip Lee, Belinda Q Chua, Lee-Sun New, Johann de Jong, Jerrold M Ward, Christopher K Y Chin, Valerie Chew, Han Chong Toh, Jean-Pierre Abastado, Touati Benoukraf, Richie Soong, Frederic A Bard, Adam J Dupuy, Randy L Johnson, George K Radda, Eric Chun Yong Chan, Lodewyk F A Wessels, David J Adams, Nancy A Jenkins & Neal G Copeland doi:10.1038/ng.2847 Neal Copeland and colleagues use a transposon mutagenesis screen to identify drivers of hepatocellular carcinoma in a mouse model of chronic hepatitis B infection. They find a very large number of candidate driver genes, many of which are implicated in cellular metabolism. Advertisement The story of Leukemia research is being re-written - one droplet at a time. See how droplet digital PCR gives scientists the power to detect what was previously undetectable. Watch Video >    Letters Top Inactivating CUX1 mutations promote tumorigenesis   pp33 - 38 Chi C Wong, Inigo Martincorena, Alistair G Rust, Mamunur Rashid, Constantine Alifrangis, Ludmil B Alexandrov, Jessamy C Tiffen, Christina Kober, Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium, Anthony R Green, Charles E Massie, Jyoti Nangalia, Stella Lempidaki, Hartmut Döhner, Konstanze Döhner, Sarah J Bray, Ultan McDermott, Elli Papaemmanuil, Peter J Campbell & David J Adams doi:10.1038/ng.2846 David Adams and colleagues identify inactivating mutations in CUX1 in diverse human cancers. They validate CUX1 as a tumor suppressor using mouse and Drosophila cancer models, and show that CUX1 deficiency activates phosphoinositide 3-kinase signaling through transcriptional downregulation of a PI3K inhibitor. Fusion of TTYH1 with the C19MC microRNA cluster drives expression of a brain-specific DNMT3B isoform in the embryonal brain tumor ETMR   pp39 - 44 Claudia L Kleinman, Noha Gerges, Simon Papillon-Cavanagh, Patrick Sin-Chan, Albena Pramatarova, Dong-Anh Khuong Quang, Véronique Adoue, Stephan Busche, Maxime Caron, Haig Djambazian, Amandine Bemmo, Adam M Fontebasso, Tara Spence, Jeremy Schwartzentruber, Steffen Albrecht, Peter Hauser, Miklos Garami, Almos Klekner, Laszlo Bognar, Jose-Luis Montes, Alfredo Staffa, Alexandre Montpetit, Pierre Berube, Magdalena Zakrzewska, Krzysztof Zakrzewski, Pawel P Liberski, Zhifeng Dong, Peter M Siegel, Thomas Duchaine, Christian Perotti, Adam Fleming, Damien Faury, Marc Remke, Marco Gallo, Peter Dirks, Michael D Taylor, Robert Sladek, Tomi Pastinen, Jennifer A Chan, Annie Huang, Jacek Majewski & Nada Jabado doi:10.1038/ng.2849 Nada Jabado, Jacek Majewski, Annie Huang and colleagues show that embryonal tumors with multilayered rosettes are characterized by a recurrent fusion of TTYH1 with the C19MC microRNA cluster. They further show that this fusion results in massive overexpression of a brain-specific isoform of DNMT3B, suggesting that this pediatric brain tumor is driven by epigenetic reactivation of an early developmental neurogenesis program. See also: News and Views by Archer & Pomeroy A large-scale screen for coding variants predisposing to psoriasis   pp45 - 50 Huayang Tang, Xin Jin, Yang Li, Hui Jiang, Xianfa Tang, Xu Yang, Hui Cheng, Ying Qiu, Gang Chen, Junpu Mei, Fusheng Zhou, Renhua Wu, Xianbo Zuo, Yong Zhang, Xiaodong Zheng, Qi Cai, Xianyong Yin, Cheng Quan, Haojing Shao, Yong Cui, Fangzhen Tian, Xia Zhao, Hong Liu, Fengli Xiao, Fengping Xu, Jianwen Han, Dongmei Shi, Anping Zhang, Cheng Zhou, Qibin Li, Xing Fan, Liya Lin, Hongqing Tian, Zaixing Wang, Huiling Fu, Fang Wang, Baoqi Yang, Shaowei Huang, Bo Liang, Xuefeng Xie, Yunqing Ren, Qingquan Gu, Guangdong Wen, Yulin Sun, Xueli Wu, Lin Dang, Min Xia, Junjun Shan, Tianhang Li, Lin Yang, Xiuyun Zhang, Yuzhen Li, Chundi He, Aie Xu, Liping Wei, Xiaohang Zhao, Xinghua Gao, Jinhua Xu, Furen Zhang, Jianzhong Zhang, Yingrui Li, Liangdan Sun, Jianjun Liu, Runsheng Chen, Sen Yang, Jun Wang & Xuejun Zhang doi:10.1038/ng.2827 Xuejun Zhang, Jun Wang and colleagues report the application of exome sequencing to a large collection of psoriasis cases and controls. They identify seven common and low-frequency nonsynonymous variants within known psoriasis susceptibility genes that are associated with psoriasis risk. A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations   pp51 - 55 Klaus Bønnelykke, Patrick Sleiman, Kasper Nielsen, Eskil Kreiner-Møller, Josep M Mercader, Danielle Belgrave, Herman T den Dekker, Anders Husby, Astrid Sevelsted, Grissel Faura-Tellez, Li Juel Mortensen, Lavinia Paternoster, Richard Flaaten, Anne Mølgaard, David E Smart, Philip F Thomsen, Morten A Rasmussen, Silvia Bonàs-Guarch, Claus Holst, Ellen A Nohr, Rachita Yadav, Michael E March, Thomas Blicher, Peter M Lackie, Vincent W V Jaddoe, Angela Simpson, John W Holloway, Liesbeth Duijts, Adnan Custovic, Donna E Davies, David Torrents, Ramneek Gupta, Mads V Hollegaard, David M Hougaard, Hakon Hakonarson & Hans Bisgaard doi:10.1038/ng.2830 Klaus Bonnelykke and colleagues identify a common variant in CDHR3 associated with early childhood asthma with severe exacerbations. CDHR3 encodes a cell adhesion protein expressed at high levels in airway epithelium, suggesting a role for altered epithelial integrity in asthma pathogenesis. A genome-wide association study identifies multiple susceptibility loci for chronic lymphocytic leukemia   pp56 - 60 Helen E Speedy, Maria Chiara Di Bernardo, Georgina P Sava, Martin J S Dyer, Amy Holroyd, Yufei Wang, Nicola J Sunter, Larry Mansouri, Gunnar Juliusson, Karin E Smedby, Göran Roos, Sandrine Jayne, Aneela Majid, Claire Dearden, Andrew G Hall, Tryfonia Mainou-Fowler, Graham H Jackson, Geoffrey Summerfield, Robert J Harris, Andrew R Pettitt, David J Allsup, James R Bailey, Guy Pratt, Chris Pepper, Chris Fegan, Richard Rosenquist, Daniel Catovsky, James M Allan & Richard S Houlston doi:10.1038/ng.2843 Richard Houlston and colleagues report results of a genome-wide association study of chronic lymphocytic leukemia. They validate several new susceptibility loci for this disease, including variants near POT1, TERC and TERT. Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis   pp61 - 64 Michael N Weedon, Inês Cebola, Ann-Marie Patch, Sarah E Flanagan, Elisa De Franco, Richard Caswell, Santiago A Rodríguez-Seguí, Charles Shaw-Smith, Candy H-H Cho, Hana Lango Allen, Jayne A L Houghton, Christian L Roth, Rongrong Chen, Khalid Hussain, Phil Marsh, Ludovic Vallier, Anna Murray, International Pancreatic Agenesis Consortium, Sian Ellard, Jorge Ferrer & Andrew T Hattersley doi:10.1038/ng.2826 Andrew Hattersley, Jorge Ferrer and colleagues use epigenomic annotation of pancreatic progenitor cells to guide the interpretation of whole-genome sequences from individuals with isolated pancreatic agenesis. They show that recessive mutations in a distal developmental enhancer of PTF1A cause pancreatic agenesis and abolish enhancer activity. See also: News and Views by Gordon & Lyonnet EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension   pp65 - 69 Mélanie Eyries, David Montani, Barbara Girerd, Claire Perret, Anne Leroy, Christine Lonjou, Nadjim Chelghoum, Florence Coulet, Damien Bonnet, Peter Dorfmüller, Elie Fadel, Olivier Sitbon, Gérald Simonneau, David-Alexandre Tregouët, Marc Humbert & Florent Soubrier doi:10.1038/ng.2844 Florent Soubrier and colleagues identify biallelic mutations in EIF2AK4 as a major cause of pulmonary veno-occlusive disease, a rare form of pulmonary hypertension. EIF2AK4 encodes a serine-threonine kinase, and the disease-causing mutations are predicted to result in loss of protein function. Gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndrome   pp70 - 76 Sérgio B Sousa, Dagan Jenkins, Estelle Chanudet, Guergana Tasseva, Miho Ishida, Glenn Anderson, James Docker, Mina Ryten, Joaquim Sa, Jorge M Saraiva, Angela Barnicoat, Richard Scott, Alistair Calder, Duangrurdee Wattanasirichaigoon, Krystyna Chrzanowska, Martina Simandlová, Lionel Van Maldergem, Philip Stanier, Philip L Beales, Jean E Vance & Gudrun E Moore doi:10.1038/ng.2829 Sérgio Sousa and colleagues show that Lenz-Majewski syndrome, a disorder featuring generalized craniotubular hyperostosis, results from de novo gain-of-function mutations in PTDSS1. The mutations lead to increased phophatidylserine synthesis, suggesting a link between phosphatidylserine production and bone metabolism. Genome-wide association study using cellular traits identifies a new regulator of root development in Arabidopsis   pp77 - 81 Mónica Meijón, Santosh B Satbhai, Takashi Tsuchimatsu & Wolfgang Busch doi:10.1038/ng.2824 Wolfgang Busch and colleagues report results of a genome-wide association study of developmental cell-type traits in Arabidopsis. They identify a new F-box gene, KUK, as a regulator of root meristem and cell length and show the feasibility of applying genome-wide association to the study of cellular traits. Genetic variation of a bacterial pathogen within individuals with cystic fibrosis provides a record of selective pressures   pp82 - 87 Tami D Lieberman, Kelly B Flett, Idan Yelin, Thomas R Martin, Alexander J McAdam, Gregory P Priebe & Roy Kishony doi:10.1038/ng.2848 Roy Kishony and colleagues sequenced the genomes of Burkholderia dolosa isolates from patients with cystic fibrosis, using colony resequencing and deep population sequencing approaches to allow comparisons of multiple isolates from each individual. They identify extensive intrastrain genomic diversity and show specific signatures of selection acting on the pathogen within individual patients. See also: News and Views by Bernier et al. Minke whale genome and aquatic adaptation in cetaceans OPEN   pp88 - 92 Hyung-Soon Yim, Yun Sung Cho, Xuanmin Guang, Sung Gyun Kang, Jae-Yeon Jeong, Sun-Shin Cha, Hyun-Myung Oh, Jae-Hak Lee, Eun Chan Yang, Kae Kyoung Kwon, Yun Jae Kim, Tae Wan Kim, Wonduck Kim, Jeong Ho Jeon, Sang-Jin Kim, Dong Han Choi, Sungwoong Jho, Hak-Min Kim, Junsu Ko, Hyunmin Kim, Young-Ah Shin, Hyun-Ju Jung, Yuan Zheng, Zhuo Wang, Yan Chen, Ming Chen, Awei Jiang, Erli Li, Shu Zhang, Haolong Hou, Tae Hyung Kim, Lili Yu, Sha Liu, Kung Ahn, Jesse Cooper, Sin-Gi Park, Chang Pyo Hong, Wook Jin, Heui-Soo Kim, Chankyu Park, Kyooyeol Lee, Sung Chun, Phillip A Morin, Stephen J O'Brien, Hang Lee, Jumpei Kimura, Dae Yeon Moon, Andrea Manica, Jeremy Edwards, Byung Chul Kim, Sangsoo Kim, Jun Wang, Jong Bhak, Hyun Sook Lee & Jung-Hyun Lee doi:10.1038/ng.2835 Jung-Hyun Lee, Jong Bhak and their colleagues report the whole-genome sequencing and de novo assembly of a male minke whale genome, as well as the genome sequences of three additional minke whales, a fin whale, a bottlenose dolphin and a finless porpoise. Their comparative analysis across cetaceans provides insights into adaptation to an aquatic lifestyle. Top Advertisement 8th annual Salk Institute, Fondation IPSEN, and Nature Symposium on Biological Complexity: Genes and Physiology January 29-31, 2014 Salk Institute for Biological Studies La Jolla, CA, USA  Click here for more information or to register for this conference today!     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. Find the latest scientific conferences, courses, meetings and symposia on natureevents.com. For event advertising opportunities across the Nature Publishing Group portfolio please contact natureevents@nature.com More Nature Events

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