Nature Genetics Contents: November 2012 pp 1171 - 1285

Advertisement Super Capabilities are Now Within Your Reach. Experience the LightCycler® 96 Instrument's intuitive user interface and powerful analysis software. Innovative optics, cutting-edge thermal resolution and data reproducibility enable research breakthroughs. Find out how to become a scientific Superhero! TABLE OF CONTENTS November 2012 Volume 44, Issue 11 Editorial News and Views Research Highlights Brief Communications Articles Letters Advertisement RNA-Seq just went from complicated to compatible. Expression Analysis will provide your data in a format you are used to -- 100% microarray compatible format. Now you can have your data and use it too! EA will help you detect 2x more differentially expressed transcripts, novel isoforms and SNVs and can achieve >97% alignment. 919-405-2248 * 866-293-6094 The publication of this issue was delayed due to Hurricane Sandy closing our New York offices temporarily. We apologize for any inconvenience caused. Subscribe   Facebook   RSS   Recommend to library   Twitter   Editorial Top Credit for clinical trial data   p1171 doi:10.1038/ng.2464 News and Views Top Tracking the evolution of cancer methylomes   pp1173 - 1174 Arnaud R Krebs & Dirk Schübeler doi:10.1038/ng.2451 Cellular transformation in cancer has long been associated with aberrant DNA methylation, most notably, hypermethylation of promoter sequences. A new study uses a clever approach of selective high-resolution profiling to follow DNA methylation over a time course of cellular transformation and challenges the notion that hypermethylation in cancer arises in an orchestrated fashion. See also: Article by Landan et al. Older males beget more mutations   pp1174 - 1176 Matthew Hurles doi:10.1038/ng.2448 Three papers characterizing human germline mutation rates bolster evidence for a relatively low rate of base substitution in modern humans and highlight a central role for paternal age in determining rates of mutation. These studies represent the advent of a transformation in our understanding of mutation rates and processes, which may ultimately have public health implications. See also: Letter by Campbell et al. FOXA1 and breast cancer risk   pp1176 - 1177 Kerstin B Meyer and Jason S Carroll doi:10.1038/ng.2449 Many SNPs associated with human disease are located in non-coding regions of the genome. A new study shows that SNPs associated with breast cancer risk are located in enhancer regions and alter binding affinity for the pioneer factor FOXA1. See also: Article by Cowper-Sal·lariet al. Genetics JOBS of the week Department of Genetics Tenure track Faculty Position University of Texas MD Anderson Cancer Center Research Associate in Statistical Genetics of Infectious Diseases University College London (UCL) 1 PhD student in the research education subject: Molecular Genetics Swedish University of Agricultural Sciences Postdoctoral Research Scientist in Statistical Genetics: Population Structure and Demographic History The Wellcome Trust Centre for Human Genetics, University of Oxford Postdoctoral Fellow in Mouse Genetics / Cancer Genomics Fred Hutchinson Cancer Research Center More Science jobs from Genetics EVENT Complex Disease Genetics for Clinicians 24.-25.01.13 Cambridge, UK More science events from Research Highlights Top Heterogeneity in genomic disorders | Rare-variant association methods | Potential Parkinson disease and ALS drug | Sensing flow at the node | Admixed genomes Brief Communications Top Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis   pp1179 - 1181 Lambert Busque, Jay P Patel, Maria E Figueroa, Aparna Vasanthakumar, Sylvie Provost, Zineb Hamilou, Luigina Mollica, Juan Li, Agnes Viale, Adriana Heguy, Maryam Hassimi, Nicholas Socci, Parva K Bhatt, Mithat Gonen, Christopher E Mason, Ari Melnick, Lucy A Godley, Cameron W Brennan, Omar Abdel-Wahab & Ross L Levine doi:10.1038/ng.2413 Ross Levine, Lambert Busque and colleagues report the identification of recurrent somatic mutations in TET2 in elderly female individuals with clonal hematopoiesis. The mutations were identified in individuals without clinically apparent hematological malignancies. Genome-wide association study identifies a common variant in RAD51B associated with male breast cancer risk   pp1182 - 1184 Nick Orr, Alina Lemnrau, Rosie Cooke, Olivia Fletcher, Katarzyna Tomczyk, Michael Jones, Nichola Johnson, Christopher J Lord, Costas Mitsopoulos, Marketa Zvelebil, Simon S McDade, Gemma Buck, Christine Blancher, KConFab Consortium, Alison H Trainer, Paul A James, Stig E Bojesen, Susanne Bokmand, Heli Nevanlinna, Johanna Mattson, Eitan Friedman, Yael Laitman, Domenico Palli, Giovanna Masala, Ines Zanna, Laura Ottini, Giuseppe Giannini, Antoinette Hollestelle, Ans M W van den Ouweland, Srdjan Novaković, Mateja Krajc, Manuela Gago-Dominguez, Jose Esteban Castelao, Håkan Olsson, Ingrid Hedenfalk, Douglas F Easton, Paul D P Pharoah, Alison M Dunning, D Timothy Bishop, Susan L Neuhausen, Linda Steele, Richard S Houlston, Montserrat Garcia-Closas, Alan Ashworth & Anthony J Swerdlow doi:10.1038/ng.2417 Nick Orr and colleagues report a genome-wide association study for male breast cancer. They identify a new susceptibility locus at RAD51B and examine association evidence for known female breast cancer loci in these cohorts. A common single-nucleotide variant in T is strongly associated with chordoma   pp1185 - 1187 Nischalan Pillay, Vincent Plagnol, Patrick S Tarpey, Samira B Lobo, Nadège Presneau, Karoly Szuhai, Dina Halai, Fitim Berisha, Stephen R Cannon, Simon Mead, Dalia Kasperaviciute, Jutta Palmen, Philippa J Talmud, Lars-Gunnar Kindblom, M Fernanda Amary, Roberto Tirabosco & Adrienne M Flanagan doi:10.1038/ng.2419 Adrienne Flanagan and colleagues identify a common variant in the T gene associated with strong risk of chordoma, a rare malignant bone tumor. The risk variant alters an amino acid in the DNA-binding domain of the T transcription factor and is associated with differential expression of T and its downstream targets. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy   pp1188 - 1190 Sarah E Heron, Katherine R Smith, Melanie Bahlo, Lino Nobili, Esther Kahana, Laura Licchetta, Karen L Oliver, Aziz Mazarib, Zaid Afawi, Amos Korczyn, Giuseppe Plazzi, Steven Petrou, Samuel F Berkovic, Ingrid E Scheffer and Leanne M Dibbens doi:10.1038/ng.2440 Samuel Berkovic and colleagues report the identification of missense mutations in KCNT1, which encodes a sodium-gated potassium channel, that cause severe autosomal dominant nocturnal frontal lobe epilepsy. Advertisement Get the most from your NGS data with Sequenom’s MassARRAY® system • Validate from tens to thousands of samples across tens to hundreds of SNPs • Design you own assays against any SNP of interest • Run a variety of applications including genotyping, DNA methylation and somatic mutation analysis   Articles Top Breast cancer risk-associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression   pp1191 - 1198 Richard Cowper-Sal·lari, Xiaoyang Zhang, Jason B Wright, Swneke D Bailey, Michael D Cole, Jerome Eeckhoute, Jason H Moore & Mathieu Lupien doi:10.1038/ng.2416 Mathieu Lupien, Jason Moore and colleagues show that breast cancer risk-associated SNPs commonly disrupt the binding of FOXA1 to chromatin, thereby directly affecting gene expression. See also: News and Views by Meyer & Carroll LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression   pp1199 - 1206 Jan J Molenaar, Raquel Domingo-Fernández, Marli E Ebus, Sven Lindner, Jan Koster, Ksenija Drabek, Pieter Mestdagh, Peter van Sluis, Linda J Valentijn, Johan van Nes, Marloes Broekmans, Franciska Haneveld, Richard Volckmann, Isabella Bray, Lukas Heukamp, Annika Sprüssel, Theresa Thor, Kristina Kieckbusch, Ludger Klein-Hitpass, Matthias Fischer, Jo Vandesompele, Alexander Schramm, Max M van Noesel, Luigi Varesio, Frank Speleman, Angelika Eggert, Raymond L Stallings, Huib N Caron, Rogier Versteeg & Johannes H Schulte doi:10.1038/ng.2436 Jan Molenaar and colleagues show that LIN28B is overexpressed and amplified in human neuroblastomas and that LIN28B regulates let-7 family miRNAs and MYCN. They create a transgenic mouse model of LIN28B overexpression and show that these mice develop neuroblastoma tumors. Epigenetic polymorphism and the stochastic formation of differentially methylated regions in normal and cancerous tissues   pp1207 - 1214 Gilad Landan, Netta Mendelson Cohen, Zohar Mukamel, Amir Bar, Alina Molchadsky, Ran Brosh, Shirley Horn-Saban, Daniela Amann Zalcenstein, Naomi Goldfinger, Adi Zundelevich, Einav Nili Gal-Yam, Varda Rotter and Amos Tanay doi:10.1038/ng.2442 Amos Tanay and colleagues characterize DNA methylation polymorphism within cell populations and track immortalized fibroblasts in culture for over 300 generations to show that formation of differentially methylated regions occurs through a stochastic process and nearly deterministic epigenetic remodeling. See also: News and Views by Krebs & Schubeler Intracontinental spread of human invasive Salmonella Typhimurium pathovariants in sub-Saharan Africa   pp1215 - 1221 Chinyere K Okoro, Robert A Kingsley, Thomas R Connor, Simon R Harris, Christopher M Parry, Manar N Al-Mashhadani, Samuel Kariuki, Chisomo L Msefula, Melita A Gordon, Elizabeth de Pinna, John Wain, Robert S Heyderman, Stephen Obaro, Pedro L Alonso, Inacio Mandomando, Calman A MacLennan, Milagritos D Tapia, Myron M Levine, Sharon M Tennant, Julian Parkhill & Gordon Dougan doi:10.1038/ng.2423 Gordon Dougan and colleagues report whole-genome sequencing of a global collection of 179 Salmonella Typhimurium isolates, including 129 diverse sub-Saharan African isolates associated with invasive disease. They determine the phylogenetic structure of invasive Salmonella Typhimurium in sub-Saharan Africa and find that the majority are from two closely related highly conserved lineages, which emerged in the last 60 years in close temporal association with the current HIV epidemic. Letters Top Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population   pp1222 - 1226 Tomomitsu Hirota, Atsushi Takahashi, Michiaki Kubo, Tatsuhiko Tsunoda, Kaori Tomita, Masafumi Sakashita, Takechiyo Yamada, Shigeharu Fujieda, Shota Tanaka, Satoru Doi, Akihiko Miyatake, Tadao Enomoto, Chiharu Nishiyama, Nobuhiro Nakano, Keiko Maeda, Ko Okumura, Hideoki Ogawa, Shigaku Ikeda, Emiko Noguchi, Tohru Sakamoto, Nobuyuki Hizawa, Koji Ebe, Hidehisa Saeki, Takashi Sasaki, Tamotsu Ebihara, Masayuki Amagai, Satoshi Takeuchi, Masutaka Furue, Yusuke Nakamura & Mayumi Tamari doi:10.1038/ng.2438 Mayumi Tamari and colleagues report a genome-wide association study for atopic dermatitis, a chronic inflammatory skin disease, in a Japanese population. They identify eight new susceptibility loci for atopic dermatitis and compare their results to those of previous studies in European and Chinese populations. CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation   pp1227 - 1230 Nataly Manjarrez-Orduño, Emiliano Marasco, Sharon A Chung, Matthew S Katz, Jenna F Kiridly, Kim R Simpfendorfer, Jan Freudenberg, David H Ballard, Emil Nashi, Thomas J Hopkins, Deborah S Cunninghame Graham, Annette T Lee, Marieke J H Coenen, Barbara Franke, Dorine W Swinkels, Robert R Graham, Robert P Kimberly, Patrick M Gaffney, Timothy J Vyse, Timothy W Behrens, Lindsey A Criswell, Betty Diamond & Peter K Gregersen doi:10.1038/ng.2439 Peter Gregersen and colleagues identify a regulatory variant in CSK, coding for an intracellular kinase that physically interacts with Lyp (PTPN22), associated with systemic lupus erythematosus (SLE). Their work suggests that the Lyp-Csk complex influences susceptibility to SLE through regulation of B-cell signaling, maturation and activation. Genome-wide association study in Chinese men identifies two new prostate cancer risk loci at 9q31.2 and 19q13.4   pp1231 - 1235 Jianfeng Xu, Zengnan Mo, Dingwei Ye, Meilin Wang, Fang Liu, Guangfu Jin, Chuanliang Xu, Xiang Wang, Qiang Shao, Zhiwen Chen, Zhihua Tao, Jun Qi, Fangjian Zhou, Zhong Wang, Yaowen Fu, Dalin He, Qiang Wei, Jianming Guo, Denglong Wu, Xin Gao, Jianlin Yuan, Gongxian Wang, Yong Xu, Guozeng Wang, Haijun Yao, Pei Dong, Yang Jiao, Mo Shen, Jin Yang, Jun Ou-Yang, Haowen Jiang, Yao Zhu, Shancheng Ren, Zhengdong Zhang, Changjun Yin, Xu Gao, Bo Dai, Zhibin Hu, Yajun Yang, Qijun Wu, Hongyan Chen, Peng Peng, Ying Zheng, Xiaodong Zheng, Yongbing Xiang, Jirong Long, Jian Gong, Rong Na, Xiaoling Lin, Hongjie Yu, Zhong Wang, Sha Tao, Junjie Feng, Jishan Sun, Wennuan Liu, Ann Hsing, Jianyu Rao, Qiang Ding, Fredirik Wiklund, Henrik Gronberg, Xiao-Ou Shu, Wei Zheng, Hongbing Shen, Li Jin, Rong Shi, Daru Lu, Xuejun Zhang, Jielin Sun, S Lilly Zheng & Yinghao Sun doi:10.1038/ng.2424 Yinghao Sun and colleagues report a genome-wide association study for prostate cancer in Han Chinese men. They identify two new risk-associated loci at chromosomes 9q31 and 19q13. Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia   pp1236 - 1242 Marta Kulis, Simon Heath, Marina Bibikova, Ana C Queirós, Alba Navarro, Guillem Clot, Alejandra Martínez-Trillos, Giancarlo Castellano, Isabelle Brun-Heath, Magda Pinyol, Sergio Barberán-Soler, Panagiotis Papasaikas, Pedro Jares, Sílvia Beà, Daniel Rico, Simone Ecker, Miriam Rubio, Romina Royo, Vincent Ho, Brandy Klotzle, Lluis Hernández, Laura Conde, Mónica López-Guerra, Dolors Colomer, Neus Villamor, Marta Aymerich, María Rozman, Mónica Bayes, Marta Gut, Josep L Gelpí, Modesto Orozco, Jian-Bing Fan, Víctor Quesada, Xose S Puente, David G Pisano, Alfonso Valencia, Armando López-Guillermo, Ivo Gut, Carlos López-Otín, Elías Campo & José I Martín-Subero doi:10.1038/ng.2443 José Martin-Subero and colleagues report whole-genome bisulfite sequencing and methylome analysis of two CLLs and three B-cell subpopulations using high-density microarrays on 139 CLLs. They identify widespread hypomethylation in the gene body that is largely associated with intragenic enhancer elements. Mutations in ADAR1 cause Aicardi-Goutieres syndrome associated with a type I interferon signature   pp1243 - 1248 Gillian I Rice, Paul R Kasher, Gabriella M A Forte, Niamh M Mannion, Sam M Greenwood, Marcin Szynkiewicz, Jonathan E Dickerson, Sanjeev S Bhaskar, Massimiliano Zampini, Tracy A Briggs, Emma M Jenkinson, Carlos A Bacino, Roberta Battini, Enrico Bertini, Paul A Brogan, Louise A Brueton, Marialuisa Carpanelli, Corinne De Laet, Pascale de Lonlay, Mireia del Toro, Isabelle Desguerre, Elisa Fazzi, Àngels Garcia-Cazorla, Arvid Heiberg, Masakazu Kawaguchi, Ram Kumar, Jean-Pierre S-M Lin, Charles M Lourenco, Alison M Male, Wilson Marques Jr, Cyril Mignot, Ivana Olivieri, Simona Orcesi, Prab Prabhakar, Magnhild Rasmussen, Robert A Robinson, Flore Rozenberg, Johanna L Schmidt, Katharina Steindl, Tiong Y Tan, William G van der Merwe, Adeline Vanderver, Grace Vassallo, Emma L Wakeling, Evangeline Wassmer, Elizabeth Whittaker, John H Livingston, Pierre Lebon, Tamio Suzuki, Paul J McLaughlin, Liam P Keegan, Mary A O'Connell, Simon C Lovell & Yanick J Crow doi:10.1038/ng.2414 Yanick Crow and colleagues show that mutations in ADAR1 cause the autoimmune disorder Aicardi-Goutieres syndrome, accompanied by upregulation of interferon-stimulated genes. ADAR1 encodes an enzyme that catalyzes the deamination of adeonosine to inosine in double-stranded RNA, and the findings suggest a possible role for RNA editing in limiting the accumulation of repeat-derived RNA species. Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm   pp1249 - 1254 Alexander J Doyle, Jefferson J Doyle, Seneca L Bessling, Samantha Maragh, Mark E Lindsay, Dorien Schepers, Elisabeth Gillis, Geert Mortier, Tessa Homfray, Kimberly Sauls, Russell A Norris, Nicholas D Huso, Dan Leahy, David W Mohr, Mark J Caulfield, Alan F Scott, Anne Destrée, Raoul C Hennekam, Pamela H Arn, Cynthia J Curry, Lut Van Laer, Andrew S McCallion, Bart L Loeys & Harry C Dietz doi:10.1038/ng.2421 Harry Dietz and colleagues report the identification of mutations in SKI in Shprintzen-Goldberg syndrome, which shares features with Marfan syndrome and Loeys-Dietz syndrome. SKI encodes a known repressor of TGF-β activity, and this work provides evidence for paradoxical increased TGF-β signaling as the mechanism underlying these related syndromes. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy   pp1255 - 1259 Giulia Barcia, Matthew R Fleming, Aline Deligniere, Valeswara-Rao Gazula, Maile R Brown, Maeva Langouet, Haijun Chen, Jack Kronengold, Avinash Abhyankar, Roberta Cilio, Patrick Nitschke, Anna Kaminska, Nathalie Boddaert, Jean-Laurent Casanova, Isabelle Desguerre, Arnold Munnich, Olivier Dulac, Leonard K Kaczmarek, Laurence Colleaux & Rima Nabbout doi:10.1038/ng.2441 Rima Nabbout and colleagues report the identification of de novo mutations in the KCNT1 potassium channel gene in individuals with malignant migrating partial seizures of infancy, a rare epileptic encephalopathy with pharmacoresistant seizures and developmental delay. The authors show that the mutations have a gain-of-function effect on KCNT1 channel activity. CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development   pp1260 - 1264 Ganeshwaran H Mochida, Vijay S Ganesh, Maria I de Michelena, Hugo Dias, Kutay D Atabay, Katie L Kathrein, Hsuan-Ting Huang, R Sean Hill, Jillian M Felie, Daniel Rakiec, Danielle Gleason, Anthony D Hill, Athar N Malik, Brenda J Barry, Jennifer N Partlow, Wen-Hann Tan, Laurie J Glader, A James Barkovich, William B Dobyns, Leonard I Zon & Christopher A Walsh doi:10.1038/ng.2425 Christopher Walsh and colleagues identify mutations in CHMP1A in human cerebellar hypoplasia and microcephaly. Cells lacking CHMP1A show decreased cell proliferation and decreased expression of BMI1, a negative regulator of stem cell proliferation. Alterations of the CIB2 calcium- and integrin-binding protein cause Usher syndrome type 1J and nonsyndromic deafness DFNB48   pp1265 - 1271 Saima Riazuddin, Inna A Belyantseva, Arnaud P J Giese, Kwanghyuk Lee, Artur A Indzhykulian, Sri Pratima Nandamuri, Rizwan Yousaf, Ghanshyam P Sinha, Sue Lee, David Terrell, Rashmi S Hegde, Rana A Ali, Saima Anwar, Paula B Andrade-Elizondo, Asli Sirmaci, Leslie V Parise, Sulman Basit, Abdul Wali, Muhammad Ayub, Muhammad Ansar, Wasim Ahmad, Shaheen N Khan, Javed Akram, Mustafa Tekin, Sheikh Riazuddin, Tiffany Cook, Elke K Buschbeck, Gregory I Frolenkov, Suzanne M Leal, Thomas B Friedman & Zubair M Ahmed doi:10.1038/ng.2426 Zubair Ahmed and colleagues identify homozygous mutations in CIB2, a gene that encodes a calcium- and integrin-binding protein, that cause Usher syndrome type 1J and nonsyndromic deafness DFNB48. CIB2 is required for hair cell development and retinal photoreceptor cells in zebrafish and Drosophila melanogaster. Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma   pp1272 - 1276 Elizabeth Pohler, Ons Mamai, Jennifer Hirst, Mozheh Zamiri, Helen Horn, Toshifumi Nomura, Alan D Irvine, Benvon Moran, Neil J Wilson, Frances J D Smith, Christabelle S M Goh, Aileen Sandilands, Christian Cole, Geoffrey J Barton, Alan T Evans, Hiroshi Shimizu, Masashi Akiyama, Mitsuhiro Suehiro, Izumi Konohana, Mohammad Shboul, Sebastien Teissier, Lobna Boussofara, Mohamed Denguezli, Ali Saad, Moez Gribaa, Patricia J Dopping-Hepenstal, John A McGrath, Sara J Brown, David R Goudie, Bruno Reversade, Colin S Munro & W H Irwin McLean doi:10.1038/ng.2444 Irwin McLean and colleagues report that heterozygous loss-of-function mutations in AAGAB, which encodes a cytosolic protein implicated in vesicular trafficking, cause punctate palmoplantar keratoderma. They further show that knockdown of AAGAB in keratinocytes leads to increased cell proliferation accompanied by highly elevated levels of epidermal growth factor receptor. Estimating the human mutation rate using autozygosity in a founder population   pp1277 - 1281 Catarina D Campbell, Jessica X Chong, Maika Malig, Arthur Ko, Beth L Dumont, Lide Han, Laura Vives, Brian J O'Roak, Peter H Sudmant, Jay Shendure, Mark Abney, Carole Ober & Evan E Eichler doi:10.1038/ng.2418 Evan Eichler and colleagues report an estimate of the mutation rate in humans that is based on the whole-genome sequences of five parent-offspring trios from a Hutterite population and genotyping data from an extended pedigree. They use a new approach for estimating the mutation rate over multiple generations that takes into account the extensive autozygosity in this founder population. See also: News and Views by Hurles Variation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission   pp1282 - 1285 Christoph Freyer, Lynsey M Cree, Arnaud Mourier, James B Stewart, Camilla Koolmeister, Dusanka Milenkovic, Timothy Wai, Vasileios I Floros, Erik Hagström, Emmanouella E Chatzidaki, Rudolf J Wiesner, David C Samuels, Nils-Göran Larsson & Patrick F Chinnery doi:10.1038/ng.2427 Patrick Chinnery, Nils-Goran Larsson and colleagues show that mitochondrial heteroplasmy levels are principally determined prenatally within the developing female germline in mice transmitting a heteroplasmic single base-pair deletion in the mitochondrial tRNAMet gene. Top Advertisement Nature Outlook: Chronic Obstructive Pulmonary Disease Although this incurable, progressive condition is difficult-to-diagnose, a bevy of new treatment options could give COPD patients a breath of fresh air. Access the Outlook free online for six months. 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