Nature Genetics Contents: March 2013 pp 227 - 337

TABLE OF CONTENTS March 2013 Volume 45, Issue 3 Editorial News and Views Research Highlights Perspective Brief Communication 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 Subscribe   Facebook   RSS   Recommend to library   Twitter   Advertisement NGS Translate (28-30 May, Boston, MA) is the definitive technical meeting for translational NGS professionals. Immerse yourself in a world where everybody is committed to making NGS a commercial reality. You'll find an unparalleled level of technical detail packed the 3 streams: tackle your challenges head on and leave with a clear idea of how to advance your NGS project.   Advertisement New Nature Journals iPad app Read Nature anytime, anywhere. Subscribe to Nature on the iPad for only $35.99 Download the new app from the app store. *Apple exchange rates apply to international prices.   Editorial Top Broader and deeper   p227 doi:10.1038/ng.2580 Cancer genomes are now rapidly yielding to analysis, showing the heterogeneity of the mutational events and processes contributing to disease. This diversity is enormous and occurs at many levels. Consequently, the first clues from exome sequencing will increasingly need to be complemented by integrated analyses and extended to implicate mutations relevant to treatment outcomes. News and Views Top RNF212 marks the spot   pp228 - 229 Cathleen M Lake and R Scott Hawley doi:10.1038/ng.2559 A new study in mice shows that, during meiosis, the decision to mature a double-strand break into a crossover is controlled by a dosage-sensitive regulator, RNF212. This finding provides insight into the crossover maturation process and may help explain how sequence polymorphisms in RNF212 alter the frequency of crossing over in humans. See also: Article by Reynolds et al. The evolutionary biography of chronic lymphocytic leukemia   pp229 - 231 Xose S Puente & Carlos López-Otín doi:10.1038/ng.2556 A recent study shows that the life history of chronic lymphocytic leukemia is characterized by a complex and dynamic architecture involving the development of subclones with changing dominance over time. This innovative study provides a framework to design anticipation-based chemotherapy approaches for cancer treatment. Filling in the gaps in cranial suture biology   pp231 - 232 David R FitzPatrick doi:10.1038/ng.2557 Two new loci for premature fusion of the cranial sutures in humans suggest a common endpoint in osteoblast regulation, linking upregulation of phosphorylated ERK1/2 and TWIST1 haploinsufficiency. See also: Letter by Sharma et al. | Letter by Twigg et al. Genetics JOBS of the week Evolutionary & Molecular Developmental Genetics of ?skin appendages & colour patterns in reptiles University of Geneva - Switzerland Division Chief, Pediatric Genetics and Metabolism The University of North Carolina at Chapel Hill Chief, Clinical Genetics Branch National Institutes of Health - National Cancer Institute Bioinformatician in human genetics University of Burgundy Postdoctoral Bioinformatician GIGA-Research, University of Liège More Science jobs from Genetics EVENT European Humen Genetics Conference 06.08.13 Paris, France More science events from Research Highlights Top Oxytricha macronuclear genome | PKCζ is a metabolic tumor suppressor | Pigeon genome | Recurrent mutations in meningiomas | TET function in primordial germ cells Perspective Top Interpreting the role of de novo protein-coding mutations in neuropsychiatric disease   pp234 - 238 Jacob Gratten, Peter M Visscher, Bryan J Mowry and Naomi R Wray doi:10.1038/ng.2555 Jake Gratten and colleagues discuss challenges in interpreting the role of de novo mutations in neuropsychiatric and other complex diseases. They argue that the burden of proof for causality for a single de novo mutation must be set high and that curation of de novo mutations and their associated phenotypes in databases will be critical for the robust interpretation of exome sequencing studies. Brief Communication Top XACT, a long noncoding transcript coating the active X chromosome in human pluripotent cells   pp239 - 241 Céline Vallot, Christophe Huret, Yann Lesecque, Alissa Resch, Noufissa Oudrhiri, Annelise Bennaceur-Griscelli, Laurent Duret & Claire Rougeulle doi:10.1038/ng.2530 Claire Rougeulle and colleagues report the discovery of a long noncoding RNA, XACT, that coats the active X chromosome in human embryonic stem cells. Articles Top The genomic landscape of hypodiploid acute lymphoblastic leukemia   pp242 - 252 Linda Holmfeldt, Lei Wei, Ernesto Diaz-Flores, Michael Walsh, Jinghui Zhang, Li Ding, Debbie Payne-Turner, Michelle Churchman, Anna Andersson, Shann-Ching Chen, Kelly McCastlain, Jared Becksfort, Jing Ma, Gang Wu, Samir N Patel, Susan L Heatley, Letha A Phillips, Guangchun Song, John Easton, Matthew Parker, Xiang Chen, Michael Rusch, Kristy Boggs, Bhavin Vadodaria, Erin Hedlund, Christina Drenberg, Sharyn Baker, Deqing Pei, Cheng Cheng, Robert Huether, Charles Lu, Robert S Fulton, Lucinda L Fulton, Yashodhan Tabib, David J Dooling, Kerri Ochoa, Mark Minden, Ian D Lewis, L Bik To, Paula Marlton, Andrew W Roberts, Gordana Raca, Wendy Stock, Geoffrey Neale, Hans G Drexler, Ross A Dickins, David W Ellison, Sheila A Shurtleff, Ching-Hon Pui, Raul C Ribeiro, Meenakshi Devidas, Andrew J Carroll, Nyla A Heerema, Brent Wood, Michael J Borowitz, Julie M Gastier-Foster, Susana C Raimondi, Elaine R Mardis, Richard K Wilson, James R Downing, Stephen P Hunger, Mignon L Loh & Charles G Mullighan doi:10.1038/ng.2532 Linda Holmfeldt, Lei Wei et al. report whole-genome and exome sequencing of 40 childhood hypodiploid acute lymphoblastic leukemias. Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation   pp253 - 261 Luc G T Morris, Andrew M Kaufman, Yongxing Gong, Deepa Ramaswami, Logan A Walsh, Şevin Turcan, Stephanie Eng, Kasthuri Kannan, Yilong Zou, Luke Peng, Victoria E Banuchi, Phillip Paty, Zhaoshi Zeng, Efsevia Vakiani, David Solit, Bhuvanesh Singh, Ian Ganly, Linda Liau, Timothy C Cloughesy, Paul S Mischel, Ingo K Mellinghoff & Timothy A Chan doi:10.1038/ng.2538 Tim Chan and colleagues report the identification of recurrent somatic mutations in FAT1 in glioblastoma, colon cancer and head and neck cancer and show that inactivation of FAT1 promotes Wnt signaling and tumorigenesis. The nexin-dynein regulatory complex subunit DRC1 is essential for motile cilia function in algae and humans   pp262 - 268 Maureen Wirschell, Heike Olbrich, Claudius Werner, Douglas Tritschler, Raqual Bower, Winfield S Sale, Niki T Loges, Petra Pennekamp, Sven Lindberg, Unne Stenram, Birgitta Carlén, Elisabeth Horak, Gabriele Köhler, Peter Nürnberg, Gudrun Nürnberg, Mary E Porter & Heymut Omran doi:10.1038/ng.2533 Heymut Omran, Mary Porter and colleagues identify the nexin link-dynein regulatory complex subunit DRC1 from Chlamydomonas and show that mutations in the human DRC1 homolog CCDC164 cause primary ciliary dyskinesia. Their analyses show that loss of DRC1 results in distinct axonemal defects and altered ciliary beat patterns. RNF212 is a dosage-sensitive regulator of crossing-over during mammalian meiosis   pp269 - 278 April Reynolds, Huanyu Qiao, Ye Yang, Jefferson K Chen, Neil Jackson, Kajal Biswas, J Kim Holloway, Frédéric Baudat, Bernard de Massy, Jeremy Wang, Christer Höög, Paula E Cohen & Neil Hunter doi:10.1038/ng.2541 Neil Hunter and colleagues show that RNF212 is essential for crossing-over during mammalian meiosis and functions to couple chromosome synapsis to the formation of crossover-specific recombination complexes. They further show that selective localization of RNF212 to a subset of recombination sites is a key step in the crossover designation process that serves to stabilize meiosis-specific recombination factors at these sites. See also: News and Views by Lake & Hawley Letters Top The genetic landscape of high-risk neuroblastoma   pp279 - 284 Trevor J Pugh, Olena Morozova, Edward F Attiyeh, Shahab Asgharzadeh, Jun S Wei, Daniel Auclair, Scott L Carter, Kristian Cibulskis, Megan Hanna, Adam Kiezun, Jaegil Kim, Michael S Lawrence, Lee Lichenstein, Aaron McKenna, Chandra Sekhar Pedamallu, Alex H Ramos, Erica Shefler, Andrey Sivachenko, Carrie Sougnez, Chip Stewart, Adrian Ally, Inanc Birol, Readman Chiu, Richard D Corbett, Martin Hirst, Shaun D Jackman, Baljit Kamoh, Alireza Hadj Khodabakshi, Martin Krzywinski, Allan Lo, Richard A Moore, Karen L Mungall, Jenny Qian, Angela Tam, Nina Thiessen, Yongjun Zhao, Kristina A Cole, Maura Diamond, Sharon J Diskin, Yael P Mosse, Andrew C Wood, Lingyun Ji, Richard Sposto, Thomas Badgett, Wendy B London, Yvonne Moyer, Julie M Gastier-Foster, Malcolm A Smith, Jaime M Guidry Auvil, Daniela S Gerhard, Michael D Hogarty, Steven J M Jones, Eric S Lander, Stacey B Gabriel, Gad Getz, Robert C Seeger, Javed Khan, Marco A Marra, Matthew Meyerson & John M Maris doi:10.1038/ng.2529 John Maris, Matthew Meyerson, Marco Marra and colleagues report results of a large-scale sequencing study of neuroblastoma. They observe a low median exonic mutation frequency and strikingly few recurrently mutated genes in these tumors, highlighting challenges for developing targeted therapeutic strategies based on frequently mutated oncogenic drivers. Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations   pp285 - 289 Priscilla K Brastianos, Peleg M Horowitz, Sandro Santagata, Robert T Jones, Aaron McKenna, Gad Getz, Keith L Ligon, Emanuele Palescandolo, Paul Van Hummelen, Matthew D Ducar, Alina Raza, Ashwini Sunkavalli, Laura E MacConaill, Anat O Stemmer-Rachamimov, David N Louis, William C Hahn, Ian F Dunn and Rameen Beroukhim doi:10.1038/ng.2526 Rameen Beroukhim, Ian Dunn, William Hahn and colleagues report genome and exome sequencing of meningiomas. They identified recurrent somatic mutations in AKT1 and SMO. Relapse-specific mutations in NT5C2 in childhood acute lymphoblastic leukemia   pp290 - 294 Julia A Meyer, Jinhua Wang, Laura E Hogan, Jun J Yang, Smita Dandekar, Jay P Patel, Zuojian Tang, Paul Zumbo, Sheng Li, Jiri Zavadil, Ross L Levine, Timothy Cardozo, Stephen P Hunger, Elizabeth A Raetz, William E Evans, Debra J Morrison, Christopher E Mason and William L Carroll doi:10.1038/ng.2558 William Carroll and colleagues report the identification of mutations in NT5C2, encoding cytosolic 5′-nucleotidase II, which are specific for relapsed childhood acute lymphoblastic leukemia. The mutations confer increased enzymatic activity and resistance to treatment with nucleoside analog therapies in vitro. Loss-of-function mutations in SMARCE1 cause an inherited disorder of multiple spinal meningiomas   pp295 - 298 Miriam J Smith, James O'Sullivan, Sanjeev S Bhaskar, Kristen D Hadfield, Gemma Poke, John Caird, Saba Sharif, Diana Eccles, David Fitzpatrick, Daniel Rawluk, Daniel du Plessis, William G Newman and D Gareth Evans doi:10.1038/ng.2552 William Newman, Gareth Evans and colleagues report that loss-of-function mutations in SMARCE1 cause an inherited disorder characterized by multiple spinal meningiomas. Tumors from individuals with SMARCE1 mutations showed loss of SMARCE1 protein, consistent with a tumor suppressor mechanism. Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing   pp299 - 303 Andrew Kirby, Andreas Gnirke, David B Jaffe, Veronika Barešová, Nathalie Pochet, Brendan Blumenstiel, Chun Ye, Daniel Aird, Christine Stevens, James T Robinson, Moran N Cabili, Irit Gat-Viks, Edward Kelliher, Riza Daza, Matthew DeFelice, Helena Hůlková, Jana Sovová, Petr Vylet'al, Corinne Antignac, Mitchell Guttman, Robert E Handsaker, Danielle Perrin, Scott Steelman, Snaevar Sigurdsson, Steven J Scheinman, Carrie Sougnez, Kristian Cibulskis, Melissa Parkin, Todd Green, Elizabeth Rossin, Michael C Zody, Ramnik J Xavier, Martin R Pollak, Seth L Alper, Kerstin Lindblad-Toh, Stacey Gabriel, P Suzanne Hart, Aviv Regev, Chad Nusbaum, Stanislav Kmoch, Anthony J Bleyer, Eric S Lander & Mark J Daly doi:10.1038/ng.2543 Anthony Bleyer, Eric Lander, Mark Daly and colleagues show that frameshift mutations in a large VNTR of MUC1 cause medullary cystic kidney disease type 1. Their discovery sheds light on the biology of this disease and highlights challenges in using massively parallel sequencing technologies to characterize certain types of sequence variants. Mutations in TCF12, encoding a basic helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis   pp304 - 307 Vikram P Sharma, Aimée L Fenwick, Mia S Brockop, Simon J McGowan, Jacqueline A C Goos, A Jeannette M Hoogeboom, Angela F Brady, Nu Owase Jeelani, Sally Ann Lynch, John B Mulliken, Dylan J Murray, Julie M Phipps, Elizabeth Sweeney, Susan E Tomkins, Louise C Wilson, Sophia Bennett, Richard J Cornall, John Broxholme, Alexander Kanapin, 500 Whole-Genome Sequences (WGS500) Consortium, David Johnson, Steven A Wall, Peter J van der Spek, Irene M J Mathijssen, Robert E Maxson, Stephen R F Twigg & Andrew O M Wilkie doi:10.1038/ng.2531 Andrew Wilkie and colleagues report that mutations in TCF12 cause coronal craniosynostosis. They found heterozygous mutations in 38 unrelated families. See also: News and Views by FitzPatrick Reduced dosage of ERF causes complex craniosynostosis in humans and mice and links ERK1/2 signaling to regulation of osteogenesis   pp308 - 313 Stephen R F Twigg, Elena Vorgia, Simon J McGowan, Ioanna Peraki, Aimée L Fenwick, Vikram P Sharma, Maryline Allegra, Andreas Zaragkoulias, Elham Sadighi Akha, Samantha J L Knight, Helen Lord, Tracy Lester, Louise Izatt, Anne K Lampe, Shehla N Mohammed, Fiona J Stewart, Alain Verloes, Louise C Wilson, Chris Healy, Paul T Sharpe, Peter Hammond, Jim Hughes, Stephen Taylor, David Johnson, Steven A Wall, George Mavrothalassitis & Andrew O M Wilkie doi:10.1038/ng.2539 George Mavrothalassitis, Andrew Wilkie and colleagues report the identification of mutations in ERF that cause a complex craniosynostosis disorder with multiple-suture synostosis, craniofacial dysmorphism, Chiari malformation and language delay. They also show that reduced dosage of Erf in mice causes craniosynostosis. See also: News and Views by FitzPatrick Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia   pp314 - 318 Virginie J M Verhoeven, Pirro G Hysi, Robert Wojciechowski, Qiao Fan, Jeremy A Guggenheim, René Höhn, Stuart MacGregor, Alex W Hewitt, Abhishek Nag, Ching-Yu Cheng, Ekaterina Yonova-Doing, Xin Zhou, M Kamran Ikram, Gabriëlle H S Buitendijk, George McMahon, John P Kemp, Beate St Pourcain, Claire L Simpson, Kari-Matti Mäkelä, Terho Lehtimäki, Mika Kähönen, Andrew D Paterson, S Mohsen Hosseini, Hoi Suen Wong, Liang Xu, Jost B Jonas, Olavi Pärssinen, Juho Wedenoja, Shea Ping Yip, Daniel W H Ho, Chi Pui Pang, Li Jia Chen, Kathryn P Burdon, Jamie E Craig, Barbara E K Klein, Ronald Klein, Toomas Haller, Andres Metspalu, Chiea-Chuen Khor, E-Shyong Tai, Tin Aung, Eranga Vithana, Wan-Ting Tay, Veluchamy A Barathi, Consortium for Refractive Error and Myopia (CREAM), Peng Chen, Ruoying Li, Jiemin Liao, Yingfeng Zheng, Rick T Ong, Angela Döring, The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Research Group, David M Evans, Nicholas J Timpson, Annemieke J M H Verkerk, Thomas Meitinger, Olli Raitakari, Felicia Hawthorne, Tim D Spector, Lennart C Karssen, Mario Pirastu, Federico Murgia, Wei Ang, Wellcome Trust Case Control Consortium 2 (WTCCC2), Aniket Mishra, Grant W Montgomery, Craig E Pennell, Phillippa M Cumberland, Ioana Cotlarciuc, Paul Mitchell, Jie Jin Wang, Maria Schache, Sarayut Janmahasathian, Robert P Igo Jr, Jonathan H Lass, Emily Chew, Sudha K Iyengar, The Fuchs' Genetics Multi-Center Study Group, Theo G M F Gorgels, Igor Rudan, Caroline Hayward, Alan F Wright, Ozren Polasek, Zoran Vatavuk, James F Wilson, Brian Fleck, Tanja Zeller, Alireza Mirshahi, Christian Müller, André G Uitterlinden, Fernando Rivadeneira, Johannes R Vingerling, Albert Hofman, Ben A Oostra, Najaf Amin, Arthur A B Bergen, Yik-Ying Teo, Jugnoo S Rahi, Veronique Vitart, Cathy Williams, Paul N Baird, Tien-Yin Wong, Konrad Oexle, Norbert Pfeiffer, David A Mackey, Terri L Young, Cornelia M van Duijn, Seang-Mei Saw, Joan E Bailey-Wilson, Dwight Stambolian, Caroline C Klaver & Christopher J Hammond doi:10.1038/ng.2554 Caroline Klaver and colleagues report a meta-analysis for refractive error and myopia, including 37,382 individuals from 27 European studies and 8,376 individuals from 5 Asian studies, as part of the Consortium for Refractive Error and Myopia (CREAM). Identification of multiple independent susceptibility loci in the HLA region in Behcet's disease   pp319 - 324 Travis Hughes, Patrick Coit, Adam Adler, Vuslat Yilmaz, Kenan Aksu, Nursen Düzgün, Gokhan Keser, Ayse Cefle, Ayten Yazici, Andac Ergen, Erkan Alpsoy, Carlo Salvarani, Bruno Casali, Ina Kötter, Javier Gutierrez-Achury, Cisca Wijmenga, Haner Direskeneli, Güher Saruhan-Direskeneli & Amr H Sawalha doi:10.1038/ng.2551 Amr Sawalha and colleagues performed dense genotyping in the HLA locus followed by imputation to fine map genetic variants associated with Behcet's disease in this region. They report four independent genetic associations in the HLA region and localize the genetic association previously attributed to HLA-B*51 to a genetic variant between the HLA-B and MICA genes. Endogenous retroviruses function as species-specific enhancer elements in the placenta   pp325 - 329 Edward B Chuong, M A Karim Rumi, Michael J Soares and Julie C Baker doi:10.1038/ng.2553 Julie Baker and colleagues report epigenome and transcriptome profiles of rat and mouse trophoblast stem cells and show that endogenous retroviruses serve as a genome-wide source of species-specific enhancer elements in the placenta. Oomycete pathogens encode RNA silencing suppressors   pp330 - 333 Yongli Qiao, Lin Liu, Qin Xiong, Cristina Flores, James Wong, Jinxia Shi, Xianbing Wang, Xigang Liu, Qijun Xiang, Shushu Jiang, Fuchun Zhang, Yuanchao Wang, Howard S Judelson, Xuemei Chen and Wenbo Ma doi:10.1038/ng.2525 Wenbo Ma and colleagues show that two effectors from the oomycete plant pathogen Phytophthora sojae suppress RNA silencing in plants by inhibiting the biogenesis of small RNAs. These findings show that some eukaryotic pathogens, like their prokaryotic and viral counterparts, have evolved virulence proteins that target host RNA silencing processes to promote infection. Quantitative variation in maize kernel row number is controlled by the FASCIATED EAR2 locus   pp334 - 337 Peter Bommert, Namiko Satoh Nagasawa and David Jackson doi:10.1038/ng.2534 Domesticated maize make 8-20 rows of kernels, whereas its ancestor teosinte makes 2 rows. David Jackson and colleagues report that variation at the FEA2 locus in maize influences kernel row number and kernels per ear, which are important crop yield traits. Top Advertisement Epigenetics: Why histone modifications matter in health and disease February 26 10am EST | 3pm GMT Histones are an integral part of chromatin as they make up the 'protein spools' DNA is wound around. 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