Nature Genetics Contents: March 2015 pp 187 - 304

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TABLE OF CONTENTS March 2015 Volume 47, Issue 3 Editorial Correspondence News and Views Research Highlights Analysis Articles Letters Technical Reports Corrigenda Advertisement Droplet Digital™ PCR (ddPCR™) is leading the way Last year more than 150 peer-reviewed publications took advantage of 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 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. Subscribe   Facebook   RSS   Recommend to library   Twitter   Advertisement Epigenome Roadmap Nature Publishing Group presents an online portal - the Epigenome Roadmap - which collects key research papers from The NIH Roadmap Epigenomics Program, complemented by thematical 'threads' to help the readers mine the wealth of available information. Access the Epigenome Roadmap for FREE at:  nature.com/epigenomeroadmap Produced with exclusive support from  Illumina   Editorial Top Announcement: double-blind peer review   p187 doi:10.1038/ng.3238 Nature and its sister journals start offering anonymity to authors during the peer-review process. Correspondence Top Evolution of Tibetan wild boars   pp188 - 189 Laurent A F Frantz, Ole Madsen, Hendrik-Jan Megens, Joshua G Schraiber, Yogesh Paudel, Mirte Bosse, Richard P M A Crooijmans, Greger Larson & Martien A M Groenen doi:10.1038/ng.3197 Reply to 'Evolution of Tibetan wild boars'   pp189 - 190 Mingzhou Li, Ying Li, Carol K L Yeung, Shilin Tian, Xuewei Li & Ruiqiang Li doi:10.1038/ng.3194 On genetic differentiation between domestic pigs and Tibetan wild boars   pp190 - 192 Miguel Pérez-Enciso, William Burgos-Paz & Sebastián E Ramos-Onsins doi:10.1038/ng.3191 Reply to 'On genetic differentiation between domestic pigs and Tibetan wild boars'   p192 Mingzhou Li, Carol K L Yeung, Ying Li, Shilin Tian, Xuewei Li & Ruiqiang Li doi:10.1038/ng.3193 News and Views Top YAP and the drug resistance highway   pp193 - 194 Alona Keren-Paz, Rafi Emmanuel & Yardena Samuels doi:10.1038/ng.3228 Deciphering mechanisms of drug resistance is crucial to winning the battle against cancer. A new study points to an unexpected function of YAP in drug resistance and illuminates its potential role as a therapeutic target. See also: Letter by Lin et al. Avalanching mutations in biallelic mismatch repair deficiency syndrome   pp194 - 196 Joshua J Waterfall & Paul S Meltzer doi:10.1038/ng.3227 Tumors from pediatric patients generally contain relatively few somatic mutations. A new study reports a striking exception in individuals in whom biallelic germline deficiency for mismatch repair is compounded by somatic loss of function in DNA proofreading polymerases, resulting in 'ultra-hypermutated' malignant brain tumors. See also: Letter by Shlien et al. Big Bang and context-driven collapse   pp196 - 197 Mark Robertson-Tessi & Alexander R A Anderson doi:10.1038/ng.3231 Heterogeneity is the single most important factor driving cancer progression and treatment failure, yet little is understood about how and when this heterogeneity arises. A new study shows that colorectal cancers acquire their dominant mutations early in development and that subsequent mutations, even if they confer greater fitness, are unlikely to sweep through the tumor. See also: Article by Sottoriva et al. Genetics JOBS of the week Postdoctoral Research Associate in Psychiatric Genetics University of Colorado Boulder Clinical Genetics / Genomics Development Technician II Massachusetts General Hospital PhD in Cancer and Genetics: New Drug Therapies Cardiff University Research Assistant / Associate in Scaling Statistical Genetics University of Bristol Postdoctoral Research Position in Statistical and Computational Genetics University of North Carolina at Chapel Hill More Science jobs from Genetics EVENT Yeast Genetics & Genomics 21.07.15 Cold Spring Harbour, USA More science events from Research Highlights Top Enhancer evolution in mammals | Long-term memory genes in C. elegans | Rb links reprogramming and cancer | Micropeptide regulates muscle performance | Stem cell metabolic and epigenetic reprogramming Analysis Top The landscape of long noncoding RNAs in the human transcriptome   pp199 - 208 Matthew K Iyer, Yashar S Niknafs, Rohit Malik, Udit Singhal, Anirban Sahu, Yasuyuki Hosono, Terrence R Barrette, John R Prensner, Joseph R Evans, Shuang Zhao, Anton Poliakov, Xuhong Cao, Saravana M Dhanasekaran, Yi-Mi Wu, Dan R Robinson, David G Beer, Felix Y Feng, Hariharan K Iyer & Arul M Chinnaiyan doi:10.1038/ng.3192 Arul Chinnaiyan and colleagues report the curation of 7,256 RNA sequencing libraries from tumors, normal tissues and cell lines. They find 58,648 lncRNAs, of which 79% are previously unnannotated. Articles Top A Big Bang model of human colorectal tumor growth   pp209 - 216 Andrea Sottoriva, Haeyoun Kang, Zhicheng Ma, Trevor A Graham, Matthew P Salomon, Junsong Zhao, Paul Marjoram, Kimberly Siegmund, Michael F Press, Darryl Shibata & Christina Curtis doi:10.1038/ng.3214 Christina Curtis, Darryl Shibata and colleagues report genomic profiling of 349 individual glands sampled from 15 human colorectal tumors. They observe high within-tumor heterogeneity and mixing of subclones in distant tumor regions, supporting a model whereby tumor growth occurs predominantly as a single expansion, with most detectable subclonal mutations arising during the earliest phases of tumor growth. See also: News and Views by Robertson-Tessi & Anderson Adaptation and possible ancient interspecies introgression in pigs identified by whole-genome sequencing   pp217 - 225 Huashui Ai, Xiaodong Fang, Bin Yang, Zhiyong Huang, Hao Chen, Likai Mao, Feng Zhang, Lu Zhang, Leilei Cui, Weiming He, Jie Yang, Xiaoming Yao, Lisheng Zhou, Lijuan Han, Jing Li, Silong Sun, Xianhua Xie, Boxian Lai, Ying Su, Yao Lu, Hui Yang, Tao Huang, Wenjiang Deng, Rasmus Nielsen, Jun Ren & Lusheng Huang doi:10.1038/ng.3199 Lusheng Huang, Jun Ren and colleagues report the genome sequences of 69 pigs, representing 11 geographically distinct breeds and 3 wild boar populations, from within China. They identify loci related to high- and low-latitude adaptation and infer a likely ancient introgression event in northern Chinese pigs. Genetic architecture of artemisinin-resistant Plasmodium falciparum   pp226 - 234 Olivo Miotto, Roberto Amato, Elizabeth A Ashley, Bronwyn MacInnis, Jacob Almagro-Garcia, Chanaki Amaratunga, Pharath Lim, Daniel Mead, Samuel O Oyola, Mehul Dhorda, Mallika Imwong, Charles Woodrow, Magnus Manske, Jim Stalker, Eleanor Drury, Susana Campino, Lucas Amenga-Etego, Thuy-Nhien Nguyen Thanh, Hien Tinh Tran, Pascal Ringwald, Delia Bethell, Francois Nosten, Aung Pyae Phyo, Sasithon Pukrittayakamee, Kesinee Chotivanich, Char Meng Chuor, Chea Nguon, Seila Suon, Sokunthea Sreng, Paul N Newton, Mayfong Mayxay, Maniphone Khanthavong, Bouasy Hongvanthong, Ye Htut, Kay Thwe Han, Myat Phone Kyaw, Md Abul Faiz, Caterina I Fanello, Marie Onyamboko, Olugbenga A Mokuolu, Christopher G Jacob, Shannon Takala-Harrison, Christopher V Plowe, Nicholas P Day, Arjen M Dondorp, Chris C A Spencer, Gilean McVean, Rick M Fairhurst, Nicholas J White & Dominic P Kwiatkowski doi:10.1038/ng.3189 Dominic Kwiatkowski and colleagues report a large multicenter genome-wide association study of Plasmodium falciparum resistance to artemisinin. They identify markers of a genetic background on which kelch13 mutations conferring artemisinin resistance are likely to emerge. The genomic and phenotypic diversity of Schizosaccharomyces pombe   pp235 - 241 Daniel C Jeffares, Charalampos Rallis, Adrien Rieux, Doug Speed, Martin Převorovský, Tobias Mourier, Francesc X Marsellach, Zamin Iqbal, Winston Lau, Tammy M K Cheng, Rodrigo Pracana, Michael Mülleder, Jonathan L D Lawson, Anatole Chessel, Sendu Bala, Garrett Hellenthal, Brendan O'Fallon, Thomas Keane, Jared T Simpson, Leanne Bischof, Bartlomiej Tomiczek, Danny A Bitton, Theodora Sideri, Sandra Codlin, Josephine E E U Hellberg, Laurent van Trigt, Linda Jeffery, Juan-Juan Li, Sophie Atkinson, Malte Thodberg, Melanie Febrer, Kirsten McLay, Nizar Drou, William Brown, Jacqueline Hayles, Rafael E Carazo Salas, Markus Ralser, Nikolas Maniatis, David J Balding, Francois Balloux, Richard Durbin & Jürg Bähler doi:10.1038/ng.3215 Daniel Jeffares, Jurg Bahler and colleagues report the genome sequences of 161 natural isolates of Schizosaccharomyces pombe, finding moderate genetic diversity and weak global population structure. They also report genome-wide association studies for 223 quantitative traits. Evolutionary history and global spread of the Mycobacterium tuberculosis Beijing lineage   pp242 - 249 Matthias Merker, Camille Blin, Stefano Mona, Nicolas Duforet-Frebourg, Sophie Lecher, Eve Willery, Michael G B Blum, Sabine Rüsch-Gerdes, Igor Mokrousov, Eman Aleksic, Caroline Allix-Béguec, Annick Antierens, Ewa Augustynowicz-Kopeć, Marie Ballif, Francesca Barletta, Hans Peter Beck, Clifton E Barry III, Maryline Bonnet, Emanuele Borroni, Isolina Campos-Herrero, Daniela Cirillo, Helen Cox, Suzanne Crowe, Valeriu Crudu, Roland Diel, Francis Drobniewski, Maryse Fauville-Dufaux, Sébastien Gagneux, Solomon Ghebremichael, Madeleine Hanekom, Sven Hoffner, Wei-wei Jiao, Stobdan Kalon, Thomas A Kohl, Irina Kontsevaya, Troels Lillebæk, Shinji Maeda, Vladyslav Nikolayevskyy, Michael Rasmussen, Nalin Rastogi, Sofia Samper, Elisabeth Sanchez-Padilla, Branislava Savic, Isdore Chola Shamputa, Adong Shen, Li-Hwei Sng, Petras Stakenas, Kadri Toit, Francis Varaine, Dragana Vukovic, Céline Wahl, Robin Warren, Philip Supply, Stefan Niemann & Thierry Wirth doi:10.1038/ng.3195 Thierry Wirth, Philip Supply, Stefan Niemann and colleagues analyze 4,987 Mycobacterium tuberculosis strains of the Beijing lineage isolated from 99 countries. They report whole-genome sequencing of 110 representative strains, characterize global population structure and reconstruct the evolutionary history of this lineage. Letters Top The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies   pp250 - 256 Luping Lin, Amit J Sabnis, Elton Chan, Victor Olivas, Lindsay Cade, Evangelos Pazarentzos, Saurabh Asthana, Dana Neel, Jenny Jiacheng Yan, Xinyuan Lu, Luu Pham, Mingxue M Wang, Niki Karachaliou, Maria Gonzalez Cao, Jose Luis Manzano, Jose Luis Ramirez, Jose Miguel Sanchez Torres, Fiamma Buttitta, Charles M Rudin, Eric A Collisson, Alain Algazi, Eric Robinson, Iman Osman, Eva Muñoz-Couselo, Javier Cortes, Dennie T Frederick, Zachary A Cooper, Martin McMahon, Antonio Marchetti, Rafael Rosell, Keith T Flaherty, Jennifer A Wargo & Trever G Bivona doi:10.1038/ng.3218 Trever Bivona and colleagues show that the Hippo pathway effector YAP promotes resistance to RAF and MEK inhibitor therapy in multiple types of BRAF-mutant tumors. The findings suggest that combined suppression of YAP and RAF-MEK signaling might enhance treatment response and prevent drug resistance. See also: News and Views by Keren-Paz et al. Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers   pp257 - 262 Adam Shlien, Brittany B Campbell, Richard de Borja, Ludmil B Alexandrov, Daniele Merico, David Wedge, Peter Van Loo, Patrick S Tarpey, Paul Coupland, Sam Behjati, Aaron Pollett, Tatiana Lipman, Abolfazl Heidari, Shriya Deshmukh, Na'ama Avitzur, Bettina Meier, Moritz Gerstung, Ye Hong, Diana M Merino, Manasa Ramakrishna, Marc Remke, Roland Arnold, Gagan B Panigrahi, Neha P Thakkar, Karl P Hodel, Erin E Henninger, A Yasemin Göksenin, Doua Bakry, George S Charames, Harriet Druker, Jordan Lerner-Ellis, Matthew Mistry, Rina Dvir, Ronald Grant, Ronit Elhasid, Roula Farah, Glenn P Taylor, Paul C Nathan, Sarah Alexander, Shay Ben-Shachar, Simon C Ling, Steven Gallinger, Shlomi Constantini, Peter Dirks, Annie Huang, Stephen W Scherer, Richard G Grundy, Carol Durno, Melyssa Aronson, Anton Gartner, M Stephen Meyn, Michael D Taylor, Zachary F Pursell, Christopher E Pearson, David Malkin, P Andrew Futreal, Michael R Stratton, Eric Bouffet, Cynthia Hawkins, Peter J Campbell, Uri Tabori & for the Biallelic Mismatch Repair Deficiency Consortium doi:10.1038/ng.3202 Adam Shlien, Peter Campbell, Uri Tabori and colleagues report genome and exome sequencing of biallelic mismatch repair deficiency cancer samples from 12 children, including 10 high-grade gliomas. The hypermutational signature of the malignant glioma samples was consistent with a driver role for observed mutations in DNA polymerases ε or δ. See also: News and Views by Waterfall & Meltzer Common variants in ACYP2 influence susceptibility to cisplatin-induced hearing loss   pp263 - 266 Heng Xu, Giles W Robinson, Jie Huang, Joshua Yew-Suang Lim, Hui Zhang, Johnnie K Bass, Alberto Broniscer, Murali Chintagumpala, Ute Bartels, Sri Gururangan, Tim Hassall, Michael Fisher, Richard Cohn, Tetsuji Yamashita, Tal Teitz, Jian Zuo, Arzu Onar-Thomas, Amar Gajjar, Clinton F Stewart & Jun J Yang doi:10.1038/ng.3217 Jun Yang, Clinton Stewart and colleagues report the results of a genome-wide association study of cisplatin-induced ototoxicity among children undergoing treatment for brain tumors. They identify common variants in ACYP2 strongly associated with cisplatin-induced hearing loss and ototoxicity severity. Discovery of six new susceptibility loci and analysis of pleiotropic effects in leprosy   pp267 - 271 Hong Liu, Astrid Irwanto, Xi'an Fu, Gongqi Yu, Yongxiang Yu, Yonghu Sun, Chuan Wang, Zhenzhen Wang, Yukinori Okada, Huiqi Low, Yi Li, Herty Liany, Mingfei Chen, Fangfang Bao, Jinghui Li, Jiabao You, Qilin Zhang, Jian Liu, Tongsheng Chu, Anand Kumar Andiappan, Na Wang, Guiye Niu, Dianchang Liu, Xiulu Yu, Lin Zhang, Hongqing Tian, Guizhi Zhou, Olaf Rotzschke, Shumin Chen, Xuejun Zhang, Jianjun Liu & Furen Zhang doi:10.1038/ng.3212 Furen Zhang and colleagues report the results of a three-stage genome-wide association study of leprosy in the Chinese population. They discover six new susceptibility loci and observe substantial overlap with loci previously implicated in autoimmune and inflammatory diseases. Convergent evolution of the genomes of marine mammals OPEN   pp272 - 275 Andrew D Foote, Yue Liu, Gregg W C Thomas, Tomáš Vinař, Jessica Alföldi, Jixin Deng, Shannon Dugan, Cornelis E van Elk, Margaret E Hunter, Vandita Joshi, Ziad Khan, Christie Kovar, Sandra L Lee, Kerstin Lindblad-Toh, Annalaura Mancia, Rasmus Nielsen, Xiang Qin, Jiaxin Qu, Brian J Raney, Nagarjun Vijay, Jochen B W Wolf, Matthew W Hahn, Donna M Muzny, Kim C Worley, M Thomas P Gilbert & Richard A Gibbs doi:10.1038/ng.3198 Andrew Foote and colleagues report the whole-genome sequences and de novo assemblies of three marine mammal species—the walrus, killer whale and manatee—and an improved bottlenose dolphin genome. Their comparative genomic analysis finds evidence of parallel evolution across the marine mammal genomes. Technical Reports Top A method for calculating probabilities of fitness consequences for point mutations across the human genome   pp276 - 283 Brad Gulko, Melissa J Hubisz, Ilan Gronau & Adam Siepel doi:10.1038/ng.3196 Adam Siepel and colleagues develop a statistical method, fitCons, which combines comparative and functional genomic data to estimate the probability that a point mutation will influence fitness. They generate fitCons scores for three human cell types from ENCODE data sets and demonstrate improved prediction power for cis regulatory elements in comparison to conventional conservation-based scores. Efficient Bayesian mixed-model analysis increases association power in large cohorts   pp284 - 290 Po-Ru Loh, George Tucker, Brendan K Bulik-Sullivan, Bjarni J Vilhjálmsson, Hilary K Finucane, Rany M Salem, Daniel I Chasman, Paul M Ridker, Benjamin M Neale, Bonnie Berger, Nick Patterson & Alkes L Price doi:10.1038/ng.3190 Alkes Price, Po-Ru Loh and colleagues report the BOLT-LMM method for mixed-model association. They apply their method to 9 quantitative traits in 23,294 samples and demonstrate that it provides improvements in computational efficiency as well as gains in power that increase with the size of the cohort, making it useful for the analysis of large cohorts. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies   pp291 - 295 Brendan K Bulik-Sullivan, Po-Ru Loh, Hilary K Finucane, Stephan Ripke, Jian Yang, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Nick Patterson, Mark J Daly, Alkes L Price & Benjamin M Neale doi:10.1038/ng.3211 Benjamin Neale and colleagues report the LD Score regression method, used to distinguish the relative contributions of confounding bias and polygenicity to inflated test statistics in GWAS. They apply their method to summary statistics from GWAS for over 30 phenotypes, confirm that polygenicity accounts for the majority of inflation in test statistics and demonstrate use of this method as a correction factor. Large multiallelic copy number variations in humans   pp296 - 303 Robert E Handsaker, Vanessa Van Doren, Jennifer R Berman, Giulio Genovese, Seva Kashin, Linda M Boettger & Steven A McCarroll doi:10.1038/ng.3200 Steven McCarroll and colleagues report an analysis of multiallelic copy number variants (mCNVs). They characterize mCNVs in 849 whole-genome sequences from the 1000 Genomes Project and find that mCNVs give rise to most gene dosage variation in humans. Corrigenda Top Corrigendum: The genome sequence of the orchid Phalaenopsis equestris   p304 Jing Cai, Xin Liu, Kevin Vanneste, Sebastian Proost, Wen-Chieh Tsai, Ke-Wei Liu, Li-Jun Chen, Ying He, Qing Xu, Chao Bian, Zhijun Zheng, Fengming Sun, Weiqing Liu, Yu-Yun Hsiao, Zhao-Jun Pan, Chia-Chi Hsu, Ya-Ping Yang, Yi-Chin Hsu, Yu-Chen Chuang, Anne Dievart, Jean-Francois Dufayard, Xun Xu, Jun-Yi Wang, Jun Wang, Xin-Ju Xiao, Xue-Min Zhao, Rong Du, Guo-Qiang Zhang, Meina Wang, Yong-Yu Su, Gao-Chang Xie, Guo-Hui Liu, Li-Qiang Li, Lai-Qiang Huang, Yi-Bo Luo, Hong-Hwa Chen, Yves Van de Peer & Zhong-Jian Liu doi:10.1038/ng0315-304a Corrigendum: Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy   p304 Cas Simons, Lachlan D Rash, Joanna Crawford, Linlin Ma, Ben Cristofori-Armstrong, David Miller, Kelin Ru, Gregory J Baillie, Yasemin Alanay, Adeline Jacquinet, François-Guillaume Debray, Alain Verloes, Joseph Shen, Gözde Yesil, Serhat Guler, Adnan Yuksel, John G Cleary, Sean M Grimmond, Julie McGaughran, Glenn F King, Michael T Gabbett & Ryan J Taft doi:10.1038/ng0315-304b Top Advertisement Nature Reviews Clinical Oncology  FREE POSTER: BREAST CANCER INTRINSIC SUBTYPES  This special Poster highlights recent achievements and development of our genetic understanding of the intrinsic subtypes of molecular breast cancer subtypes. 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