Nature Genetics Contents: January 2012 pp 1 - 110

TABLE OF CONTENTS January 2012 Volume 44, Issue 1 Editorial Correspondence News and Views Research Highlights Brief Communications Articles Letters Subscribe   Facebook   RSS   Recommend to library   Twitter   Advertisement Nature Outlook: Allergies The increased prevalence of allergies and asthma, especially in the developed world, has raised the stakes in the quest for prevention and cure. Access the Outlook free online for six months. Produced with support from: Nestlé Research Center   Editorial Top Full spectrum genetics p1 doi:10.1038/ng.1057 Every instance of a variant in the human genome causing or correlated with a trait deserves to be databased and analyzed. As a consequence of rapidly evolving technology and strategies, more of the mutational spectrum of human disease is now accessible to research. Advised by our referees' progressively higher standards, we continue to select the most informative and useful results. Full Text | PDF Correspondence Top Rare and functional SIAE variants are not associated with autoimmune disease risk in up to 66,924 individuals of European ancestry pp3 - 5 Karen A Hunt, Deborah J Smyth, Tobias Balschun, Maria Ban, Vanisha Mistry, Tariq Ahmad, Vidya Anand, Jeffrey C Barrett, Leena Bhaw-Rosun, Nicholas A Bockett, Oliver J Brand, Elisabeth Brouwer, Patrick Concannon, Jason D Cooper, Kerith-Rae M Dias, Cleo C van Diemen, Patrick C Dubois, Sarah Edkins, Regina Fölster-Holst, Karin Fransen, David N Glass, Graham A R Heap, Sylvia Hofmann, Tom W J Huizinga, Sarah Hunt, Cordelia Langford, James Lee, John Mansfield, Maria Giovanna Marrosu, Christopher G Mathew, Charles A Mein, Joachim Müller-Quernheim, Sarah Nutland, Suna Onengut-Gumuscu, Willem Ouwehand, Kerra Pearce, Natalie J Prescott, Marcel D Posthumus, Simon Potter, Giulio Rosati, Jennifer Sambrook, Jack Satsangi, Stefan Schreiber, Corina Shtir, Matthew J Simmonds, Marc Sudman, Susan D Thompson, Rene Toes, Gosia Trynka, Timothy J Vyse, Neil M Walker, Stephan Weidinger, Alexandra Zhernakova, Magdalena Zoledziewska, Type 1 Diabetes Genetics Consortium , UK Inflammatory Bowel Disease (IBD) Genetics Consortium , Wellcome Trust Case Control Consortium , Rinse K Weersma, Stephen C L Gough, Stephen Sawcer, Cisca Wijmenga, Miles Parkes, Francesco Cucca, Andre Franke, Panos Deloukas, Stephen S Rich, John A Todd & David A van Heel doi:10.1038/ng.1037 Full Text | PDF Improved imputation of common and uncommon SNPs with a new reference set pp6 - 7 Zhaoming Wang, Kevin B Jacobs, Meredith Yeager, Amy Hutchinson, Joshua Sampson, Nilanjan Chatterjee, Demetrius Albanes, Sonja I Berndt, Charles C Chung, W Ryan Diver, Susan M Gapstur, Lauren R Teras, Christopher A Haiman, Brian E Henderson, Daniel Stram, Xiang Deng, Ann W Hsing, Jarmo Virtamo, Michael A Eberle, Jennifer L Stone, Mark P Purdue, Phil Taylor, Margaret Tucker & Stephen J Chanock doi:10.1038/ng.1044 Full Text | PDF News and Views Top Spliceosome mutations in hematopoietic malignancies pp9 - 10 Christopher N Hahn and Hamish S Scott doi:10.1038/ng.1045 Recent studies, including two in this issue, report heterozygous missense mutations in the U2AF1 and SF3B1 genes that encode spliceosome subunits. U2AF1 is frequently mutated in myeloid hematopoietic malignancies, especially in myelodysplastic syndrome (MDS), and SF3B1 is frequently mutated in both MDS and chronic lymphocytic leukemia (CLL). Full Text | PDF See also: Letter by Quesada et al. | Letter by Graubert et al. Following evolution of bacterial antibiotic resistance in real time pp11 - 13 Adam Z Rosenthal and Michael B Elowitz doi:10.1038/ng.1048 A new study reports the development of the 'morbidostat', a device that allows for continuous culture of bacteria under a constant drug selection pressure using computer feedback control of antibiotic concentration. This device, together with bacterial whole-genome sequencing, allowed the authors to follow the evolution of resistance-conferring mutations in Escherichia coli populations in real time, providing support for deterministic evolution of resistance in some situations. Full Text | PDF See also: Letter by Toprak et al. | Letter by Comas et al. Dnmt3a silences hematopoietic stem cell self-renewal pp13 - 14 Jennifer J Trowbridge and Stuart H Orkin doi:10.1038/ng.1043 DNA methylation is an epigenetic mark stably directing gene expression throughout development. A new study uncovers a role for the DNA methyltransferase Dnmt3a in silencing self-renewal genes in hematopoietic stem cells (HSCs) to permit efficient hematopoietic differentiation. Full Text | PDF See also: Article by Challen et al. Genetics JOBS of the week Two Tenure Track Junior Faculty Positions Vienna University of Technology Faculty Positions Rutgers, the State University of New Jersey Research Associate in Bioprocess Scale-Down UCL Research Associate Imperial College London More Science jobs from Genetics EVENT Complex Traits: Genomics and Computational Approaches (B5) 20.-25.02.12 CO, US More science events from Research Highlights Top Joint-rank for Mendelian sequencing | Hedgehog in the blood-brain barrier | Unifying antipsychotic drugs | Lamarckian viral defense in worms | Intestinal stem cell interconversion Brief Communications Top Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma pp17 - 19 Guangwu Guo, Yaoting Gui, Shengjie Gao, Aifa Tang, Xueda Hu, Yi Huang, Wenlong Jia, Zesong Li, Minghui He, Liang Sun, Pengfei Song, Xiaojuan Sun, Xiaokun Zhao, Sangming Yang, Chaozhao Liang, Shengqing Wan, Fangjian Zhou, Chao Chen, Jialou Zhu, Xianxin Li, Minghan Jian, Liang Zhou, Rui Ye, Peide Huang, Jing Chen, Tao Jiang, Xiao Liu, Yong Wang, Jing Zou, Zhimao Jiang, Renhua Wu, Song Wu, Fan Fan, Zhongfu Zhang, Lin Liu, Ruilin Yang, Xingwang Liu, Haibo Wu, Weihua Yin, Xia Zhao, Yuchen Liu, Huanhuan Peng, Binghua Jiang, Qingxin Feng, Cailing Li, Jun Xie, Jingxiao Lu, Karsten Kristiansen, Yingrui Li, Xiuqing Zhang, Songgang Li, Jian Wang, Huanming Yang, Zhiming Cai & Jun Wang doi:10.1038/ng.1014 Huanming Yang, Zhiming Cai, Jun Wang and colleagues report whole-exome sequencing of 10 clear cell renal cell carcinomas followed by a screen of ~1,100 genes in a total of 98 tumors. They found 12 new disease-associated genes and detected frequent alterations in the ubiquitin-mediated proteolysis pathway. First paragraph | Full Text | PDF GATA6 haploinsufficiency causes pancreatic agenesis in humans pp20 - 22 Hana Lango Allen, Sarah E Flanagan, Charles Shaw-Smith, Elisa De Franco, Ildem Akerman, Richard Caswell, the International Pancreatic Agenesis Consortium: A full list of members is provided in the Supplementary Note. Jorge Ferrer, Andrew T Hattersley and Sian Ellard doi:10.1038/ng.1035 Andrew Hattersley and colleagues report an exome sequencing study that identifies de novo heterozygous inactivating mutations in GATA6 as a common cause of pancreatic agenesis. This suggests an essential function for GATA6 in human pancreas development. First paragraph | Full Text | PDF Articles Top Dnmt3a is essential for hematopoietic stem cell differentiation pp23 - 31 Grant A Challen, Deqiang Sun, Mira Jeong, Min Luo, Jaroslav Jelinek, Jonathan S Berg, Christoph Bock, Aparna Vasanthakumar, Hongcang Gu, Yuanxin Xi, Shoudan Liang, Yue Lu, Gretchen J Darlington, Alexander Meissner, Jean-Pierre J Issa, Lucy A Godley, Wei Li and Margaret A Goodell doi:10.1038/ng.1009 Margaret Goodell, Wei Li and colleagues report conditional ablation of the Dnmt3a DNA methyltransferase in hematopoietic stem cells (HSCs) in mice. They show that Dnmt3a is critical for epigenetic silencing of HSC regulatory genes and for HSC differentiation. Abstract | Full Text | PDF See also: News and Views by Trowbridge & Orkin Genome-wide association study of flowering time and grain yield traits in a worldwide collection of rice germplasm pp32 - 39 Xuehui Huang, Yan Zhao, Xinghua Wei, Canyang Li, Ahong Wang, Qiang Zhao, Wenjun Li, Yunli Guo, Liuwei Deng, Chuanrang Zhu, Danlin Fan, Yiqi Lu, Qijun Weng, Kunyan Liu, Taoying Zhou, Yufeng Jing, Lizhen Si, Guojun Dong, Tao Huang, Tingting Lu, Qi Feng, Qian Qian, Jiayang Li and Bin Han doi:10.1038/ng.1018 Bin Han and colleagues report low-coverage sequencing for 950 diverse rice accessions. They develop a framework for haplotype-based de novo assembly, phenotyped the 950 lines for 11 agronomic traits and used this information to conduct genome-wide association studies. They identify 32 new loci associated with these traits. Abstract | Full Text | PDF Letters Top Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina-associated domains pp40 - 46 Benjamin P Berman, Daniel J Weisenberger, Joseph F Aman, Toshinori Hinoue, Zachary Ramjan, Yaping Liu, Houtan Noushmehr, Christopher P E Lange, Cornelis M van Dijk, Rob A E M Tollenaar, David Van Den Berg and Peter W Laird doi:10.1038/ng.969 Peter Laird and colleagues performed whole-genome bisulfite sequencing in a human colorectal tumor and a matched normal sample. They find regions of methylation variation that coincide with domains associated with the nuclear lamina. First paragraph | Full Text | PDF Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia pp47 - 52 Víctor Quesada, Laura Conde, Neus Villamor, Gonzalo R Ordóñez, Pedro Jares, Laia Bassaganyas, Andrew J Ramsay, Sílvia Beà, Magda Pinyol, Alejandra Martínez-Trillos, Mónica López-Guerra, Dolors Colomer, Alba Navarro, Tycho Baumann, Marta Aymerich, María Rozman, Julio Delgado, Eva Giné, Jesús M Hernández, Marcos González-Díaz, Diana A Puente, Gloria Velasco, José M P Freije, José M C Tubío, Romina Royo, Josep L Gelpí, Modesto Orozco, David G Pisano, Jorge Zamora, Miguel Vázquez, Alfonso Valencia, Heinz Himmelbauer, Mónica Bayés, Simon Heath, Marta Gut, Ivo Gut, Xavier Estivill, Armando López-Guillermo, Xose S Puente, Elías Campo & Carlos López-Otín doi:10.1038/ng.1032 Carlos López-Otín, Elías Campo and colleagues report exome sequencing of tumor and normal samples from 105 individuals with chronic lymphocytic leukemia (CLL). They identify 1,246 somatic mutations predicted to affect gene function and 78 genes with recurrent predicted functional mutations. They find recurrent mutations in the gene encoding the SF3B1 splicing factor, which was mutated in 10% of the CLL samples. First paragraph | Full Text | PDF See also: News and Views by Hahn & Scott Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes pp53 - 57 Timothy A Graubert, Dong Shen, Li Ding, Theresa Okeyo-Owuor, Cara L Lunn, Jin Shao, Kilannin Krysiak, Christopher C Harris, Daniel C Koboldt, David E Larson, Michael D McLellan, David J Dooling, Rachel M Abbott, Robert S Fulton, Heather Schmidt, Joelle Kalicki-Veizer, Michelle O'Laughlin, Marcus Grillot, Jack Baty, Sharon Heath, John L Frater, Talat Nasim, Daniel C Link, Michael H Tomasson, Peter Westervelt, John F DiPersio, Elaine R Mardis, Timothy J Ley, Richard K Wilson & Matthew J Walter doi:10.1038/ng.1031 Matthew Walter and colleagues report the whole-genome sequencing of a secondary acute myeloid leukemia sample and a matched normal tissue sample. Further analysis of additional subjects identified recurrent mutations in U2AF1 in 13/150 (8.7%) individuals with myelodysplastic syndrome. First paragraph | Full Text | PDF See also: News and Views by Hahn & Scott Common variation at 3p22.1 and 7p15.3 influences multiple myeloma risk pp58 - 61 Peter Broderick, Daniel Chubb, David C Johnson, Niels Weinhold, Asta Försti, Amy Lloyd, Bianca Olver, Yussanne P Ma, Sara E Dobbins, Brian A Walker, Faith E Davies, Walter A Gregory, J Anthony Child, Fiona M Ross, Graham H Jackson, Kai Neben, Anna Jauch, Per Hoffmann, Thomas W Mühleisen, Markus M Nöthen, Susanne Moebus, Ian P Tomlinson, Hartmut Goldschmidt, Kari Hemminki, Gareth J Morgan & Richard S Houlston doi:10.1038/ng.993 Richard Houlston, Gareth Morgan, Kari Hemminki and colleagues report the results of a genome-wide association study of multiple myeloma. They identify two regions influencing susceptibility to this hematological malignancy. First paragraph | Full Text | PDF Genome-wide association study identifies five loci associated with susceptibility to pancreatic cancer in Chinese populations pp62 - 66 Chen Wu, Xiaoping Miao, Liming Huang, Xu Che, Guoliang Jiang, Dianke Yu, Xianghong Yang, Guangwen Cao, Zhibin Hu, Yongjian Zhou, Chaohui Zuo, Chunyou Wang, Xianghong Zhang, Yifeng Zhou, Xianjun Yu, Wanjin Dai, Zhaoshen Li, Hongbing Shen, Luming Liu, Yanling Chen, Sheng Zhang, Xiaoqi Wang, Kan Zhai, Jiang Chang, Yu Liu, Menghong Sun, Wei Cao, Jun Gao, Ying Ma, Xiongwei Zheng, Siu Tim Cheung, Yongfeng Jia, Jian Xu, Wen Tan, Ping Zhao, Tangchun Wu, Chengfeng Wang & Dongxin Lin doi:10.1038/ng.1020 Dongxin Lin and colleagues report a genome-wide association study for pancreatic cancer in Chinese populations. The authors identify five new genetic loci associated with risk of pancreatic cancer. First paragraph | Full Text | PDF Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians pp67 - 72 Yoon Shin Cho, Chien-Hsiun Chen, Cheng Hu, Jirong Long, Rick Twee Hee Ong, Xueling Sim, Fumihiko Takeuchi, Ying Wu, Min Jin Go, Toshimasa Yamauchi, Yi-Cheng Chang, Soo Heon Kwak, Ronald C W Ma, Ken Yamamoto, Linda S Adair, Tin Aung, Qiuyin Cai, Li-Ching Chang, Yuan-Tsong Chen, Yutang Gao, Frank B Hu, Hyung-Lae Kim, Sangsoo Kim, Young Jin Kim, Jeannette Jen-Mai Lee, Nanette R Lee, Yun Li, Jian Jun Liu, Wei Lu, Jiro Nakamura, Eitaro Nakashima, Daniel Peng-Keat Ng, Wan Ting Tay, Fuu-Jen Tsai, Tien Yin Wong, Mitsuhiro Yokota, Wei Zheng, Rong Zhang, Congrong Wang, Wing Yee So, Keizo Ohnaka, Hiroshi Ikegami, Kazuo Hara, Young Min Cho, Nam H Cho, Tien-Jyun Chang, Yuqian Bao, Åsa K Hedman, Andrew P Morris, Mark I McCarthy, DIAGRAM Consortium, MuTHER Consortium, Ryoichi Takayanagi, Kyong Soo Park, Weiping Jia, Lee-Ming Chuang, Juliana C N Chan, Shiro Maeda, Takashi Kadowaki, Jong-Young Lee, Jer-Yuarn Wu, Yik Ying Teo, E Shyong Tai, Xiao Ou Shu, Karen L Mohlke, Norihiro Kato, Bok-Ghee Han & Mark Seielstad doi:10.1038/ng.1019 Yoon Shin Cho, Mark Seielstad and colleagues report a meta-analysis of genome-wide association studies for type 2 diabetes in individuals of east Asian ancestry. They identify eight new loci associated with type 2 diabetes. First paragraph | Full Text | PDF A genome-wide association study in Han Chinese identifies new susceptibility loci for ankylosing spondylitis pp73 - 77 Zhiming Lin, Jin-Xin Bei, Meixin Shen, Qiuxia Li, Zetao Liao, Yanli Zhang, Qing Lv, Qiujing Wei, Hui-Qi Low, Yun-Miao Guo, Shuangyan Cao, Mingcan Yang, Zaiying Hu, Manlong Xu, Xinwei Wang, Yanlin Wei, Li Li, Chao Li, Tianwang Li, Jianlin Huang, Yunfeng Pan, Ou Jin, Yuqiong Wu, Jing Wu, Zishi Guo, Peigen He, Shaoxian Hu, Husheng Wu, Hui Song, Feng Zhan, Shengyun Liu, Guanmin Gao, Zhangsuo Liu, Yinong Li, Changhong Xiao, Juan Li, Zhizhong Ye, Weizhen He, Dongzhou Liu, Lingxun Shen, Anbin Huang, Henglian Wu, Yi Tao, Xieping Pan, Buyun Yu, E Shyong Tai, Yi-Xin Zeng, Ee Chee Ren, Yan Shen, Jianjun Liu & Jieruo Gu doi:10.1038/ng.1005 Jieruo Gu, Jianjun Liu and colleagues report the results of a genome-wide association study of ankylosing spondylitis in Han Chinese. They identify two new susceptibility loci for this inflammatory disease and confirm strong associations with variants in the HLA-B region. First paragraph | Full Text | PDF Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder pp78 - 84 Josephine Elia, Joseph T Glessner, Kai Wang, Nagahide Takahashi, Corina J Shtir, Dexter Hadley, Patrick M A Sleiman, Haitao Zhang, Cecilia E Kim, Reid Robison, Gholson J Lyon, James H Flory, Jonathan P Bradfield, Marcin Imielinski, Cuiping Hou, Edward C Frackelton, Rosetta M Chiavacci, Takeshi Sakurai, Cara Rabin, Frank A Middleton, Kelly A Thomas, Maria Garris, Frank Mentch, Christine M Freitag, Hans-Christoph Steinhausen, Alexandre A Todorov, Andreas Reif, Aribert Rothenberger, Barbara Franke, Eric O Mick, Herbert Roeyers, Jan Buitelaar, Klaus-Peter Lesch, Tobias Banaschewski, Richard P Ebstein, Fernando Mulas, Robert D Oades, Joseph Sergeant, Edmund Sonuga-Barke, Tobias J Renner, Marcel Romanos, Jasmin Romanos, Andreas Warnke, Susanne Walitza, Jobst Meyer, Haukur Pálmason, Christiane Seitz, Sandra K Loo, Susan L Smalley, Joseph Biederman, Lindsey Kent, Philip Asherson, Richard J L Anney, J William Gaynor, Philip Shaw, Marcella Devoto, Peter S White, Struan F A Grant, Joseph D Buxbaum, Judith L Rapoport, Nigel M Williams, Stanley F Nelson, Stephen V Faraone & Hakon Hakonarson doi:10.1038/ng.1013 Hakon Hakonarson and colleagues report a genome-wide copy number variation study in 3,506 cases of attention-deficit hyperactivity disorder. The authors identify a statistically significant enrichment of CNVs impacting metabotropic glutamate receptor genes. First paragraph | Full Text | PDF Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome pp85 - 88 Carine Le Goff, Clémentine Mahaut, Avinash Abhyankar, Wilfried Le Goff, Valérie Serre, Alexandra Afenjar, Anne Destrée, Maja di Rocco, Delphine Héron, Sébastien Jacquemont, Sandrine Marlin, Marleen Simon, John Tolmie, Alain Verloes, Jean-Laurent Casanova, Arnold Munnich & Valérie Cormier-Daire doi:10.1038/ng.1016 Valérie Cormier-Daire and colleagues report the identification of mutations in SMAD4 that cause Myhre syndrome, a developmental disorder characterized by short stature, short hands and feet, facial dysmorphism, muscular hypertrophy, deafness and cognitive delay. All of the mutations alter a single codon in the Mad Homology 2 domain of SMAD4. First paragraph | Full Text | PDF Large-scale discovery of enhancers from human heart tissue pp89 - 93 Dalit May, Matthew J Blow, Tommy Kaplan, David J McCulley, Brian C Jensen, Jennifer A Akiyama, Amy Holt, Ingrid Plajzer-Frick, Malak Shoukry, Crystal Wright, Veena Afzal, Paul C Simpson, Edward M Rubin, Brian L Black, James Bristow, Len A Pennacchio and Axel Visel doi:10.1038/ng.1006 Len Pennacchio, Axel Visel and colleagues use an epigenomic approach to identify a large number of candidate enhancers from human heart tissue. This work will facilitate further studies into the role of enhancers in human cardiac development and disease. First paragraph | Full Text | PDF A chromatin-modifying function of JNK during stem cell differentiation pp94 - 100 Vijay K Tiwari, Michael B Stadler, Christiane Wirbelauer, Renato Paro, Dirk Schübeler & Christian Beisel doi:10.1038/ng.1036 Dirk Schübeler, Michael Stadler and colleagues show that the c-Jun NH2-terminal kinase (JNK) binds directly to active promoters during the differentiation of stem cells to neurons and targets histone H3 serine 10 for phosphorylation. First paragraph | Full Text | PDF Evolutionary paths to antibiotic resistance under dynamically sustained drug selection pp101 - 105 Erdal Toprak, Adrian Veres, Jean-Baptiste Michel, Remy Chait, Daniel L Hartl and Roy Kishony doi:10.1038/ng.1034 Roy Kishony and colleagues develop a device for the continuous culture of bacterial populations under constant antibiotic selection pressure. They use this morbidostat, together with whole-genome sequencing of E. coli strains, to follow evolutionary paths leading to high levels of resistance to three individual drugs. First paragraph | Full Text | PDF See also: News and Views by Rosenthal & Elowitz Whole-genome sequencing of rifampicin-resistant Mycobacterium tuberculosis strains identifies compensatory mutations in RNA polymerase genes pp106 - 110 Iñaki Comas, Sonia Borrell, Andreas Roetzer, Graham Rose, Bijaya Malla, Midori Kato-Maeda, James Galagan, Stefan Niemann & Sebastien Gagneux doi:10.1038/ng.1038 Sebastien Gagneux and colleagues identify a set of compensatory mutations in the RNA polymerase of rifampicin-resistant M. tuberculosis by comparing the whole-genome sequences of ten paired clinical isolates and strains evolved in vitro. These mutations are associated with high competitive fitness in vitro and occur with increased clinical frequency in affected populations with a high burden of drug-resistant tuberculosis. First paragraph | Full Text | PDF See also: News and Views by Rosenthal & Elowitz Top Advertisement NCI Physical Sciences in Oncology Reprint Collection This reprint collection brings together a selection of articles funded by the Physical Sciences–Oncology Centers programme, a network of research centres launched by the National Cancer Institute to explore ways in which physical sciences perspectives could be applied to the study of cancer. Access the collection free online for 6 months Produced with support from Office of Physical Sciences-Oncology/Center for Strategic Scientific Initiatives/Office of the Director/National Cancer Institute   Natureevents is a fully searchable, multi-disciplinary database designed to maximise exposure for events organisers. 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