Nature Genetics Contents: August 2012 pp 835 - 959

Advertisement Uncover the regulation of any gene in vivo The LightSwitch Luciferase Reporter Assay System provides everything you need to study gene regulation in living cells: 18,000 pre-cloned human promoters and 12,000 3'UTRs in luciferase reporter vectors, synthetic elements, and optimized reagents. Measure promoter induction and miRNA target validation in vivo. Visit SwitchGear Genomics and explore both our genome-wide collections and validated pathway screening sets. TABLE OF CONTENTS August 2012 Volume 44, Issue 8 Editorial Obituary News and Views Research Highlights Perspective Analysis Articles Letters Technical Report 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 Nature Genetics and the Wellcome Trust present: The Genomics of Common Diseases 2012 September 19-22, 2012 - Potomac, MD, USA Keynote Speakers: Francis Collins (National Institutes of Health, USA), Thomas Hudson (Ontario Institute for Cancer Research, Canada), Neil Risch (University of California, San Francisco, USA), Sarah Tishkoff (University of Pennsylvania School of Medicine, USA) Register today!   Editorial Top Can we all just get along?   p833 doi:10.1038/ng.2374 Familiarity with developments in all areas of genetics[mdash]from the trained intuition of dysmorphology to algorithms for SNP calling in next-generation sequencing[mdash]is extraordinarily productive in research and clinical translation. Actively organized conferences modeled on the recent European Society of Human Genetics (ESHG) meeting in Nuremberg go a long way in preparing the field for future success. Obituary Top James F. Crow 1916-2012   p834 Bruce Weir doi:10.1038/ng.2365 News and Views Top AXL and acquired resistance to EGFR inhibitors   pp835 - 836 Sophie Postel-Vinay and Alan Ashworth doi:10.1038/ng.2362 A combination of in vitro and in vivo models with validation in human tumors has identified AXL activation as a new mechanism of acquired resistance to EGFR inhibitors in non-small cell lung cancer. The identification of this mechanism, alongside the current development of specific AXL inhibitors, provides the rationale for further studies that may improve treatment for EGFR inhibitor-resistant patients. See also: Article by Zhang et al. Genome stability, progressive kidney failure and aging   pp836 - 838 Hannes Lans and Jan H J Hoeijmakers doi:10.1038/ng.2363 Two new studies report mutations in FAN1 and three other genome-stability genes that tie the DNA damage response to progressive kidney failure and the dysfunction of several other organs. These findings provide clues to the underlying causes of tissue decline and may add a series of genes to the growing list of genome maintenance factors that protect against premature aging. See also: Letter by Zhou et al. The paradoxical TGF-β vasculopathies   pp838 - 839 Rosemary J. Akhurst doi:10.1038/ng.2366 Two new studies show that haploinsufficiency for TGFB2 causes a familial syndrome of thoracic aortic aneurysms and dissections with other clinical features that overlap the Marfan, Loeys-Dietz spectrum of syndromes. Their finding of loss-of-function mutations in yet another transforming growth factor (TGF)-β pathway gene reinforces the seeming paradox of observed increases in the downstream TGF-β signaling pathway. See also: Letter by Boileau et al. | Letter by Lindsay et al. Genetics JOBS of the week Statistical Genetics Analyst INSERM UNIT U708 Senior Researcher in quantitative / population genetics Aarhus University, Department of Molecular Biology and Genetics Temporary postdoctoral position Yeshiva University - Albert Einstein College of Medicine Postdoc in Genetics Dept. Chemistry and Molecular Biology Microbiology and Molecular Genetics Faculty positions The University of Texas Health Science Center at Houston More Science jobs from Genetics EVENT 25th Annual Mouse Molecular Genetics Conference 02.-06.10.12 CA, US More science events from Research Highlights Top Regulatory changes in primates | iPS models of neural development | CXCL1 and CXCL2 link metastasis and chemoresistance | Transgenerational epigenetic inheritance and piRNAs | Light-green tomatoes Perspective Top Leveraging models of cell regulation and GWAS data in integrative network-based association studies   pp841 - 847 Andrea Califano, Atul J Butte, Stephen Friend, Trey Ideker and Eric Schadt doi:10.1038/ng.2355 Analysis Top Including known covariates can reduce power to detect genetic effects in case-control studies   pp848 - 851 Matti Pirinen, Peter Donnelly and Chris C A Spencer doi:10.1038/ng.2346 Peter Donnelly and colleagues report an analysis considering the inclusion of non-confounding covariates within genome-wide association studies and provide software that can be used to assess the impact on power within a particular study. They find that, when the disease prevalence is low, including known covariates, such as sex or established genetic associations, can reduce the power to detect new associations. 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 Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer   pp852 - 860 Zhenfeng Zhang, Jae Cheol Lee, Luping Lin, Victor Olivas, Valerie Au, Thomas LaFramboise, Mohamed Abdel-Rahman, Xiaoqi Wang, Alan D Levine, Jin Kyung Rho, Yun Jung Choi, Chang-Min Choi, Sang-We Kim, Se Jin Jang, Young Soo Park, Woo Sung Kim, Dae Ho Lee, Jung-Shin Lee, Vincent A Miller, Maria Arcila, Marc Ladanyi, Philicia Moonsamy, Charles Sawyers, Titus J Boggon, Patrick C Ma, Carlota Costa, Miquel Taron, Rafael Rosell, Balazs Halmos & Trever G Bivona doi:10.1038/ng.2330 Trever Bivona and colleagues identify the upregulation of the AXL kinase in human non-small cell lung cancer with acquired resistance to erlotinib. Inhibition of AXL restores sensitivity to erlotinib in in vitro and in vivo tumor models. The authors suggest AXL as a potential therapeutic target that may prevent or overcome acquired resistance in patients with EGFR-mutant lung cancer. See also: News and Views by Postel-Vinay & Ashworth The Blk pathway functions as a tumor suppressor in chronic myeloid leukemia stem cells   pp861 - 871 Haojian Zhang, Cong Peng, Yiguo Hu, Huawei Li, Zhi Sheng, Yaoyu Chen, Con Sullivan, Jan Cerny, Lloyd Hutchinson, Anne Higgins, Patricia Miron, Xueqing Zhang, Michael A Brehm, Dongguang Li, Michael R Green & Shaoguang Li doi:10.1038/ng.2350 Shaoguang Li and colleagues show that the Blk pathway functions as a tumor suppressor in cancer stem cells of chronic myeloid leukemia but has no effect on normal hematopoietic stem cells. These results support the feasibility of selectively targeting leukemic stem cells without harming the normal stem cell compartment. Structural diversity and African origin of the 17q21.31 inversion polymorphism   pp872 - 880 Karyn Meltz Steinberg, Francesca Antonacci, Peter H Sudmant, Jeffrey M Kidd, Catarina D Campbell, Laura Vives, Maika Malig, Laura Scheinfeldt, William Beggs, Muntaser Ibrahim, Godfrey Lema, Thomas B Nyambo, Sabah A Omar, Jean-Marie Bodo, Alain Froment, Michael P Donnelly, Kenneth K Kidd, Sarah A Tishkoff & Evan E Eichler doi:10.1038/ng.2335 Evan Eichler and colleagues explore the structural diversity and ancestral origins of the 17q21.31 inversion region. They find that complex duplication architectures have arisen independently on both inversion haplotypes and have recently reached high frequencies among Europeans, either through extraordinary genetic drift or selective sweeps. Advertisement Human & Mouse Exome $798/each, guaranteed coverage RNA-Seq $798/20million guaranteed reads 4-6 wks fastest turnaround time in the industry http://www.otogenetics.com/   Letters Top Structural haplotypes and recent evolution of the human 17q21.31 region   pp881 - 885 Linda M Boettger, Robert E Handsaker, Michael C Zody and Steven A McCarroll doi:10.1038/ng.2334 Steven McCarroll and colleagues use a population genetics approach to identify nine different structural forms of the 17q21.31 inversion region. They show that duplications have arisen independently on both ancestral forms of the inversion and have reached high frequencies in Europeans. Exome sequencing of extreme phenotypes identifies DCTN4 as a modifier of chronic Pseudomonas aeruginosa infection in cystic fibrosis   pp886 - 889 Mary J Emond, Tin Louie, Julia Emerson, Wei Zhao, Rasika A Mathias, Michael R Knowles, Fred A Wright, Mark J Rieder, Holly K Tabor, Deborah A Nickerson, Kathleen C Barnes, National Heart, Lung, and Blood Institute (NHLBI) GO Exome Sequencing Project, Lung GO, Ronald L Gibson & Michael J Bamshad doi:10.1038/ng.2344 Michael Bamshad and colleagues report an exome sequencing study of extreme phenotypes to identify genetic variants that modify the risk for chronic Pseudomonas aeruginosa airway infection in individuals with cystic fibrosis. Genome-wide association study in Han Chinese identifies four new susceptibility loci for coronary artery disease   pp890 - 894 Xiangfeng Lu, Laiyuan Wang, Shufeng Chen, Lin He, Xueli Yang, Yongyong Shi, Jing Cheng, Liang Zhang, C Charles Gu, Jianfeng Huang, Tangchun Wu, Yitong Ma, Jianxin Li, Jie Cao, Jichun Chen, Dongliang Ge, Zhongjie Fan, Ying Li, Liancheng Zhao, Hongfan Li, Xiaoyang Zhou, Lanying Chen, Donghua Liu, Jingping Chen, Xiufang Duan, Yongchen Hao, Ligui Wang, Fanghong Lu, Zhendong Liu, Cailiang Yao, Chong Shen, Xiaodong Pu, Lin Yu, Xianghua Fang, Lihua Xu, Jianjun Mu, Xianping Wu, Runping Zheng, Naqiong Wu, Qi Zhao, Yun Li, Xiaoli Liu, Mengqin Wang, Dahai Yu, Dongsheng Hu, Xu Ji, Dongshuang Guo, Dongling Sun, Qianqian Wang, Ying Yang, Fangchao Liu, Qunxia Mao, Xiaohua Liang, Jingfeng Ji, Panpan Chen, Xingbo Mo, Dianjiang Li, Guoping Chai, Yida Tang, Xiangdong Li, Zhenhan Du, Xuehui Liu, Chenlong Dou, Zili Yang, Qingjie Meng, Dong Wang, Renping Wang, Jun Yang, Heribert Schunkert, Nilesh J Samani, Sekar Kathiresan, Muredach P Reilly, Jeanette Erdmann, The Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) Consortium, Xiaozhong Peng, Xigui Wu, Depei Liu, Yuejin Yang, Runsheng Chen, Boqin Qiang & Dongfeng Gu doi:10.1038/ng.2337 Dongfeng Gu and colleagues report a genome-wide association study for coronary artery disease in Han Chinese individuals. They identify four loci newly associated with coronary artery disease. Association analyses identify multiple new lung cancer susceptibility loci and their interactions with smoking in the Chinese population   pp895 - 899 Jing Dong, Zhibin Hu, Chen Wu, Huan Guo, Baosen Zhou, Jiachun Lv, Daru Lu, Kexin Chen, Yongyong Shi, Minjie Chu, Cheng Wang, Ruyang Zhang, Juncheng Dai, Yue Jiang, Songyu Cao, Zhenzhen Qin, Dianke Yu, Hongxia Ma, Guangfu Jin, Jianhang Gong, Chongqi Sun, Xueying Zhao, Zhihua Yin, Lei Yang, Zhiqiang Li, Qifei Deng, Jiucun Wang, Wei Wu, Hong Zheng, Guoquan Zhou, Hongyan Chen, Peng Guan, Zhihang Peng, Yijiang Chen, Yongqian Shu, Lin Xu, Xiangyang Liu, Li Liu, Pin Xu, Baohui Han, Chunxue Bai, Yuxia Zhao, Haibo Zhang, Ying Yan, Christopher I Amos, Feng Chen, Wen Tan, Li Jin, Tangchun Wu, Dongxin Lin & Hongbing Shen doi:10.1038/ng.2351 Hongbing Shen and colleagues identify three new susceptibility loci for lung cancer in the Chinese population. Their follow-up analyses suggest that two of these loci interact multiplicatively with smoking dose to influence lung cancer risk. A genome-wide association study identifies two new susceptibility loci for lung adenocarcinoma in the Japanese population   pp900 - 903 Kouya Shiraishi, Hideo Kunitoh, Yataro Daigo, Atsushi Takahashi, Koichi Goto, Hiromi Sakamoto, Sumiko Ohnami, Yoko Shimada, Kyota Ashikawa, Akira Saito, Shun-ichi Watanabe, Koji Tsuta, Naoyuki Kamatani, Teruhiko Yoshida, Yusuke Nakamura, Jun Yokota, Michiaki Kubo & Takashi Kohno doi:10.1038/ng.2353 Takashi Kohno and colleagues identify two new susceptibility loci for lung adenocarcinoma in the Japanese population. They also replicate previously identified risk loci near TERT and TP63. Meta-analysis identifies multiple loci associated with kidney function-related traits in east Asian populations   pp904 - 909 Yukinori Okada, Xueling Sim, Min Jin Go, Jer-Yuarn Wu, Dongfeng Gu, Fumihiko Takeuchi, Atsushi Takahashi, Shiro Maeda, Tatsuhiko Tsunoda, Peng Chen, Su-Chi Lim, Tien-Yin Wong, Jianjun Liu, Terri L Young, Tin Aung, Mark Seielstad, Yik-Ying Teo, Young Jin Kim, Jong-Young Lee, Bok-Ghee Han, Daehee Kang, Chien-Hsiun Chen, Fuu-Jen Tsai, Li-Ching Chang, S-J Cathy Fann, Hao Mei, Dabeeru C Rao, James E Hixson, Shufeng Chen, Tomohiro Katsuya, Masato Isono, Toshio Ogihara, John C Chambers, Weihua Zhang, Jaspal S Kooner, The KidneyGen Consortium, The CKDGen Consortium, Eva Albrecht, The GUGC consortium, Kazuhiko Yamamoto, Michiaki Kubo, Yusuke Nakamura, Naoyuki Kamatani, Norihiro Kato, Jiang He, Yuan-Tsong Chen, Yoon Shin Cho, E-Shyong Tai & Toshihiro Tanaka doi:10.1038/ng.2352 Yukinori Okada and colleagues report a meta-analysis of genome-wide association studies for kidney function-related traits in 71,149 individuals from east Asia. They identify 17 loci newly associated with the concentrations of blood urea nitrogen, serum creatinine and uric acid, and with glomerular filtration rate (eGFRcrea), several of which are also associated with chronic kidney disease. FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair   pp910 - 915 Weibin Zhou, Edgar A Otto, Andrew Cluckey, Rannar Airik, Toby W Hurd, Moumita Chaki, Katrina Diaz, Francis P Lach, Geoffrey R Bennett, Heon Yung Gee, Amiya K Ghosh, Sivakumar Natarajan, Supawat Thongthip, Uma Veturi, Susan J Allen, Sabine Janssen, Gokul Ramaswami, Joanne Dixon, Felix Burkhalter, Martin Spoendlin, Holger Moch, Michael J Mihatsch, Jerome Verine, Richard Reade, Hany Soliman, Michel Godin, Denes Kiss, Guido Monga, Gianna Mazzucco, Kerstin Amann, Ferruh Artunc, Ronald C Newland, Thorsten Wiech, Stefan Zschiedrich, Tobias B Huber, Andreas Friedl, Gisela G Slaats, Jaap A Joles, Roel Goldschmeding, Joseph Washburn, Rachel H Giles, Shawn Levy, Agata Smogorzewska & Friedhelm Hildebrandt doi:10.1038/ng.2347 Friedhelm Hildebrandt, Agata Smogorzewska and colleagues show that mutations in the DNA repair gene FAN1 cause karyomegalic interstitial nephritis. These findings implicate deficient DNA damage response signaling in the pathophysiology of renal fibrosis. See also: News and Views by Lans & Hoeijmakers TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome   pp916 - 921 Catherine Boileau, Dong-Chuan Guo, Nadine Hanna, Ellen S Regalado, Delphine Detaint, Limin Gong, Mathilde Varret, Siddharth K Prakash, Alexander H Li, Hyacintha d'Indy, Alan C Braverman, Bernard Grandchamp, Callie S Kwartler, Laurent Gouya, Regie Lyn P Santos-Cortez, Marianne Abifadel, Suzanne M Leal, Christine Muti, Jay Shendure, Marie-Sylvie Gross, Mark J Rieder, Alec Vahanian, Deborah A Nickerson, Jean Baptiste Michel, National Heart, Lung, and Blood Institute (NHLBI) Go Exome Sequencing Project, Guillaume Jondeau & Dianna M Milewicz doi:10.1038/ng.2348 Dianna Milewicz and colleagues report the identification of loss-of-function mutations in TGFB2 in individuals with familial thoracic aortic aneurysm and acute aortic dissection associated with mild systemic features of the Marfan syndrome. See also: News and Views by Akhurst Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm   pp922 - 927 Mark E Lindsay, Dorien Schepers, Nikhita Ajit Bolar, Jefferson J Doyle, Elena Gallo, Justyna Fert-Bober, Marlies J E Kempers, Elliot K Fishman, Yichun Chen, Loretha Myers, Djahita Bjeda, Gretchen Oswald, Abdallah F Elias, Howard P Levy, Britt-Marie Anderlid, Margaret H Yang, Ernie M H F Bongers, Janneke Timmermans, Alan C Braverman, Natalie Canham, Geert R Mortier, Han G Brunner, Peter H Byers, Jennifer Van Eyk, Lut Van Laer, Harry C Dietz & Bart L Loeys doi:10.1038/ng.2349 Bart Loeys and colleagues identify mutations or deletions of TGFB2 in individuals with thoracic aortic aneurysm and other features of Loeys-Dietz syndrome. TGFB2 encodes the transforming growth factor-β2 ligand. See also: News and Views by Akhurst Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA    pp928 - 933 Marjorie J Lindhurst, Victoria E R Parker, Felicity Payne, Julie C Sapp, Simon Rudge, Julie Harris, Alison M Witkowski, Qifeng Zhang, Matthijs P Groeneveld, Carol E Scott, Allan Daly, Susan M Huson, Laura L Tosi, Michael L Cunningham, Thomas N Darling, Joseph Geer, Zoran Gucev, V Reid Sutton, Christos Tziotzios, Adrian K Dixon, Timothy Helliwell, Stephen O'Rahilly, David B Savage, Michael J O Wakelam, Inês Barroso, Leslie G Biesecker & Robert K Semple doi:10.1038/ng.2332 Leslie Biesecker and colleagues report an exome sequencing study identifying somatic activating mutations in PIK3CA as the cause of a new progressive segmental overgrowth disorder. They identify mutations in PIK3CA in ten additional individuals with overlapping syndromes. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes   pp934 - 940 Jean-Baptiste Rivière, Ghayda M Mirzaa, Brian J O'Roak, Margaret Beddaoui, Diana Alcantara, Robert L Conway, Judith St-Onge, Jeremy A Schwartzentruber, Karen W Gripp, Sarah M Nikkel, Thea Worthylake, Christopher T Sullivan, Thomas R Ward, Hailly E Butler, Nancy A Kramer, Beate Albrecht, Christine M Armour, Linlea Armstrong, Oana Caluseriu, Cheryl Cytrynbaum, Beth A Drolet, A Micheil Innes, Julie L Lauzon, Angela E Lin, Grazia M S Mancini, Wendy S Meschino, James D Reggin, Anand K Saggar, Tally Lerman-Sagie, Gökhan Uyanik, Rosanna Weksberg, Birgit Zirn, Chandree L Beaulieu, Finding of Rare Disease Genes (FORGE) Canada Consortium, Jacek Majewski, Dennis E Bulman, Mark O'Driscoll, Jay Shendure, John M Graham Jr, Kym M Boycott & William B Dobyns doi:10.1038/ng.2331 William Dobyns and colleagues report de novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA in the sporadic overgrowth syndromes megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) and megalencephaly-capillary malformation (MCAP). De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly   pp941 - 945 Jeong Ho Lee, My Huynh, Jennifer L Silhavy, Sangwoo Kim, Tracy Dixon-Salazar, Andrew Heiberg, Eric Scott, Vineet Bafna, Kiley J Hill, Adrienne Collazo, Vincent Funari, Carsten Russ, Stacey B Gabriel, Gary W Mathern & Joseph G Gleeson doi:10.1038/ng.2329 Joseph Gleeson and colleagues report exome sequencing of 20 individuals with hemimegalencephaly (HME), identifying de novo somatic mutations in the PIK3CA, AKT3 and MTOR genes. The yak genome and adaptation to life at high altitude   pp946 - 949 Qiang Qiu, Guojie Zhang, Tao Ma, Wubin Qian, Junyi Wang, Zhiqiang Ye, Changchang Cao, Quanjun Hu, Jaebum Kim, Denis M Larkin, Loretta Auvil, Boris Capitanu, Jian Ma, Harris A Lewin, Xiaoju Qian, Yongshan Lang, Ran Zhou, Lizhong Wang, Kun Wang, Jinquan Xia, Shengguang Liao, Shengkai Pan, Xu Lu, Haolong Hou, Yan Wang, Xuetao Zang, Ye Yin, Hui Ma, Jian Zhang, Zhaofeng Wang, Yingmei Zhang, Dawei Zhang, Takahiro Yonezawa, Masami Hasegawa, Yang Zhong, Wenbin Liu, Yan Zhang, Zhiyong Huang, Shengxiang Zhang, Ruijun Long, Huanming Yang, Jian Wang, Johannes A Lenstra, David N Cooper, Yi Wu, Jun Wang, Peng Shi, Jian Wang & Jianquan Liu doi:10.1038/ng.2343 Jianquan Liu and colleagues report the draft genome sequence of the domestic yak, Bos grunniens. Their comparative analyses with low-altitude cattle provide insights into high-altitude adaptation in the yak. Control of grain size, shape and quality by OsSPL16 in rice   pp950 - 954 Shaokui Wang, Kun Wu, Qingbo Yuan, Xueying Liu, Zhengbin Liu, Xiaoyan Lin, Ruizhen Zeng, Haitao Zhu, Guojun Dong, Qian Qian, Guiquan Zhang & Xiangdong Fu doi:10.1038/ng.2327 Xiangdong Fu and colleagues map variants in OsSPL16 that influence grain width and yield in a cross between a slender-grain Basmati and a wide-grain indica variety of rice. The authors show that higher expression of OsSPL16 promotes cell division and grain filling and can lead to improvements in grain quality and yield. Technical Report Top Fast and accurate genotype imputation in genome-wide association studies through pre-phasing   pp955 - 959 Bryan Howie, Christian Fuchsberger, Matthew Stephens, Jonathan Marchini & Gonçalo R Abecasis doi:10.1038/ng.2354 Goncalo Abecasis, Jonathan Marchini and colleagues report a pre-phasing strategy for genotype imputation in GWAS, which they show maintains accuracy while substantially lowering computational costs. Their approach has been implemented in both MACH and IMPUTE 2.0 software. Top Advertisement Nature Communications #4 in multidisciplinary sciences with first Impact Factor Nature Communications has joined Nature at the top of the multidisciplinary sciences category with its first impact factor of 7.396. 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