Nature Genetics Contents: July 2016 pp 701 - 820

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Advertisement Nature Index 2016 Saudi Arabia  Saudi Arabia had the largest growth of its region in the production of high-quality research in 2015 tracked by the Nature Index, propelling the country into a leading position.  Click here to see how strong and fruitful collaborations with international powerhouses have been integral to Saudi Arabia's rapid rise. The country has now firmly set its sights on becoming a global player in science. Produced with support from: KACST   TABLE OF CONTENTS July 2016 Volume 48, Issue 7 Editorial Correspondence News and Views Analysis Articles Letters Technical Reports Subscribe   Facebook   RSS   Recommend to library   Twitter   Advertisement Genome Informatics (19-22 September 2016)  This meeting will focus on large-scale approaches to understanding the structure and biology of genomes and look at technologies such as variant-calling, transcriptomic analysis, and variant interpretation, applied to very large genomic data sets. Deadlines: Bursary: 12 July / Abstract: 26 July / Registration: 23 August   Advertisement Nature Conferences THE GENOMICS OF COMMON DISEASES 2016  Presented by Nature Genetics in association with the Wellcome Trust September 25-28, 2016 Renaissance Baltimore Harborplace Hotel | Baltimore, MD, USA REGISTER NOW!   Advertisement BioPharma Dealmakers  A supplement to Nature Biotechnology & Nature Reviews Drug Discovery Sign up to our NEW networking forum to connect with life sciences companies and partnering professionals looking for dealmaking opportunities.  Stay up to date on emerging therapeutic areas  Ask for advice from our editors and experts in the field SIGN UP NOW   Editorial Top Genome variation in precision medicine   p701 doi:10.1038/ng.3614 Precision medicine is a sufficiently imprecise term to cover cohort research in epidemiology as well as evidence-based improvements in clinical delivery and informatics. We think it should continue to build and improve upon the rigorous standards for measurement of genome sequence variation. Correspondence Top Rapid evaluation of phenotypes, SNPs and results through the dbGaP CHARGE Summary Results site   pp702 - 703 Stephen S Rich, Zeng Y Wang, Anne Sturcke, Lora Ziyabari, Mike Feolo, Christopher J O'Donnell, Ken Rice, Joshua C Bis & Bruce M Psaty doi:10.1038/ng.3582 News and Views Top Meristems take their cues from organ primordia   pp704 - 705 Josh Strable & Michael J Scanlon doi:10.1038/ng.3601 Stem cell regulation is critical to the development of all multicellular organisms; in plants, stem cell niches reside in meristems. Two newly identified plant genes establish a novel signaling feedback from the incipient leaf primordia back to the meristem that is required to regulate stem cell proliferation. See also: Article by Je et al. Perhaps a wee bit of sugar would help   pp705 - 707 Hudson H Freeze doi:10.1038/ng.3600 A new genetic disorder might be treatable through consumption of a simple sugar, but the relative contributions of endogenous and dietary sources are mostly unknown. It's time to change that. See also: Article by van Karnebeek et al. A plethora of pleiotropy across complex traits   pp707 - 708 Peter M Visscher & Jian Yang doi:10.1038/ng.3604 A new analysis has identified hundreds of loci that are associated with multiple traits or diseases by comparing genome-wide association study (GWAS) data for 42 complex traits. The study uses the power of GWAS to provide evidence of pairs of traits with a likely causal relationship. See also: Analysis by Pickrell et al. Genetics JOBS of the week Junior Group Leader Position, Tenure Track: Neural Basis of Animal Behavior Friedrich Miescher Institute for Biomedical Research (FMI) PhD Candidate / Student Uniklinik Koln Postdoctoral Scientists Cedars-Sinai Postdoctoral Fellow The Scripps Research Institute (TSRI) More Science jobs from Genetics EVENT Advances in the Neurobiology of Mental Illness 07.10.16 New York, USA More science events from Analysis Top Detection and interpretation of shared genetic influences on 42 human traits   pp709 - 717 Joseph K Pickrell, Tomaz Berisa, Jimmy Z Liu, Laure Ségurel, Joyce Y Tung & David A Hinds doi:10.1038/ng.3570 Joseph Pickrell and colleagues analyze genome-wide association data for 42 human phenotypes or diseases and identify several hundred loci influencing multiple traits. They also find several traits with overlapping genetic architectures as well as pairs of traits showing evidence of a causal relationship. See also: News and Views by Visscher & Yang Risk of psychiatric illness from advanced paternal age is not predominantly from de novo mutations   pp718 - 724 Jacob Gratten, Naomi R Wray, Wouter J Peyrot, John J McGrath, Peter M Visscher & Michael E Goddard doi:10.1038/ng.3577 Jacob Gratten and colleagues use population genetic models to assess the genetic relationship between paternal age and risk of psychiatric illness. These models suggest that age-related mutations are unlikely to explain much of the increased risk of psychiatric disorders in children of older fathers. Landscape of tumor-infiltrating T cell repertoire of human cancers   pp725 - 732 Bo Li, Taiwen Li, Jean-Christophe Pignon, Binbin Wang, Jinzeng Wang, Sachet A Shukla, Ruoxu Dou, Qianming Chen, F Stephen Hodi, Toni K Choueiri, Catherine Wu, Nir Hacohen, Sabina Signoretti, Jun S Liu & X Shirley Liu doi:10.1038/ng.3581 Shirley Liu, Jun Liu and colleagues present a computational method to infer the CDR3 sequences of tumor-infiltrating T cells from RNA-seq data. They apply the method to 9,142 samples across 29 cancer types and show that it can be used to simultaneously identify immunogenic neoantigens and tumor-reactive T cell clonotypes. Articles Top Identification of TMEM230 mutations in familial Parkinson's disease   pp733 - 739 Han-Xiang Deng, Yong Shi, Yi Yang, Kreshnik B Ahmeti, Nimrod Miller, Cao Huang, Lijun Cheng, Hong Zhai, Sheng Deng, Karen Nuytemans, Nicola J Corbett, Myung Jong Kim, Hao Deng, Beisha Tang, Ziquang Yang, Yanming Xu, Piu Chan, Bo Huang, Xiao-Ping Gao, Zhi Song, Zhenhua Liu, Faisal Fecto, Nailah Siddique, Tatiana Foroud, Joseph Jankovic, Bernardino Ghetti, Daniel A Nicholson, Dimitri Krainc, Onur Melen, Jeffery M Vance, Margaret A Pericak-Vance, Yong-Chao Ma, Ali H Rajput & Teepu Siddique doi:10.1038/ng.3589 Han-Xiang Deng and colleagues identify TMEM230 mutations in Lewy body-confirmed Parkinson's disease. They also show evidence that disease-associated TMEM230 mutants impair synaptic vesicle trafficking in neurons. Deep sequencing of the MHC region in the Chinese population contributes to studies of complex disease   pp740 - 746 Fusheng Zhou, Hongzhi Cao, Xianbo Zuo, Tao Zhang, Xiaoguang Zhang, Xiaomin Liu, Ricong Xu, Gang Chen, Yuanwei Zhang, Xiaodong Zheng, Xin Jin, Jinping Gao, Junpu Mei, Yujun Sheng, Qibin Li, Bo Liang, Juan Shen, Changbing Shen, Hui Jiang, Caihong Zhu, Xing Fan, Fengping Xu, Min Yue, Xianyong Yin, Chen Ye, Cuicui Zhang, Xiao Liu, Liang Yu, Jinghua Wu, Mengyun Chen, Xuehan Zhuang, Lili Tang, Haojing Shao, Longmao Wu, Jian Li, Yu Xu, Yijie Zhang, Suli Zhao, Yu Wang, Ge Li, Hanshi Xu, Lei Zeng, Jianan Wang, Mingzhou Bai, Yanling Chen, Wei Chen, Tian Kang, Yanyan Wu, Xun Xu, Zhengwei Zhu, Yong Cui, Zaixing Wang, Chunjun Yang, Peiguang Wang, Leihong Xiang, Xiang Chen, Anping Zhang, Xinghua Gao, Furen Zhang, Jinhua Xu, Min Zheng, Jie Zheng, Jianzhong Zhang, Xueqing Yu, Yingrui Li, Sen Yang, Huanming Yang, Jian Wang, Jianjun Liu, Lennart Hammarström, Liangdan Sun, Jun Wang & Xuejun Zhang doi:10.1038/ng.3576 Xuejun Zhang, Jun Wang, Liangdan Sun, Lennart Hammarström and colleagues sequence the MHC region in 20,635 Han Chinese individuals. Their Han-MHC database allows identification of new susceptibility loci for psoriasis and could serve as a tool for investigating the role of the MHC region in other complex diseases. Pancreatic cancer risk variant in LINC00673 creates a miR-1231 binding site and interferes with PTPN11 degradation   pp747 - 757 Jian Zheng, Xudong Huang, Wen Tan, Dianke Yu, Zhongli Du, Jiang Chang, Lixuan Wei, Yaling Han, Chengfeng Wang, Xu Che, Yifeng Zhou, Xiaoping Miao, Guoliang Jiang, Xianjun Yu, Xianghong Yang, Guangwen Cao, Chaohui Zuo, Zhaoshen Li, Chunyou Wang, Siu Tim Cheung, Yongfeng Jia, Xiongwei Zheng, Hongbing Shen, Chen Wu & Dongxin Lin doi:10.1038/ng.3568 Dongxin Lin, Chen Wu and colleagues identify a LINC00673 variant that associates with pancreatic cancer risk in Han Chinese cohorts. They show that the variant creates a target site for miR-1231 and that LINC00673 regulates PTPN11 degradation and leads to altered SRC-ERK and STAT1-dependent signaling. Divergent modes of clonal spread and intraperitoneal mixing in high-grade serous ovarian cancer   pp758 - 767 Andrew McPherson, Andrew Roth, Emma Laks, Tehmina Masud, Ali Bashashati, Allen W Zhang, Gavin Ha, Justina Biele, Damian Yap, Adrian Wan, Leah M Prentice, Jaswinder Khattra, Maia A Smith, Cydney B Nielsen, Sarah C Mullaly, Steve Kalloger, Anthony Karnezis, Karey Shumansky, Celia Siu, Jamie Rosner, Hector Li Chan, Julie Ho, Nataliya Melnyk, Janine Senz, Winnie Yang, Richard Moore, Andrew J Mungall, Marco A Marra, Alexandre Bouchard-Côté, C Blake Gilks, David G Huntsman, Jessica N McAlpine, Samuel Aparicio & Sohrab P Shah doi:10.1038/ng.3573 Sohrab Shah, Samuel Aparicio and colleagues analyze whole genomes and single cells from ovarian cancers in the peritoneal cavity to establish patterns of disease spread. They determine the clonal relationships between multiple tumor sites and characterize the migratory potential of genomically diverse clones. Clonal evolution of glioblastoma under therapy   pp768 - 776 Jiguang Wang, Emanuela Cazzato, Erik Ladewig, Veronique Frattini, Daniel I S Rosenbloom, Sakellarios Zairis, Francesco Abate, Zhaoqi Liu, Oliver Elliott, Yong-Jae Shin, Jin-Ku Lee, In-Hee Lee, Woong-Yang Park, Marica Eoli, Andrew J Blumberg, Anna Lasorella, Do-Hyun Nam, Gaetano Finocchiaro, Antonio Iavarone & Raul Rabadan doi:10.1038/ng.3590 Raul Rabadan, Antonio Iavarone, Gaetano Finocchiaro, Do-Hyun Nam and colleagues analyze longitudinal genomic and transcriptomic data from 114 patients with glioblastoma. They find that relapse-associated clones typically exist before diagnosis, that expression subtypes are not stable under therapy and that recurrence tumors harbor specific alterations in several genes, including LTBP4 and MGMT. NANS-mediated synthesis of sialic acid is required for brain and skeletal development   pp777 - 784 Clara D M van Karnebeek, Luisa Bonafé, Xiao-Yan Wen, Maja Tarailo-Graovac, Sara Balzano, Beryl Royer-Bertrand, Angel Ashikov, Livia Garavelli, Isabella Mammi, Licia Turolla, Catherine Breen, Dian Donnai, Valerie Cormier, Delphine Heron, Gen Nishimura, Shinichi Uchikawa, Belinda Campos-Xavier, Antonio Rossi, Thierry Hennet, Koroboshka Brand-Arzamendi, Jacob Rozmus, Keith Harshman, Brian J Stevenson, Enrico Girardi, Giulio Superti-Furga, Tammie Dewan, Alissa Collingridge, Jessie Halparin, Colin J Ross, Margot I Van Allen, Andrea Rossi, Udo F Engelke, Leo A J Kluijtmans, Ed van der Heeft, Herma Renkema, Arjan de Brouwer, Karin Huijben, Fokje Zijlstra, Thorben Heisse, Thomas Boltje, Wyeth W Wasserman, Carlo Rivolta, Sheila Unger, Dirk J Lefeber, Ron A Wevers & Andrea Superti-Furga doi:10.1038/ng.3578 Andrea Superti-Furga, Ron Wevers, Clara van Karnebeek, Luisa Bonafé and colleagues identify mutations in NANS, which encodes the sialic acid synthase, in nine individuals with severe infantile-onset developmental delay and skeletal dysplasia. They describe abnormal metabolites accumulating because of deficient NANS enzyme activity and show that impaired sialic acid synthesis in zebrafish perturbs skeletal development, which can partially be rescued by supplementation with exogenous sialic acid. See also: News and Views by Freeze Signaling from maize organ primordia via FASCIATED EAR3 regulates stem cell proliferation and yield traits   pp785 - 791 Byoung Il Je, Jeremy Gruel, Young Koung Lee, Peter Bommert, Edgar Demesa Arevalo, Andrea L Eveland, Qingyu Wu, Alexander Goldshmidt, Robert Meeley, Madelaine Bartlett, Mai Komatsu, Hajime Sakai, Henrik Jönsson & David Jackson doi:10.1038/ng.3567 David Jackson and colleagues identify FEA3, encoding an LRR-receptor-like protein in maize, which responds to signals from organ primordia to the stem cell niche to regulate stem cell proliferation, a function that is conserved in Arabidopsis. They find that weak alleles of fea3 enhance hybrid maize yield traits. See also: News and Views by Strable & Scanlon Letters Top SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7   pp792 - 797 Satoshi Narumi, Naoko Amano, Tomohiro Ishii, Noriyuki Katsumata, Koji Muroya, Masanori Adachi, Katsuaki Toyoshima, Yukichi Tanaka, Ryuji Fukuzawa, Kenichi Miyako, Saori Kinjo, Shouichi Ohga, Kenji Ihara, Hirosuke Inoue, Tadamune Kinjo, Toshiro Hara, Miyuki Kohno, Shiro Yamada, Hironaka Urano, Yosuke Kitagawa, Koji Tsugawa, Asumi Higa, Masakazu Miyawaki, Takahiro Okutani, Zenro Kizaki, Hiroyuki Hamada, Minako Kihara, Kentaro Shiga, Tetsuya Yamaguchi, Manabu Kenmochi, Hiroyuki Kitajima, Maki Fukami, Atsushi Shimizu, Jun Kudoh, Shinsuke Shibata, Hideyuki Okano, Noriko Miyake, Naomichi Matsumoto & Tomonobu Hasegawa doi:10.1038/ng.3569 Satoshi Narumi, Tomonobu Hasegawa and colleagues describe a new adrenal hypoplasia syndrome termed MIRAGE that is caused by mutations in the endosome fusion facilitator SAMD9. They find that patients with these mutations have severe growth restriction phenotypes, and they observe adaptation by aneuploidy, where there is accompanying protective loss of mutation-carrying chromosome 7. Selfish drive can trump function when animal mitochondrial genomes compete   pp798 - 802 Hansong Ma & Patrick H O'Farrell doi:10.1038/ng.3587 Patrick H O'Farrell and Hansong Ma simultaneously introduce mitochondrial genomes from distantly related strains or other species into Drosophila melanogaster, rate fly fitness and follow mitochondrial DNA transmission. They find evidence for selfish selection, where genomes with compromised function outcompete fully competent ones, and identify mitochondrial sequences responsible for the selfish behavior. Technical Reports Top A method to decipher pleiotropy by detecting underlying heterogeneity driven by hidden subgroups applied to autoimmune and neuropsychiatric diseases   pp803 - 810 Buhm Han, Jennie G Pouget, Kamil Slowikowski, Eli Stahl, Cue Hyunkyu Lee, Dorothee Diogo, Xinli Hu, Yu Rang Park, Eunji Kim, Peter K Gregersen, Solbritt Rantapää Dahlqvist, Jane Worthington, Javier Martin, Steve Eyre, Lars Klareskog, Tom Huizinga, Wei-Min Chen, Suna Onengut-Gumuscu, Stephen S Rich, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Naomi R Wray & Soumya Raychaudhuri doi:10.1038/ng.3572 Soumya Raychaudhuri, Buhm Han and colleagues present a statistical method to distinguish whether shared genetic risk variants among complex traits are driven by whole-group pleiotropy or a subset of individuals who constitute a genetically heterogeneous subgroup. They use the method to examine genetic sharing among autoimmune diseases and between major depressive disorder and schizophrenia and find that most genetic sharing cannot be explained by subgroup heterogeneity but that, in contrast, seronegative rheumatoid arthritis is a heterogeneous condition. Fast and accurate long-range phasing in a UK Biobank cohort   pp811 - 816 Po-Ru Loh, Pier Francesco Palamara & Alkes L Price doi:10.1038/ng.3571 Po-Ru Loh, Pier Francesco Palamara and Alkes Price develop a new long-range phasing method, Eagle, that harnesses long, shared identical-by-descent tracts and can be applied to large outbred populations. They use Eagle to phase samples from the UK Biobank and find that it is faster and has better accuracy than existing methods. See also: Technical Report by O'Connell et al. Haplotype estimation for biobank-scale data sets   pp817 - 820 Jared O'Connell, Kevin Sharp, Nick Shrine, Louise Wain, Ian Hall, Martin Tobin, Jean-Francois Zagury, Olivier Delaneau & Jonathan Marchini doi:10.1038/ng.3583 Jonathan Marchini and colleagues develop a new method for haplotype phasing, SHAPEIT3, capable of handling large data sets from biobanks containing >100,000 genotyped samples. They find that their method is fast and accurate, with a low switch error rate, and can be scaled to data sets from increasingly larger cohorts. See also: Technical Report by Loh et al. Top Advertisement npj Molecular Phenomics is a new open access journal that is now open for submissions. The journal encourages studies that integrate diverse phenotyping approaches to understand the molecular aspects of phenomes.  Sign up for e-alerts   Natureevents is a fully searchable, multi-disciplinary database designed to maximise exposure for events organisers. 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