Table of contents



Genome variation in precision medicine p701


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.



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



News and Views

Meristems take their cues from organ primordia pp704 - 705

Josh Strable & Michael J Scanlon


See also: Article by Je et al.

Perhaps a wee bit of sugar would help pp705 - 707

Hudson H Freeze


See also: Article by van Karnebeek et al.

A plethora of pleiotropy across complex traits pp707 - 708

Peter M Visscher & Jian Yang


See also: Analysis by Pickrell et al.



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


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


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


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.



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


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


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


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


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


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, Valérie Cormier-Daire, 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, Torben Heise, Thomas Boltje, Wyeth W Wasserman, Carlo Rivolta, Sheila Unger, Dirk J Lefeber, Ron A Wevers & Andrea Superti-Furga


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


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



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


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


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

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


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


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


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.