Volume 49 Issue 10, 1 October 2017

Letter

  • Letter |

    Martin Zenker, Corinne Antignac, Friedhelm Hildebrandt and colleagues report that mutations in OSGEP, TP53RK, TPRKB and LAGE3, genes encoding KEOPS-complex subunits, cause Galloway–Mowat syndrome, a recessive disease characterized by early-onset steroid-resistant nephrotic syndrome and microcephaly. Functional studies suggest that the phenotypes result from impaired protein translation, thus leading to endoplasmic reticulum stress and apoptosis.

    • Daniela A Braun
    • , Jia Rao
    • , Geraldine Mollet
    • , David Schapiro
    • , Marie-Claire Daugeron
    • , Weizhen Tan
    • , Olivier Gribouval
    • , Olivia Boyer
    • , Patrick Revy
    • , Tilman Jobst-Schwan
    • , Johanna Magdalena Schmidt
    • , Jennifer A Lawson
    • , Denny Schanze
    • , Shazia Ashraf
    • , Jeremy F P Ullmann
    • , Charlotte A Hoogstraten
    • , Nathalie Boddaert
    • , Bruno Collinet
    • , Gaëlle Martin
    • , Dominique Liger
    • , Svjetlana Lovric
    • , Monica Furlano
    • , I Chiara Guerrera
    • , Oraly Sanchez-Ferras
    • , Jennifer F Hu
    • , Anne-Claire Boschat
    • , Sylvia Sanquer
    • , Björn Menten
    • , Sarah Vergult
    • , Nina De Rocker
    • , Merlin Airik
    • , Tobias Hermle
    • , Shirlee Shril
    • , Eugen Widmeier
    • , Heon Yung Gee
    • , Won-Il Choi
    • , Carolin E Sadowski
    • , Werner L Pabst
    • , Jillian K Warejko
    • , Ankana Daga
    • , Tamara Basta
    • , Verena Matejas
    • , Karin Scharmann
    • , Sandra D Kienast
    • , Babak Behnam
    • , Brendan Beeson
    • , Amber Begtrup
    • , Malcolm Bruce
    • , Gaik-Siew Ch'ng
    • , Shuan-Pei Lin
    • , Jui-Hsing Chang
    • , Chao-Huei Chen
    • , Megan T Cho
    • , Patrick M Gaffney
    • , Patrick E Gipson
    • , Chyong-Hsin Hsu
    • , Jameela A Kari
    • , Yu-Yuan Ke
    • , Cathy Kiraly-Borri
    • , Wai-ming Lai
    • , Emmanuelle Lemyre
    • , Rebecca Okashah Littlejohn
    • , Amira Masri
    • , Mastaneh Moghtaderi
    • , Kazuyuki Nakamura
    • , Fatih Ozaltin
    • , Marleen Praet
    • , Chitra Prasad
    • , Agnieszka Prytula
    • , Elizabeth R Roeder
    • , Patrick Rump
    • , Rhonda E Schnur
    • , Takashi Shiihara
    • , Manish D Sinha
    • , Neveen A Soliman
    • , Kenza Soulami
    • , David A Sweetser
    • , Wen-Hui Tsai
    • , Jeng-Daw Tsai
    • , Rezan Topaloglu
    • , Udo Vester
    • , David H Viskochil
    • , Nithiwat Vatanavicharn
    • , Jessica L Waxler
    • , Klaas J Wierenga
    • , Matthias T F Wolf
    • , Sik-Nin Wong
    • , Sebastian A Leidel
    • , Gessica Truglio
    • , Peter C Dedon
    • , Annapurna Poduri
    • , Shrikant Mane
    • , Richard P Lifton
    • , Maxime Bouchard
    • , Peter Kannu
    • , David Chitayat
    • , Daniella Magen
    • , Bert Callewaert
    • , Herman van Tilbeurgh
    • , Martin Zenker
    • , Corinne Antignac
    •  & Friedhelm Hildebrandt
  • Letter |

    Adam Rubin, Brook Barajas, Mayra Furlan-Magaril and colleagues studied dynamic chromatin across the genome of differentiating human skin keratinocytes, identifying both stable and reorganizing classes of transcriptional enhancers.

    • Adam J Rubin
    • , Brook C Barajas
    • , Mayra Furlan-Magaril
    • , Vanessa Lopez-Pajares
    • , Maxwell R Mumbach
    • , Imani Howard
    • , Daniel S Kim
    • , Lisa D Boxer
    • , Jonathan Cairns
    • , Mikhail Spivakov
    • , Steven W Wingett
    • , Minyi Shi
    • , Zhixin Zhao
    • , William J Greenleaf
    • , Anshul Kundaje
    • , Michael Snyder
    • , Howard Y Chang
    • , Peter Fraser
    •  & Paul A Khavari

    Collection:

  • Letter |

    Greg Gibson and colleagues integrate summary-level GWAS and eQTL data with RNA-seq data from a cohort of pediatric Crohn's disease and report transcriptional risk scores that identify patients who will progress to complicated disease. Their dissection of eQTL effects may be used to distinguish genes whose association with disease is through promotion or protection.

    • Urko M Marigorta
    • , Lee A Denson
    • , Jeffrey S Hyams
    • , Kajari Mondal
    • , Jarod Prince
    • , Thomas D Walters
    • , Anne Griffiths
    • , Joshua D Noe
    • , Wallace V Crandall
    • , Joel R Rosh
    • , David R Mack
    • , Richard Kellermayer
    • , Melvin B Heyman
    • , Susan S Baker
    • , Michael C Stephens
    • , Robert N Baldassano
    • , James F Markowitz
    • , Mi-Ok Kim
    • , Marla C Dubinsky
    • , Judy Cho
    • , Bruce J Aronow
    • , Subra Kugathasan
    •  & Greg Gibson
  • Letter |

    Doris Wagner and colleagues define Polycomb response elements (PREs) that direct the placement of Polycomb repressive complex 2 (PRC2) at developmental genes in Arabidopsis. They identify transcription factor families that bind to PREs, physically interact with and recruit PRC2, and are required for gene silencing in vivo.

    • Jun Xiao
    • , Run Jin
    • , Xiang Yu
    • , Max Shen
    • , John D Wagner
    • , Armaan Pai
    • , Claire Song
    • , Michael Zhuang
    • , Samantha Klasfeld
    • , Chongsheng He
    • , Alexandre M Santos
    • , Chris Helliwell
    • , Jose L Pruneda-Paz
    • , Steve A Kay
    • , Xiaowei Lin
    • , Sujuan Cui
    • , Meilin Fernandez Garcia
    • , Oliver Clarenz
    • , Justin Goodrich
    • , Xiaoyu Zhang
    • , Ryan S Austin
    • , Roberto Bonasio
    •  & Doris Wagner
  • Letter |

    Frank Uhlmann and colleagues use chromosome conformation capture (Hi-C) to study mitotic chromosome condensation in the fission yeast Schizosaccharomyces pombe, reporting that small chromatin domains in interphase are replaced by fewer and larger domains in mitosis. They show that condensin sets up longer-range DNA interactions that compact and individualize chromosomes while also restraining local chromatin contacts.

    • Yasutaka Kakui
    • , Adam Rabinowitz
    • , David J Barry
    •  & Frank Uhlmann
  • Letter |

    Stefan Mundlos, Darío Lupiáñez and colleagues investigate CNVs involving the regulatory landscape of IHH (Indian hedgehog), which cause craniosynostosis and synpolydactyly. Using genetic manipulation in mice, they show that Ihh is regulated by at least nine enhancers with individual tissue specificities and that duplications in this region can cause dose-dependent upregulation and also misexpression of Ihh.

    • Anja J Will
    • , Giulia Cova
    • , Marco Osterwalder
    • , Wing-Lee Chan
    • , Lars Wittler
    • , Norbert Brieske
    • , Verena Heinrich
    • , Jean-Pierre de Villartay
    • , Martin Vingron
    • , Eva Klopocki
    • , Axel Visel
    • , Darío G Lupiáñez
    •  & Stefan Mundlos
  • Letter |

    Robert Graham and colleagues carried out a GWAS meta-analysis for Parkinson's disease (PD) and report 17 new risk loci. Their analyses support a key role for autophagy and lysosomal biology in PD risk.

    • Diana Chang
    • , Mike A Nalls
    • , Ingileif B Hallgrímsdóttir
    • , Julie Hunkapiller
    • , Marcel van der Brug
    • , Fang Cai
    • , International Parkinson's Disease Genomics Consortium
    • , 23andMe Research Team
    • , Geoffrey A Kerchner
    • , Gai Ayalon
    • , Baris Bingol
    • , Morgan Sheng
    • , David Hinds
    • , Timothy W Behrens
    • , Andrew B Singleton
    • , Tushar R Bhangale
    •  & Robert R Graham

Article

  • Article |

    Paz Polak, Jaegil Kim, Lior Z. Braunstein and colleagues have identified patterns of genome-wide mutation in certain breast cancers that can be used to identify those with DNA-repair deficiencies that make the tumor more likely to respond to therapies based on PARP inhibitors or platinum. In contrast, oncogenic mutations in several other DNA-repair genes do not generate these patterns.

    • Paz Polak
    • , Jaegil Kim
    • , Lior Z Braunstein
    • , Rosa Karlic
    • , Nicholas J Haradhavala
    • , Grace Tiao
    • , Daniel Rosebrock
    • , Dimitri Livitz
    • , Kirsten Kübler
    • , Kent W Mouw
    • , Atanas Kamburov
    • , Yosef E Maruvka
    • , Ignaty Leshchiner
    • , Eric S Lander
    • , Todd R Golub
    • , Aviad Zick
    • , Alexandre Orthwein
    • , Michael S Lawrence
    • , Rajbir N Batra
    • , Carlos Caldas
    • , Daniel A Haber
    • , Peter W Laird
    • , Hui Shen
    • , Leif W Ellisen
    • , Alan D D'Andrea
    • , Stephen J Chanock
    • , William D Foulkes
    •  & Gad Getz
  • Article |

    Elizabeth Perlman and colleagues use genome-wide sequencing, RNA expression, DNA copy number and methylation analyses to characterize the genomic landscape of Wilms tumors. Their integrated analyses implicate two major classes of genetic changes in Wilms tumors that preserve the progenitor state and/or interrupt normal kidney development.

    • Samantha Gadd
    • , Vicki Huff
    • , Amy L Walz
    • , Ariadne H A G Ooms
    • , Amy E Armstrong
    • , Daniela S Gerhard
    • , Malcolm A Smith
    • , Jaime M Guidry Auvil
    • , Daoud Meerzaman
    • , Qing-Rong Chen
    • , Chih Hao Hsu
    • , Chunhua Yan
    • , Cu Nguyen
    • , Ying Hu
    • , Leandro C Hermida
    • , Tanja Davidsen
    • , Patee Gesuwan
    • , Yussanne Ma
    • , Zusheng Zong
    • , Andrew J Mungall
    • , Richard A Moore
    • , Marco A Marra
    • , Jeffrey S Dome
    • , Charles G Mullighan
    • , Jing Ma
    • , David A Wheeler
    • , Oliver A Hampton
    • , Nicole Ross
    • , Julie M Gastier-Foster
    • , Stefan T Arold
    •  & Elizabeth J Perlman
  • Article |

    Danish Saleheen, Benjamin Voight and colleagues perform genome-wide analysis of multi-ancestry cohorts to identify genetic associations with type 2 diabetes (T2D) and coronary heart disease (CHD). They find novel loci and show that 24% of T2D loci are also associated with CHD and that greater genetic risk of T2D increases risk of CHD.

    • Wei Zhao
    • , Asif Rasheed
    • , Emmi Tikkanen
    • , Jung-Jin Lee
    • , Adam S Butterworth
    • , Joanna M M Howson
    • , Themistocles L Assimes
    • , Rajiv Chowdhury
    • , Marju Orho-Melander
    • , Scott Damrauer
    • , Aeron Small
    • , Senay Asma
    • , Minako Imamura
    • , Toshimasa Yamauch
    • , John C Chambers
    • , Peng Chen
    • , Bishwa R Sapkota
    • , Nabi Shah
    • , Sehrish Jabeen
    • , Praveen Surendran
    • , Yingchang Lu
    • , Weihua Zhang
    • , Atif Imran
    • , Shahid Abbas
    • , Faisal Majeed
    • , Kevin Trindade
    • , Nadeem Qamar
    • , Nadeem Hayyat Mallick
    • , Zia Yaqoob
    • , Tahir Saghir
    • , Syed Nadeem Hasan Rizvi
    • , Anis Memon
    • , Syed Zahed Rasheed
    • , Fazal-ur-Rehman Memon
    • , Khalid Mehmood
    • , Naveeduddin Ahmed
    • , Irshad Hussain Qureshi
    • , Tanveer-us-Salam
    • , Wasim Iqbal
    • , Uzma Malik
    • , Narinder Mehra
    • , Jane Z Kuo
    • , Wayne H-H Sheu
    • , Xiuqing Guo
    • , Chao A Hsiung
    • , Jyh-Ming J Juang
    • , Kent D Taylor
    • , Yi-Jen Hung
    • , Wen-Jane Lee
    • , Thomas Quertermous
    • , I-Te Lee
    • , Chih-Cheng Hsu
    • , Erwin P Bottinger
    • , Sarju Ralhan
    • , Yik Ying Teo
    • , Tzung-Dau Wang
    • , Dewan S Alam
    • , Emanuele Di Angelantonio
    • , Steve Epstein
    • , Sune F Nielsen
    • , Børge G Nordestgaard
    • , Anne Tybjaerg-Hansen
    • , Robin Young
    • , CHD Exome+ Consortium
    • , Marianne Benn
    • , Ruth Frikke-Schmidt
    • , Pia R Kamstrup
    • , EPIC-CVD Consortium
    • , EPIC-Interact Consortium
    • , Michigan Biobank
    • , J Wouter Jukema
    • , Naveed Sattar
    • , Roelof Smit
    • , Ren-Hua Chung
    • , Kae-Woei Liang
    • , Sonia Anand
    • , Dharambir K Sanghera
    • , Samuli Ripatti
    • , Ruth J F Loos
    • , Jaspal S Kooner
    • , E Shyong Tai
    • , Jerome I Rotter
    • , Yii-Der Ida Chen
    • , Philippe Frossard
    • , Shiro Maeda
    • , Takashi Kadowaki
    • , Muredach Reilly
    • , Guillaume Pare
    • , Olle Melander
    • , Veikko Salomaa
    • , Daniel J Rader
    • , John Danesh
    • , Benjamin F Voight
    •  & Danish Saleheen
  • Article |

    Maria-Elena Torres-Padilla and colleagues use a targeted epigenomic approach to investigate the role of LINE-1 retroelements during early mouse development. Their data suggest that timely activation of LINE-1 regulates global chromatin accessibility and is integral to the mouse developmental program.

    • Joanna W Jachowicz
    • , Xinyang Bing
    • , Julien Pontabry
    • , Ana Bošković
    • , Oliver J Rando
    •  & Maria-Elena Torres-Padilla
  • Article |

    Eric Schadt and colleagues present a predictive causal model of the immune component of inflammatory bowel disease through integration of genetic, regulatory and transcriptional data. They prioritize and validate 12 of the top key drivers experimentally in mouse colitis models and human macrophages.

    • Lauren A Peters
    • , Jacqueline Perrigoue
    • , Arthur Mortha
    • , Alina Iuga
    • , Won-min Song
    • , Eric M Neiman
    • , Sean R Llewellyn
    • , Antonio Di Narzo
    • , Brian A Kidd
    • , Shannon E Telesco
    • , Yongzhong Zhao
    • , Aleksandar Stojmirovic
    • , Jocelyn Sendecki
    • , Khader Shameer
    • , Riccardo Miotto
    • , Bojan Losic
    • , Hardik Shah
    • , Eunjee Lee
    • , Minghui Wang
    • , Jeremiah J Faith
    • , Andrew Kasarskis
    • , Carrie Brodmerkel
    • , Mark Curran
    • , Anuk Das
    • , Joshua R Friedman
    • , Yoshinori Fukui
    • , Mary Beth Humphrey
    • , Brian M Iritani
    • , Nicholas Sibinga
    • , Teresa K Tarrant
    • , Carmen Argmann
    • , Ke Hao
    • , Panos Roussos
    • , Jun Zhu
    • , Bin Zhang
    • , Radu Dobrin
    • , Lloyd F Mayer
    •  & Eric E Schadt
  • Article |

    David Evans, Brent Richards and colleagues carried out a genome-wide association study in 142,487 individuals from the UK Biobank and identified 153 new loci associated with heel bone mineral density. They also conducted in vivo studies that implicated GPC6 and several other genes in osteoporosis.

    • John P Kemp
    • , John A Morris
    • , Carolina Medina-Gomez
    • , Vincenzo Forgetta
    • , Nicole M Warrington
    • , Scott E Youlten
    • , Jie Zheng
    • , Celia L Gregson
    • , Elin Grundberg
    • , Katerina Trajanoska
    • , John G Logan
    • , Andrea S Pollard
    • , Penny C Sparkes
    • , Elena J Ghirardello
    • , Rebecca Allen
    • , Victoria D Leitch
    • , Natalie C Butterfield
    • , Davide Komla-Ebri
    • , Anne-Tounsia Adoum
    • , Katharine F Curry
    • , Jacqueline K White
    • , Fiona Kussy
    • , Keelin M Greenlaw
    • , Changjiang Xu
    • , Nicholas C Harvey
    • , Cyrus Cooper
    • , David J Adams
    • , Celia M T Greenwood
    • , Matthew T Maurano
    • , Stephen Kaptoge
    • , Fernando Rivadeneira
    • , Jonathan H Tobias
    • , Peter I Croucher
    • , Cheryl L Ackert-Bicknell
    • , J H Duncan Bassett
    • , Graham R Williams
    • , J Brent Richards
    •  & David M Evans
  • Article |

    Yoichiro Kamatani and colleagues perform a genome-wide association study (GWAS) for body mass index using data from 173,430 Japanese individuals. They find 85 significant loci, 51 of which are novel, and use trans-ancestral meta-analysis of GWAS from European samples to identify 61 additional new loci.

    • Masato Akiyama
    • , Yukinori Okada
    • , Masahiro Kanai
    • , Atsushi Takahashi
    • , Yukihide Momozawa
    • , Masashi Ikeda
    • , Nakao Iwata
    • , Shiro Ikegawa
    • , Makoto Hirata
    • , Koichi Matsuda
    • , Motoki Iwasaki
    • , Taiki Yamaji
    • , Norie Sawada
    • , Tsuyoshi Hachiya
    • , Kozo Tanno
    • , Atsushi Shimizu
    • , Atsushi Hozawa
    • , Naoko Minegishi
    • , Shoichiro Tsugane
    • , Masayuki Yamamoto
    • , Michiaki Kubo
    •  & Yoichiro Kamatani
  • Article |

    Melissa Gymrek and colleagues estimate mutation parameters for each short tandem repeat (STR) in the human genome. They find that local sequence features impact these estimates and they create a framework for measuring constraint at STRs by comparing observed and expected mutation rates, providing a tool for prioritizing pathogenic variants.

    • Melissa Gymrek
    • , Thomas Willems
    • , David Reich
    •  & Yaniv Erlich

Analysis

  • Analysis |

    Kevin Yip and colleagues report a method for determining the target genes of enhancers in specific cells and tissues by combining global trends across many samples with sample-specific information, and considering the joint effect of multiple enhancers. They apply their method to reconstruct enhancer–target networks in 935 samples of human primary cells, tissues and cell lines.

    • Qin Cao
    • , Christine Anyansi
    • , Xihao Hu
    • , Liangliang Xu
    • , Lei Xiong
    • , Wenshu Tang
    • , Myth T S Mok
    • , Chao Cheng
    • , Xiaodan Fan
    • , Mark Gerstein
    • , Alfred S L Cheng
    •  & Kevin Y Yip
  • Analysis |

    Steven Gazal, Alkes Price and colleagues extend stratified LD score regression to continuous annotations. They analyze summary statistics from 56 complex diseases and traits and find that SNPs with low levels of linkage disequilibrium have larger per-SNP heritability, consistent with the action of negative selection on deleterious variants that affect complex traits.

    • Steven Gazal
    • , Hilary K Finucane
    • , Nicholas A Furlotte
    • , Po-Ru Loh
    • , Pier Francesco Palamara
    • , Xuanyao Liu
    • , Armin Schoech
    • , Brendan Bulik-Sullivan
    • , Benjamin M Neale
    • , Alexander Gusev
    •  & Alkes L Price

News & Views

  • News & Views |

    The functional role of repetitive elements in mammalian genomes is still largely unexplored. A new study provides evidence that LINE-1 retrotransposons regulate chromatin dynamics and are essential for normal embryonic development in mice.

    • Edward J Grow
  • News & Views |

    Regulation of epigenetic factors through their recruitment to specific genomic regions is still poorly understood. A recent study demonstrates a global mechanism of tethering Polycomb group (PcG) proteins through sequence-specific DNA-binding factors.

    • Eduardo March
    •  & Sara Farrona
  • News & Views |

    A new study uses a Hi-C technique to demonstrate that condensin has a major role in remodeling interphase chromatin into mitotic chromosomes. This study provides insight into the mechanism whereby a centimeters-long DNA molecule is folded into a micrometers-long rod-shaped chromosome.

    • Tatsuya Hirano

Editorial

  • Editorial |

    This issue highlights a range of genetic techniques and cell biological models required to begin to understand the levels of long-range regulation of gene expression as it occurs during cell differentiation. Explanations based on the specificity of covalent modifications and binding interactions intersect with evidence for conjectured mechanisms of topological loop creation and maintenance by transcription and motile protein activities.

Corrigendum

  • Corrigendum |

    • Helen R Warren
    • , Evangelos Evangelou
    • , Claudia P Cabrera
    • , He Gao
    • , Meixia Ren
    • , Borbala Mifsud
    • , Ioanna Ntalla
    • , Praveen Surendran
    • , Chunyu Liu
    • , James P Cook
    • , Aldi T Kraja
    • , Fotios Drenos
    • , Marie Loh
    • , Niek Verweij
    • , Jonathan Marten
    • , Ibrahim Karaman
    • , Marcelo P Segura Lepe
    • , Paul F O'Reilly
    • , Joanne Knight
    • , Harold Snieder
    • , Norihiro Kato
    • , Jiang He
    • , E Shyong Tai
    • , M Abdullah Said
    • , David Porteous
    • , Maris Alver
    • , Neil Poulter
    • , Martin Farrall
    • , Ron T Gansevoort
    • , Sandosh Padmanabhan
    • , Reedik Mägi
    • , Alice Stanton
    • , John Connell
    • , Stephan J L Bakker
    • , Andres Metspalu
    • , Denis C Shields
    • , Simon Thom
    • , Morris Brown
    • , Peter Sever
    • , Tõnu Esko
    • , Caroline Hayward
    • , Pim van der Harst
    • , Danish Saleheen
    • , Rajiv Chowdhury
    • , John C Chambers
    • , Daniel I Chasman
    • , Aravinda Chakravarti
    • , Christopher Newton-Cheh
    • , Cecilia M Lindgren
    • , Daniel Levy
    • , Jaspal S Kooner
    • , Bernard Keavney
    • , Maciej Tomaszewski
    • , Nilesh J Samani
    • , Joanna M M Howson
    • , Martin D Tobin
    • , Patricia B Munroe
    • , Georg B Ehret
    • , Louise V Wain
    • , The International Consortium of Blood Pressure (ICBP) 1000G Analyses, The CHD Exome+ Consortium, The ExomeBP Consortium, The T2D-GENES Consortium, The GoT2DGenes Consortium, The Cohorts for Heart and Ageing Research in Genome Epidemiology (CHARGE) BP Exome Consortium, The International Genomics of Blood Pressure (iGEN-BP) Consortium
    • , Michael R Barnes
    • , Ioanna Tzoulaki
    • , Mark J Caulfield
    • , Paul Elliott
    •  & for The UK Biobank CardioMetabolic Consortium BP working group

Erratum