Volume 49 Issue 12, December 2017

Volume 49 Issue 12

GTExStyles by Erin Dewalt (CC-BY source images doi:10.1038/nature24277)

Editorial

  • Editorial |

    In the motivation, conduct and reporting of science, there is no substitute for reason, and it must prevail whenever scientific methods are used. Similarly, scientific recommendations can only be useful if they meet with rational decision-making. Because people come to decisions from diverse viewpoints and values, listening to the values and views of scientists and non-scientists—while explicitly refraining from debate and persuasion—may point the way to determining when and where scientific ideas are of interest and likely to be adopted.

Commentary

  • Commentary |

    Genetic variants have been associated with myriad molecular phenotypes that provide new insight into the range of mechanisms underlying genetic traits and diseases. Identifying any particular genetic variant's cascade of effects, from molecule to individual, requires assaying multiple layers of molecular complexity. We introduce the Enhancing GTEx (eGTEx) project that extends the GTEx project to combine gene expression with additional intermediate molecular measurements on the same tissues to provide a resource for studying how genetic differences cascade through molecular phenotypes to impact human health.

    • eGTEx Project
    • , Barbara E Stranger
    • , Lori E Brigham
    • , Richard Hasz
    • , Marcus Hunter
    • , Christopher Johns
    • , Mark Johnson
    • , Gene Kopen
    • , William F Leinweber
    • , John T Lonsdale
    • , Alisa McDonald
    • , Bernadette Mestichelli
    • , Kevin Myer
    • , Brian Roe
    • , Michael Salvatore
    • , Saboor Shad
    • , Jeffrey A Thomas
    • , Gary Walters
    • , Michael Washington
    • , Joseph Wheeler
    • , Jason Bridge
    • , Barbara A Foster
    • , Bryan M Gillard
    • , Ellen Karasik
    • , Rachna Kumar
    • , Mark Miklos
    • , Michael T Moser
    • , Scott D Jewell
    • , Robert G Montroy
    • , Daniel C Rohrer
    • , Dana R Valley
    • , David A Davis
    • , Deborah C Mash
    • , Sarah E Gould
    • , Ping Guan
    • , Susan Koester
    • , A Roger Little
    • , Casey Martin
    • , Helen M Moore
    • , Abhi Rao
    • , Jeffery P Struewing
    • , Simona Volpi
    • , Kasper D Hansen
    • , Peter F Hickey
    • , Lindsay F Rizzardi
    • , Lei Hou
    • , Yaping Liu
    • , Benoit Molinie
    • , Yongjin Park
    • , Nicola Rinaldi
    • , Li Wang
    • , Nicholas Van Wittenberghe
    • , Melina Claussnitzer
    • , Ellen T Gelfand
    • , Qin Li
    • , Sandra Linder
    • , Rui Zhang
    • , Kevin S Smith
    • , Emily K Tsang
    • , Lin S Chen
    • , Kathryn Demanelis
    • , Jennifer A Doherty
    • , Farzana Jasmine
    • , Muhammad G Kibriya
    • , Lihua Jiang
    • , Shin Lin
    • , Meng Wang
    • , Ruiqi Jian
    • , Xiao Li
    • , Joanne Chan
    • , Daniel Bates
    • , Morgan Diegel
    • , Jessica Halow
    • , Eric Haugen
    • , Audra Johnson
    • , Rajinder Kaul
    • , Kristen Lee
    • , Matthew T Maurano
    • , Jemma Nelson
    • , Fidencio J Neri
    • , Richard Sandstrom
    • , Marian S Fernando
    • , Caroline Linke
    • , Meritxell Oliva
    • , Andrew Skol
    • , Fan Wu
    • , Joshua M Akey
    • , Andrew P Feinberg
    • , Jin Billy Li
    • , Brandon L Pierce
    • , John A Stamatoyannopoulos
    • , Hua Tang
    • , Kristin G Ardlie
    • , Manolis Kellis
    • , Michael P Snyder
    •  & Stephen B Montgomery

News and Views

  • News & Views |

    A new study reports genome-wide variation in 163 vervet monkeys from across their taxonomic and geographic ranges. The analysis suggests a complex history of admixture and identifies signals of repeated evolutionary selection, some of which may be linked to response to simian immunodeficiency virus.

    • Ellen M Leffler
  • News & Views |

    A new analysis of cancer genomes identifies a decrease in the mutation burden of exons, but not introns, as compared to expectation. This difference can be explained by preferential recruitment of the DNA mismatch repair machinery to a protein modification that marks exons.

    • Dashiell J Massey
    •  & Amnon Koren
  • News & Views |

    The CRISPR–Cas9 system enables global screens of gene function with high sensitivity and specificity, but off-target effects have been reported for CRISPR guide RNAs targeting genes that are amplified at high copy number. A new study describes a computational approach to correct for this copy number effect, increasing the specificity of CRIPSR screens to identify essential genes.

    • John Paul Shen
    •  & Trey Ideker

Analysis

  • Analysis |

    This study presents a new approach to estimate the tissues contributing to the genetic causality for complex traits and diseases. The method assesses tissue sharing of eQTLs among 44 tissues and then uses these tissue-sharing estimates to infer the tissues where trait-associated variants likely exert their function.

    • Halit Ongen
    • , Andrew A Brown
    • , Olivier Delaneau
    • , Nikolaos I Panousis
    • , Alexandra C Nica
    • , GTEx Consortium
    •  & Emmanouil T Dermitzakis
  • Analysis |

    This analysis of cancer sequencing data identifies a reduced somatic mutation rate in exons and shows that this phenomenon is due to higher mismatch-repair activity in exons as compared to introns. These findings have implications for the understanding of mutational and DNA repair processes and for studying the evolution of both tumors and species.

    • Joan Frigola
    • , Radhakrishnan Sabarinathan
    • , Loris Mularoni
    • , Ferran Muiños
    • , Abel Gonzalez-Perez
    •  & Núria López-Bigas

Articles

  • Article |

    Analysis of a large cohort of EGFR-mutant lung cancer cell-free DNA samples along with longitudinal samples from a patient with EGFR-mutant lung cancer identifies pathways that inhibit EGFR-inhibitor response. Co-occurring genetic alterations influence clinical outcomes and underscore the need for combination therapies.

    • Collin M Blakely
    • , Thomas B K Watkins
    • , Wei Wu
    • , Beatrice Gini
    • , Jacob J Chabon
    • , Caroline E McCoach
    • , Nicholas McGranahan
    • , Gareth A Wilson
    • , Nicolai J Birkbak
    • , Victor R Olivas
    • , Julia Rotow
    • , Ashley Maynard
    • , Victoria Wang
    • , Matthew A Gubens
    • , Kimberly C Banks
    • , Richard B Lanman
    • , Aleah F Caulin
    • , John St John
    • , Anibal R Cordero
    • , Petros Giannikopoulos
    • , Andrew D Simmons
    • , Philip C Mack
    • , David R Gandara
    • , Hatim Husain
    • , Robert C Doebele
    • , Jonathan W Riess
    • , Maximilian Diehn
    • , Charles Swanton
    •  & Trever G Bivona
  • Article |

    Analysis of whole-genome sequencing data from 163 vervet monkeys from Africa and the Caribbean shows high diversity among taxa and identifies signatures of selection. Selection signals affect viral processes, and genes that show response to SIV in vervets but not macaques have elevated selection scores.

    • Hannes Svardal
    • , Anna J Jasinska
    • , Cristian Apetrei
    • , Giovanni Coppola
    • , Yu Huang
    • , Christopher A Schmitt
    • , Beatrice Jacquelin
    • , Vasily Ramensky
    • , Michaela Müller-Trutwin
    • , Martin Antonio
    • , George Weinstock
    • , J Paul Grobler
    • , Ken Dewar
    • , Richard K Wilson
    • , Trudy R Turner
    • , Wesley C Warren
    • , Nelson B Freimer
    •  & Magnus Nordborg
  • Article |

    Nelson Freimer and colleagues analyze gene expression data from multiple tissue samples combined with genotype data from vervet monkeys to catalog expression quantitative trait loci (eQTLs). They generate a transcriptome resource analogous to the GTEx project and perform comparative and eQTL enrichment analyses for various traits.

    • Anna J Jasinska
    • , Ivette Zelaya
    • , Susan K Service
    • , Christine B Peterson
    • , Rita M Cantor
    • , Oi-Wa Choi
    • , Joseph DeYoung
    • , Eleazar Eskin
    • , Lynn A Fairbanks
    • , Scott Fears
    • , Allison E Furterer
    • , Yu S Huang
    • , Vasily Ramensky
    • , Christopher A Schmitt
    • , Hannes Svardal
    • , Matthew J Jorgensen
    • , Jay R Kaplan
    • , Diego Villar
    • , Bronwen L Aken
    • , Paul Flicek
    • , Rishi Nag
    • , Emily S Wong
    • , John Blangero
    • , Thomas D Dyer
    • , Marina Bogomolov
    • , Yoav Benjamini
    • , George M Weinstock
    • , Ken Dewar
    • , Chiara Sabatti
    • , Richard K Wilson
    • , J David Jentsch
    • , Wesley Warren
    • , Giovanni Coppola
    • , Roger P Woods
    •  & Nelson B Freimer
  • Article |

    A meta-analysis of exome-wide association studies for blood lipid levels in East Asian populations identifies a novel coding variant. Exome array data from the Global Lipids Genetics Consortium were integrated and led to the discovery of novel and population-specific variants associated with cholesterol and triglycerides.

    • Xiangfeng Lu
    • , Gina M Peloso
    • , Dajiang J Liu
    • , Ying Wu
    • , He Zhang
    • , Wei Zhou
    • , Jun Li
    • , Clara Sze-man Tang
    • , Rajkumar Dorajoo
    • , Huaixing Li
    • , Jirong Long
    • , Xiuqing Guo
    • , Ming Xu
    • , Cassandra N Spracklen
    • , Yang Chen
    • , Xuezhen Liu
    • , Yan Zhang
    • , Chiea Chuen Khor
    • , Jianjun Liu
    • , Liang Sun
    • , Laiyuan Wang
    • , Yu-Tang Gao
    • , Yao Hu
    • , Kuai Yu
    • , Yiqin Wang
    • , Chloe Yu Yan Cheung
    • , Feijie Wang
    • , Jianfeng Huang
    • , Qiao Fan
    • , Qiuyin Cai
    • , Shufeng Chen
    • , Jinxiu Shi
    • , Xueli Yang
    • , Wanting Zhao
    • , Wayne H-H Sheu
    • , Stacey Shawn Cherny
    • , Meian He
    • , Alan B Feranil
    • , Linda S Adair
    • , Penny Gordon-Larsen
    • , Shufa Du
    • , Rohit Varma
    • , Yii-Der Ida Chen
    • , Xiao-Ou Shu
    • , Karen Siu Ling Lam
    • , Tien Yin Wong
    • , Santhi K Ganesh
    • , Zengnan Mo
    • , Kristian Hveem
    • , Lars G Fritsche
    • , Jonas Bille Nielsen
    • , Hung-fat Tse
    • , Yong Huo
    • , Ching-Yu Cheng
    • , Y Eugene Chen
    • , Wei Zheng
    • , E Shyong Tai
    • , Wei Gao
    • , Xu Lin
    • , Wei Huang
    • , Goncalo Abecasis
    • , GLGC Consortium
    • , Sekar Kathiresan
    • , Karen L Mohlke
    • , Tangchun Wu
    • , Pak Chung Sham
    • , Dongfeng Gu
    •  & Cristen J Willer
  • Article |

    RNA Capture Long Seq (CLS) is a new method for transcript annotation that combines targeted RNA capture with long-read sequencing. CLS reannotates GENCODE lncRNAs and increases the number of validated splice junctions and transcript models for targeted loci.

    • Julien Lagarde
    • , Barbara Uszczynska-Ratajczak
    • , Silvia Carbonell
    • , Sílvia Pérez-Lluch
    • , Amaya Abad
    • , Carrie Davis
    • , Thomas R Gingeras
    • , Adam Frankish
    • , Jennifer Harrow
    • , Roderic Guigo
    •  & Rory Johnson
  • Article |

    Analysis of a large bread-wheat genomic data set through a quantitative genetic framework designed to study the genetic basis of heterosis shows that hybrids outperform midparents in grain yield by 10%. Genome-wide prediction and association mapping indicate that epistasis plays a significant role in heterosis of grain yield in wheat.

    • Yong Jiang
    • , Renate H Schmidt
    • , Yusheng Zhao
    •  & Jochen C Reif

Letters

  • Letter |

    CaVEMaN is a new method that uses whole-genome sequencing and RNA-sequencing data to implicate likely causal variants affecting gene expression. The set of high-confidence causal variants found in multiple tissues is enriched for variants associated with complex traits.

    • Andrew Anand Brown
    • , Ana Viñuela
    • , Olivier Delaneau
    • , Tim D Spector
    • , Kerrin S Small
    •  & Emmanouil T Dermitzakis
  • Letter |

    This large-scale genome-wide association analysis of subjects with asthma, hay fever or eczema provides insights into the shared genetic basis of these allergic diseases. The findings suggest that these diseases partly co-occur because they share many genetic risk variants that dysregulate the expression of immune-related genes.

    • Manuel A Ferreira
    • , Judith M Vonk
    • , Hansjörg Baurecht
    • , Ingo Marenholz
    • , Chao Tian
    • , Joshua D Hoffman
    • , Quinta Helmer
    • , Annika Tillander
    • , Vilhelmina Ullemar
    • , Jenny van Dongen
    • , Yi Lu
    • , Franz Rüschendorf
    • , Jorge Esparza-Gordillo
    • , Chris W Medway
    • , Edward Mountjoy
    • , Kimberley Burrows
    • , Oliver Hummel
    • , Sarah Grosche
    • , Ben M Brumpton
    • , John S Witte
    • , Jouke-Jan Hottenga
    • , Gonneke Willemsen
    • , Jie Zheng
    • , Elke Rodríguez
    • , Melanie Hotze
    • , Andre Franke
    • , Joana A Revez
    • , Jonathan Beesley
    • , Melanie C Matheson
    • , Shyamali C Dharmage
    • , Lisa M Bain
    • , Lars G Fritsche
    • , Maiken E Gabrielsen
    • , Brunilda Balliu
    • , 23andMe Research Team
    • , AAGC collaborators
    • , BIOS consortium
    • , LifeLines Cohort Study
    • , Jonas B Nielsen
    • , Wei Zhou
    • , Kristian Hveem
    • , Arnulf Langhammer
    • , Oddgeir L Holmen
    • , Mari Løset
    • , Gonçalo R Abecasis
    • , Cristen J Willer
    • , Andreas Arnold
    • , Georg Homuth
    • , Carsten O Schmidt
    • , Philip J Thompson
    • , Nicholas G Martin
    • , David L Duffy
    • , Natalija Novak
    • , Holger Schulz
    • , Stefan Karrasch
    • , Christian Gieger
    • , Konstantin Strauch
    • , Ronald B Melles
    • , David A Hinds
    • , Norbert Hübner
    • , Stephan Weidinger
    • , Patrik K E Magnusson
    • , Rick Jansen
    • , Eric Jorgenson
    • , Young-Ae Lee
    • , Dorret I Boomsma
    • , Catarina Almqvist
    • , Robert Karlsson
    • , Gerard H Koppelman
    •  & Lavinia Paternoster
  • Letter |

    Exome-wide genetic analysis on >300,000 individuals identifies associations with plasma lipid traits. Loci significantly associated with cholesterol and triglycerides are examined together to determine the effects of alleles on type 2 diabetes and coronary artery disease risk.

    • Dajiang J Liu
    • , Gina M Peloso
    • , Haojie Yu
    • , Adam S Butterworth
    • , Xiao Wang
    • , Anubha Mahajan
    • , Danish Saleheen
    • , Connor Emdin
    • , Dewan Alam
    • , Alexessander Couto Alves
    • , Philippe Amouyel
    • , Emanuele Di Angelantonio
    • , Dominique Arveiler
    • , Themistocles L Assimes
    • , Paul L Auer
    • , Usman Baber
    • , Christie M Ballantyne
    • , Lia E Bang
    • , Marianne Benn
    • , Joshua C Bis
    • , Michael Boehnke
    • , Eric Boerwinkle
    • , Jette Bork-Jensen
    • , Erwin P Bottinger
    • , Ivan Brandslund
    • , Morris Brown
    • , Fabio Busonero
    • , Mark J Caulfield
    • , John C Chambers
    • , Daniel I Chasman
    • , Y Eugene Chen
    • , Yii-Der Ida Chen
    • , Rajiv Chowdhury
    • , Cramer Christensen
    • , Audrey Y Chu
    • , John M Connell
    • , Francesco Cucca
    • , L Adrienne Cupples
    • , Scott M Damrauer
    • , Gail Davies
    • , Ian J Deary
    • , George Dedoussis
    • , Joshua C Denny
    • , Anna Dominiczak
    • , Marie-Pierre Dubé
    • , Tapani Ebeling
    • , Gudny Eiriksdottir
    • , Tõnu Esko
    • , Aliki-Eleni Farmaki
    • , Mary F Feitosa
    • , Marco Ferrario
    • , Jean Ferrieres
    • , Ian Ford
    • , Myriam Fornage
    • , Paul W Franks
    • , Timothy M Frayling
    • , Ruth Frikke-Schmidt
    • , Lars G Fritsche
    • , Philippe Frossard
    • , Valentin Fuster
    • , Santhi K Ganesh
    • , Wei Gao
    • , Melissa E Garcia
    • , Christian Gieger
    • , Franco Giulianini
    • , Mark O Goodarzi
    • , Harald Grallert
    • , Niels Grarup
    • , Leif Groop
    • , Megan L Grove
    • , Vilmundur Gudnason
    • , Torben Hansen
    • , Tamara B Harris
    • , Caroline Hayward
    • , Joel N Hirschhorn
    • , Oddgeir L Holmen
    • , Jennifer Huffman
    • , Yong Huo
    • , Kristian Hveem
    • , Sehrish Jabeen
    • , Anne U Jackson
    • , Johanna Jakobsdottir
    • , Marjo-Riitta Jarvelin
    • , Gorm B Jensen
    • , Marit E Jørgensen
    • , J Wouter Jukema
    • , Johanne M Justesen
    • , Pia R Kamstrup
    • , Stavroula Kanoni
    • , Fredrik Karpe
    • , Frank Kee
    • , Amit V Khera
    • , Derek Klarin
    • , Heikki A Koistinen
    • , Jaspal S Kooner
    • , Charles Kooperberg
    • , Kari Kuulasmaa
    • , Johanna Kuusisto
    • , Markku Laakso
    • , Timo Lakka
    • , Claudia Langenberg
    • , Anne Langsted
    • , Lenore J Launer
    • , Torsten Lauritzen
    • , David C M Liewald
    • , Li An Lin
    • , Allan Linneberg
    • , Ruth J F Loos
    • , Yingchang Lu
    • , Xiangfeng Lu
    • , Reedik Mägi
    • , Anders Malarstig
    • , Ani Manichaikul
    • , Alisa K Manning
    • , Pekka Mäntyselkä
    • , Eirini Marouli
    • , Nicholas G D Masca
    • , Andrea Maschio
    • , James B Meigs
    • , Olle Melander
    • , Andres Metspalu
    • , Andrew P Morris
    • , Alanna C Morrison
    • , Antonella Mulas
    • , Martina Müller-Nurasyid
    • , Patricia B Munroe
    • , Matt J Neville
    • , Jonas B Nielsen
    • , Sune F Nielsen
    • , Børge G Nordestgaard
    • , Jose M Ordovas
    • , Roxana Mehran
    • , Christoper J O'Donnell
    • , Marju Orho-Melander
    • , Cliona M Molony
    • , Pieter Muntendam
    • , Sandosh Padmanabhan
    • , Colin N A Palmer
    • , Dorota Pasko
    • , Aniruddh P Patel
    • , Oluf Pedersen
    • , Markus Perola
    • , Annette Peters
    • , Charlotta Pisinger
    • , Giorgio Pistis
    • , Ozren Polasek
    • , Neil Poulter
    • , Bruce M Psaty
    • , Daniel J Rader
    • , Asif Rasheed
    • , Rainer Rauramaa
    • , Dermot F Reilly
    • , Alex P Reiner
    • , Frida Renström
    • , Stephen S Rich
    • , Paul M Ridker
    • , John D Rioux
    • , Neil R Robertson
    • , Dan M Roden
    • , Jerome I Rotter
    • , Igor Rudan
    • , Veikko Salomaa
    • , Nilesh J Samani
    • , Serena Sanna
    • , Naveed Sattar
    • , Ellen M Schmidt
    • , Robert A Scott
    • , Peter Sever
    • , Raquel S Sevilla
    • , Christian M Shaffer
    • , Xueling Sim
    • , Suthesh Sivapalaratnam
    • , Kerrin S Small
    • , Albert V Smith
    • , Blair H Smith
    • , Sangeetha Somayajula
    • , Lorraine Southam
    • , Timothy D Spector
    • , Elizabeth K Speliotes
    • , John M Starr
    • , Kathleen E Stirrups
    • , Nathan Stitziel
    • , Konstantin Strauch
    • , Heather M Stringham
    • , Praveen Surendran
    • , Hayato Tada
    • , Alan R Tall
    • , Hua Tang
    • , Jean-Claude Tardif
    • , Kent D Taylor
    • , Stella Trompet
    • , Philip S Tsao
    • , Jaakko Tuomilehto
    • , Anne Tybjaerg-Hansen
    • , Natalie R van Zuydam
    • , Anette Varbo
    • , Tibor V Varga
    • , Jarmo Virtamo
    • , Melanie Waldenberger
    • , Nan Wang
    • , Nick J Wareham
    • , Helen R Warren
    • , Peter E Weeke
    • , Joshua Weinstock
    • , Jennifer Wessel
    • , James G Wilson
    • , Peter W F Wilson
    • , Ming Xu
    • , Hanieh Yaghootkar
    • , Robin Young
    • , Eleftheria Zeggini
    • , He Zhang
    • , Neil S Zheng
    • , Weihua Zhang
    • , Yan Zhang
    • , Wei Zhou
    • , Yanhua Zhou
    • , Magdalena Zoledziewska
    • , Charge Diabetes Working Group
    • , The EPIC-InterAct Consortium
    • , EPIC-CVD Consortium
    • , GOLD Consortium
    • , VA Million Veteran Program
    • , Joanna M M Howson
    • , John Danesh
    • , Mark I McCarthy
    • , Chad A Cowan
    • , Goncalo Abecasis
    • , Panos Deloukas
    • , Kiran Musunuru
    • , Cristen J Willer
    •  & Sekar Kathiresan
  • Letter |

    Roger Milne and colleagues conduct a genome-wide association study for estrogen receptor (ER)-negative breast cancer combined with BRCA1 mutation carriers in a large cohort. They identify ten new risk variants and find high genetic correlation between breast cancer risk for BRCA1 mutation carriers and risk of ER-negative breast cancer in the general population.

    • Roger L Milne
    • , Karoline B Kuchenbaecker
    • , Kyriaki Michailidou
    • , Jonathan Beesley
    • , Siddhartha Kar
    • , Sara Lindström
    • , Shirley Hui
    • , Audrey Lemaçon
    • , Penny Soucy
    • , Joe Dennis
    • , Xia Jiang
    • , Asha Rostamianfar
    • , Hilary Finucane
    • , Manjeet K Bolla
    • , Lesley McGuffog
    • , Qin Wang
    • , Cora M Aalfs
    • , ABCTB Investigators
    • , Marcia Adams
    • , Julian Adlard
    • , Simona Agata
    • , Shahana Ahmed
    • , Habibul Ahsan
    • , Kristiina Aittomäki
    • , Fares Al-Ejeh
    • , Jamie Allen
    • , Christine B Ambrosone
    • , Christopher I Amos
    • , Irene L Andrulis
    • , Hoda Anton-Culver
    • , Natalia N Antonenkova
    • , Volker Arndt
    • , Norbert Arnold
    • , Kristan J Aronson
    • , Bernd Auber
    • , Paul L Auer
    • , Margreet G E M Ausems
    • , Jacopo Azzollini
    • , François Bacot
    • , Judith Balmaña
    • , Monica Barile
    • , Laure Barjhoux
    • , Rosa B Barkardottir
    • , Myrto Barrdahl
    • , Daniel Barnes
    • , Daniel Barrowdale
    • , Caroline Baynes
    • , Matthias W Beckmann
    • , Javier Benitez
    • , Marina Bermisheva
    • , Leslie Bernstein
    • , Yves-Jean Bignon
    • , Kathleen R Blazer
    • , Marinus J Blok
    • , Carl Blomqvist
    • , William Blot
    • , Kristie Bobolis
    • , Bram Boeckx
    • , Natalia V Bogdanova
    • , Anders Bojesen
    • , Stig E Bojesen
    • , Bernardo Bonanni
    • , Anne-Lise Børresen-Dale
    • , Aniko Bozsik
    • , Angela R Bradbury
    • , Judith S Brand
    • , Hiltrud Brauch
    • , Hermann Brenner
    • , Brigitte Bressac-de Paillerets
    • , Carole Brewer
    • , Louise Brinton
    • , Per Broberg
    • , Angela Brooks-Wilson
    • , Joan Brunet
    • , Thomas Brüning
    • , Barbara Burwinkel
    • , Saundra S Buys
    • , Jinyoung Byun
    • , Qiuyin Cai
    • , Trinidad Caldés
    • , Maria A Caligo
    • , Ian Campbell
    • , Federico Canzian
    • , Olivier Caron
    • , Angel Carracedo
    • , Brian D Carter
    • , J Esteban Castelao
    • , Laurent Castera
    • , Virginie Caux-Moncoutier
    • , Salina B Chan
    • , Jenny Chang-Claude
    • , Stephen J Chanock
    • , Xiaoqing Chen
    • , Ting-Yuan David Cheng
    • , Jocelyne Chiquette
    • , Hans Christiansen
    • , Kathleen B M Claes
    • , Christine L Clarke
    • , Thomas Conner
    • , Don M Conroy
    • , Jackie Cook
    • , Emilie Cordina-Duverger
    • , Sten Cornelissen
    • , Isabelle Coupier
    • , Angela Cox
    • , David G Cox
    • , Simon S Cross
    • , Katarina Cuk
    • , Julie M Cunningham
    • , Kamila Czene
    • , Mary B Daly
    • , Francesca Damiola
    • , Hatef Darabi
    • , Rosemarie Davidson
    • , Kim De Leeneer
    • , Peter Devilee
    • , Ed Dicks
    • , Orland Diez
    • , Yuan Chun Ding
    • , Nina Ditsch
    • , Kimberly F Doheny
    • , Susan M Domchek
    • , Cecilia M Dorfling
    • , Thilo Dörk
    • , Isabel dos-Santos-Silva
    • , Stéphane Dubois
    • , Pierre-Antoine Dugué
    • , Martine Dumont
    • , Alison M Dunning
    • , Lorraine Durcan
    • , Miriam Dwek
    • , Bernd Dworniczak
    • , Diana Eccles
    • , Ros Eeles
    • , Hans Ehrencrona
    • , Ursula Eilber
    • , Bent Ejlertsen
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    • , Georgia Chenevix-Trench
    • , Montserrat García-Closas
    • , Marjanka K Schmidt
    • , Antonis C Antoniou
    •  & Jacques Simard
  • Letter |

    CERES is a new computational method to estimate gene-dependency levels from CRISPR–Cas9 essentiality screens while accounting for copy number effects and variable sgRNA activity. Applying CERES to new genome-scale CRISPR–Cas9 essentiality screen data from 342 cancer cell lines and other published data sets shows that CERES decreases false-positive results and provides consistent estimates of sgRNA activity.

    • Robin M Meyers
    • , Jordan G Bryan
    • , James M McFarland
    • , Barbara A Weir
    • , Ann E Sizemore
    • , Han Xu
    • , Neekesh V Dharia
    • , Phillip G Montgomery
    • , Glenn S Cowley
    • , Sasha Pantel
    • , Amy Goodale
    • , Yenarae Lee
    • , Levi D Ali
    • , Guozhi Jiang
    • , Rakela Lubonja
    • , William F Harrington
    • , Matthew Strickland
    • , Ting Wu
    • , Derek C Hawes
    • , Victor A Zhivich
    • , Meghan R Wyatt
    • , Zohra Kalani
    • , Jaime J Chang
    • , Michael Okamoto
    • , Kimberly Stegmaier
    • , Todd R Golub
    • , Jesse S Boehm
    • , Francisca Vazquez
    • , David E Root
    • , William C Hahn
    •  & Aviad Tsherniak
  • Letter |

    This study presents a probabilistic framework for inferring negative and positive selection in human cancers that addresses the problem of mutation rate variation. Applying the model to sequencing data from 17 cancer types identifies new significantly mutated genes and detects significant signals of negative selection in many cancer types.

    • Donate Weghorn
    •  & Shamil Sunyaev

Technical Report

  • Technical Report |

    Covariates for multiphenotype studies (CMS), a new approach for testing for associations from large-scale datasets, leverages genetic and environmental factors shared between correlated variables measured on the same samples. Applying CMS to real and simulated data demonstrates a large increase in power equivalent to that gained by doubling the sample size.

    • Hugues Aschard
    • , Vincent Guillemot
    • , Bjarni Vilhjalmsson
    • , Chirag J Patel
    • , David Skurnik
    • , Chun J Ye
    • , Brian Wolpin
    • , Peter Kraft
    •  & Noah Zaitlen