Volume 43 Issue 8, August 2011

Volume 43 Issue 8

Cover Art: Fabric of Life Series-Ecological Symmetries Bicyclus anynana HMPR1X1 by John Arabolos http://arabolosart.com/

Editorial

  • Editorial |

    Although Nature Genetics generally urges authors to keep their claims within the research arena, basic research occasionally turns up results that are ready for immediate application. In these cases we aim to assign some peer referees familiar with the needs of policy makers and to provide accompanying commentary that puts the research into an appropriate societal perspective.

News and Views

  • News & Views |

    New work has identified networks of protein interactions at the transition zones of cilia. These discoveries provide insights into the molecular pathogenesis of ciliopathies and illustrate the power of linking proteomics technologies with human genetics to uncover critical disease pathways.

    • Thomas Benzing
    •  & Bernhard Schermer
  • News & Views |

    The human genome contains large areas with hypervariable DNA methylation that are associated with deregulation of gene expression. This epigenetic variation may be necessary for differentiation, but it also provides a mechanism for Darwinian evolution at the cellular level that may underlie age-related diseases such as cancer.

    • Jean-Pierre Issa
  • News & Views |

    Somatic mutations in mitochondrial DNA build up in aging tissues and are thought to contribute to physiological aging. Surprisingly, it is not known if these mutations occur early or late in life. A new study looks at mechanisms of accelerated mitochondrial aging in HIV-infected individuals treated with nucleoside analog anti-retroviral drugs and offers support for an early origin of mitochondrial DNA mutations.

    • Konstantin Khrapko

Research Highlights

Brief Communications

  • Brief Communication |

    Han Brunner and colleagues report the identification of de novo nonsense mutations in ASXL1 in individuals with Bohring-Opitz syndrome, which is characterized by intellectual disability, distinctive facial features and multiple congenital malformations.

    • Alexander Hoischen
    • , Bregje W M van Bon
    • , Benjamín Rodríguez-Santiago
    • , Christian Gilissen
    • , Lisenka E L M Vissers
    • , Petra de Vries
    • , Irene Janssen
    • , Bart van Lier
    • , Rob Hastings
    • , Sarah F Smithson
    • , Ruth Newbury-Ecob
    • , Susanne Kjaergaard
    • , Judith Goodship
    • , Ruth McGowan
    • , Deborah Bartholdi
    • , Anita Rauch
    • , Maarit Peippo
    • , Jan M Cobben
    • , Dagmar Wieczorek
    • , Gabriele Gillessen-Kaesbach
    • , Joris A Veltman
    • , Han G Brunner
    •  & Bert B B A de Vries
  • Brief Communication |

    Meral Gunay-Aygun and colleagues report that NBEAL2 is mutated in gray platelet syndrome (GPS). GPS is a recessive platelet disorder that can lead to severe bleeding.

    • Meral Gunay-Aygun
    • , Tzipora C Falik-Zaccai
    • , Thierry Vilboux
    • , Yifat Zivony-Elboum
    • , Fatma Gumruk
    • , Mualla Cetin
    • , Morad Khayat
    • , Cornelius F Boerkoel
    • , Nehama Kfir
    • , Yan Huang
    • , Dawn Maynard
    • , Heidi Dorward
    • , Katherine Berger
    • , Robert Kleta
    • , Yair Anikster
    • , Mutlu Arat
    • , Andrew S Freiberg
    • , Beate E Kehrel
    • , Kerstin Jurk
    • , Pedro Cruz
    • , Jim C Mullikin
    • , James G White
    • , Marjan Huizing
    •  & William A Gahl
  • Brief Communication |

    Cornelis Albers and colleagues identify NBEAL2 as the causative gene for gray platelet syndrome (GPS). Knockdown of this gene in zebrafish leads to spontaneous bleeding and defects in thrombocyte formation.

    • Cornelis A Albers
    • , Ana Cvejic
    • , Rémi Favier
    • , Evelien E Bouwmans
    • , Marie-Christine Alessi
    • , Paul Bertone
    • , Gregory Jordan
    • , Ross N W Kettleborough
    • , Graham Kiddle
    • , Myrto Kostadima
    • , Randy J Read
    • , Botond Sipos
    • , Suthesh Sivapalaratnam
    • , Peter A Smethurst
    • , Jonathan Stephens
    • , Katrin Voss
    • , Alan Nurden
    • , Augusto Rendon
    • , Paquita Nurden
    •  & Willem H Ouwehand
  • Brief Communication |

    Walter Kahr and colleagues report mutations in NBEAL2 in gray platelet syndrome (GPS). Using RNA-seq, the authors observed abnormal pre-mRNA processing in NBEAL2 in platelets from an individual with GPS.

    • Walter HA Kahr
    • , Jesse Hinckley
    • , Ling Li
    • , Hansjörg Schwertz
    • , Hilary Christensen
    • , Jesse W Rowley
    • , Fred G Pluthero
    • , Denisa Urban
    • , Shay Fabbro
    • , Brie Nixon
    • , Rick Gadzinski
    • , Mike Storck
    • , Kai Wang
    • , Gi-Yung Ryu
    • , Shawn M Jobe
    • , Brian C Schutte
    • , Jack Moseley
    • , Noeleen B Loughran
    • , John Parkinson
    • , Andrew S Weyrich
    •  & Jorge Di Paola
  • Brief Communication |

    Alon Keinan and colleagues estimate the ratio of genetic diversity on the X chromosome to that on the autosome (X/A) on the basis of whole-genome sequencing of 69 females from the 1000 Genomes Project. They find that across populations, the X/A ratio increases with genetic distance from genes. They further find that this ratio is reduced in Europeans compared to West Africans, which may be explained by demographic history.

    • Srikanth Gottipati
    • , Leonardo Arbiza
    • , Adam Siepel
    • , Andrew G Clark
    •  & Alon Keinan

Articles

  • Article |

    Jeong Sun-Seo and colleagues report whole-genome sequencing of ten Korean individuals and exome sequencing on an additional eight Korean individuals. They also performed transcriptome sequencing on 17 of these individuals. The authors identified approximately 1.83 million previously unidentified SNPs.

    • Young Seok Ju
    • , Jong-Il Kim
    • , Sheehyun Kim
    • , Dongwan Hong
    • , Hansoo Park
    • , Jong-Yeon Shin
    • , Seungbok Lee
    • , Won-Chul Lee
    • , Sujung Kim
    • , Saet-Byeol Yu
    • , Sung-Soo Park
    • , Seung-Hyun Seo
    • , Ji-Young Yun
    • , Hyun-Jin Kim
    • , Dong-Sung Lee
    • , Maryam Yavartanoo
    • , Hyunseok Peter Kang
    • , Omer Gokcumen
    • , Diddahally R Govindaraju
    • , Jung Hee Jung
    • , Hyonyong Chong
    • , Kap-Seok Yang
    • , Hyungtae Kim
    • , Charles Lee
    •  & Jeong-Sun Seo
  • Article |

    Ruth Loos and colleagues use genome-wide association to identify common variants influencing body fat percentage. Unexpectedly, they show that a body-fat–decreasing allele near IRS1 is associated with an impaired metabolic profile, including increased risk of type 2 diabetes and coronary artery disease.

    • Tuomas O Kilpeläinen
    • , M Carola Zillikens
    • , Alena Stančákova
    • , Francis M Finucane
    • , Janina S Ried
    • , Claudia Langenberg
    • , Weihua Zhang
    • , Jacques S Beckmann
    • , Jian'an Luan
    • , Liesbeth Vandenput
    • , Unnur Styrkarsdottir
    • , Yanhua Zhou
    • , Albert Vernon Smith
    • , Jing-Hua Zhao
    • , Najaf Amin
    • , Sailaja Vedantam
    • , So-Youn Shin
    • , Talin Haritunians
    • , Mao Fu
    • , Mary F Feitosa
    • , Meena Kumari
    • , Bjarni V Halldorsson
    • , Emmi Tikkanen
    • , Massimo Mangino
    • , Caroline Hayward
    • , Ci Song
    • , Alice M Arnold
    • , Yurii S Aulchenko
    • , Ben A Oostra
    • , Harry Campbell
    • , L Adrienne Cupples
    • , Kathryn E Davis
    • , Angela Döring
    • , Gudny Eiriksdottir
    • , Karol Estrada
    • , José Manuel Fernández-Real
    • , Melissa Garcia
    • , Christian Gieger
    • , Nicole L Glazer
    • , Candace Guiducci
    • , Albert Hofman
    • , Steve E Humphries
    • , Bo Isomaa
    • , Leonie C Jacobs
    • , Antti Jula
    • , David Karasik
    • , Magnus K Karlsson
    • , Kay-Tee Khaw
    • , Lauren J Kim
    • , Mika Kivimäki
    • , Norman Klopp
    • , Brigitte Kühnel
    • , Johanna Kuusisto
    • , Yongmei Liu
    • , Östen Ljunggren
    • , Mattias Lorentzon
    • , Robert N Luben
    • , Barbara McKnight
    • , Dan Mellström
    • , Braxton D Mitchell
    • , Vincent Mooser
    • , José Maria Moreno
    • , Satu Männistö
    • , Jeffery R O'Connell
    • , Laura Pascoe
    • , Leena Peltonen
    • , Belén Peral
    • , Markus Perola
    • , Bruce M Psaty
    • , Veikko Salomaa
    • , David B Savage
    • , Robert K Semple
    • , Tatjana Skaric-Juric
    • , Gunnar Sigurdsson
    • , Kijoung S Song
    • , Timothy D Spector
    • , Ann-Christine Syvänen
    • , Philippa J Talmud
    • , Gudmar Thorleifsson
    • , Unnur Thorsteinsdottir
    • , André G Uitterlinden
    • , Cornelia M van Duijn
    • , Antonio Vidal-Puig
    • , Sarah H Wild
    • , Alan F Wright
    • , Deborah J Clegg
    • , Eric Schadt
    • , James F Wilson
    • , Igor Rudan
    • , Samuli Ripatti
    • , Ingrid B Borecki
    • , Alan R Shuldiner
    • , Erik Ingelsson
    • , John-Olov Jansson
    • , Robert C Kaplan
    • , Vilmundur Gudnason
    • , Tamara B Harris
    • , Leif Groop
    • , Douglas P Kiel
    • , Fernando Rivadeneira
    • , Mark Walker
    • , Inês Barroso
    • , Peter Vollenweider
    • , Gérard Waeber
    • , John C Chambers
    • , Jaspal S Kooner
    • , Nicole Soranzo
    • , Joel N Hirschhorn
    • , Kari Stefansson
    • , H-Erich Wichmann
    • , Claes Ohlsson
    • , Stephen O'Rahilly
    • , Nicholas J Wareham
    • , Elizabeth K Speliotes
    • , Caroline S Fox
    • , Markku Laakso
    •  & Ruth J F Loos
  • Article |

    Matthew Brown, Peter Donnelly and colleagues report results of a genome-wide association meta-analysis and follow-up study of ankylosing spondylitis. They identify three new risk variants and report a genetic interaction between ERAP1 and HLA-B27, implicating aberrant peptide handling in the pathophysiology of this disease.

    • The Australo-Anglo-American Spondyloarthritis Consortium (TASC)
    • , the Wellcome Trust Case Control Consortium 2 (WTCCC2)
    • , David M Evans
    • , Chris C A Spencer
    • , Jennifer J Pointon
    • , Zhan Su
    • , David Harvey
    • , Grazyna Kochan
    • , Udo Oppermann
    • , Alexander Dilthey
    • , Matti Pirinen
    • , Millicent A Stone
    • , Louise Appleton
    • , Loukas Moutsianas
    • , Stephen Leslie
    • , Tom Wordsworth
    • , Tony J Kenna
    • , Tugce Karaderi
    • , Gethin P Thomas
    • , Michael M Ward
    • , Michael H Weisman
    • , Claire Farrar
    • , Linda A Bradbury
    • , Patrick Danoy
    • , Robert D Inman
    • , Walter Maksymowych
    • , Dafna Gladman
    • , Proton Rahman
    • , Spondyloarthritis Research Consortium of Canada (SPARCC)
    • , Ann Morgan
    • , Helena Marzo-Ortega
    • , Paul Bowness
    • , Karl Gaffney
    • , J S Hill Gaston
    • , Malcolm Smith
    • , Jacome Bruges-Armas
    • , Ana-Rita Couto
    • , Rosa Sorrentino
    • , Fabiana Paladini
    • , Manuel A Ferreira
    • , Huji Xu
    • , Yu Liu
    • , Lei Jiang
    • , Carlos Lopez-Larrea
    • , Roberto Díaz-Peña
    • , Antonio López-Vázquez
    • , Tetyana Zayats
    • , Gavin Band
    • , Céline Bellenguez
    • , Hannah Blackburn
    • , Jenefer M Blackwell
    • , Elvira Bramon
    • , Suzannah J Bumpstead
    • , Juan P Casas
    • , Aiden Corvin
    • , Nicholas Craddock
    • , Panos Deloukas
    • , Serge Dronov
    • , Audrey Duncanson
    • , Sarah Edkins
    • , Colin Freeman
    • , Matthew Gillman
    • , Emma Gray
    • , Rhian Gwilliam
    • , Naomi Hammond
    • , Sarah E Hunt
    • , Janusz Jankowski
    • , Alagurevathi Jayakumar
    • , Cordelia Langford
    • , Jennifer Liddle
    • , Hugh S Markus
    • , Christopher G Mathew
    • , Owen T McCann
    • , Mark I McCarthy
    • , Colin N A Palmer
    • , Leena Peltonen
    • , Robert Plomin
    • , Simon C Potter
    • , Anna Rautanen
    • , Radhi Ravindrarajah
    • , Michelle Ricketts
    • , Nilesh Samani
    • , Stephen J Sawcer
    • , Amy Strange
    • , Richard C Trembath
    • , Ananth C Viswanathan
    • , Matthew Waller
    • , Paul Weston
    • , Pamela Whittaker
    • , Sara Widaa
    • , Nicholas W Wood
    • , Gilean McVean
    • , John D Reveille
    • , B Paul Wordsworth
    • , Matthew A Brown
    •  & Peter Donnelly
  • Article |

    Andrew Feinberg and colleagues report whole-genome bisulfite sequencing of three colon cancers and matched normal tissue and two adenomatous polyps. The authors identify large blocks of relative hypomethylation over half of the genome.

    • Kasper Daniel Hansen
    • , Winston Timp
    • , Héctor Corrada Bravo
    • , Sarven Sabunciyan
    • , Benjamin Langmead
    • , Oliver G McDonald
    • , Bo Wen
    • , Hao Wu
    • , Yun Liu
    • , Dinh Diep
    • , Eirikur Briem
    • , Kun Zhang
    • , Rafael A Irizarry
    •  & Andrew P Feinberg
  • Article |

    Jeremy Reiter and colleagues show that Tctn1 is a component of a transition zone complex that regulates ciliogenesis and ciliary membrane composition. They also identify a likely causal mutation in TCTN1 in two siblings with Joubert syndrome.

    • Francesc R Garcia-Gonzalo
    • , Kevin C Corbit
    • , María Salomé Sirerol-Piquer
    • , Gokul Ramaswami
    • , Edgar A Otto
    • , Thomas R Noriega
    • , Allen D Seol
    • , Jon F Robinson
    • , Christopher L Bennett
    • , Dragana J Josifova
    • , José Manuel García-Verdugo
    • , Nicholas Katsanis
    • , Friedhelm Hildebrandt
    •  & Jeremy F Reiter

Letters

  • Letter |

    Rosalind Eeles and colleagues report a multistage genome-wide association study of prostate cancer, identifying seven new prostate cancer susceptibility loci.

    • Zsofia Kote-Jarai
    • , Ali Amin Al Olama
    • , Graham G Giles
    • , Gianluca Severi
    • , Johanna Schleutker
    • , Maren Weischer
    • , Daniele Campa
    • , Elio Riboli
    • , Tim Key
    • , Henrik Gronberg
    • , David J Hunter
    • , Peter Kraft
    • , Michael J Thun
    • , Sue Ingles
    • , Stephen Chanock
    • , Demetrius Albanes
    • , Richard B Hayes
    • , David E Neal
    • , Freddie C Hamdy
    • , Jenny L Donovan
    • , Paul Pharoah
    • , Fredrick Schumacher
    • , Brian E Henderson
    • , Janet L Stanford
    • , Elaine A Ostrander
    • , Karina Dalsgaard Sorensen
    • , Thilo Dörk
    • , Gerald Andriole
    • , Joanne L Dickinson
    • , Cezary Cybulski
    • , Jan Lubinski
    • , Amanda Spurdle
    • , Judith A Clements
    • , Suzanne Chambers
    • , Joanne Aitken
    • , R A Frank Gardiner
    • , Stephen N Thibodeau
    • , Dan Schaid
    • , Esther M John
    • , Christiane Maier
    • , Walther Vogel
    • , Kathleen A Cooney
    • , Jong Y Park
    • , Lisa Cannon-Albright
    • , Hermann Brenner
    • , Tomonori Habuchi
    • , Hong-Wei Zhang
    • , Yong-Jie Lu
    • , Radka Kaneva
    • , Ken Muir
    • , Sara Benlloch
    • , Daniel A Leongamornlert
    • , Edward J Saunders
    • , Malgorzata Tymrakiewicz
    • , Nadiya Mahmud
    • , Michelle Guy
    • , Lynne T O'Brien
    • , Rosemary A Wilkinson
    • , Amanda L Hall
    • , Emma J Sawyer
    • , Tokhir Dadaev
    • , Jonathan Morrison
    • , David P Dearnaley
    • , Alan Horwich
    • , Robert A Huddart
    • , Vincent S Khoo
    • , Christopher C Parker
    • , Nicholas Van As
    • , Christopher J Woodhouse
    • , Alan Thompson
    • , Tim Christmas
    • , Chris Ogden
    • , Colin S Cooper
    • , Aritaya Lophatonanon
    • , Melissa C Southey
    • , John L Hopper
    • , Dallas R English
    • , Tiina Wahlfors
    • , Teuvo L J Tammela
    • , Peter Klarskov
    • , Børge G Nordestgaard
    • , M Andreas Røder
    • , Anne Tybjærg-Hansen
    • , Stig E Bojesen
    • , Ruth Travis
    • , Federico Canzian
    • , Rudolf Kaaks
    • , Fredrik Wiklund
    • , Markus Aly
    • , Sara Lindstrom
    • , W Ryan Diver
    • , Susan Gapstur
    • , Mariana C Stern
    • , Roman Corral
    • , Jarmo Virtamo
    • , Angela Cox
    • , Christopher A Haiman
    • , Loic Le Marchand
    • , Liesel FitzGerald
    • , Suzanne Kolb
    • , Erika M Kwon
    • , Danielle M Karyadi
    • , Torben Falck Ørntoft
    • , Michael Borre
    • , Andreas Meyer
    • , Jürgen Serth
    • , Meredith Yeager
    • , Sonja I Berndt
    • , James R Marthick
    • , Briony Patterson
    • , Dominika Wokolorczyk
    • , Jyotsna Batra
    • , Felicity Lose
    • , Shannon K McDonnell
    • , Amit D Joshi
    • , Ahva Shahabi
    • , Antje E Rinckleb
    • , Ana Ray
    • , Thomas A Sellers
    • , Hui-Yi Lin
    • , Robert A Stephenson
    • , James Farnham
    • , Heiko Muller
    • , Dietrich Rothenbacher
    • , Norihiko Tsuchiya
    • , Shintaro Narita
    • , Guang-Wen Cao
    • , Chavdar Slavov
    • , Vanio Mitev
    • , The UK Genetic Prostate Cancer Study Collaborators/British Association of Urological Surgeons' Section of Oncology
    • , The UK ProtecT Study Collaborators, The Australian Prostate Cancer BioResource
    • , The PRACTICAL Consortium
    • , Douglas F Easton
    •  & Rosalind A Eeles
  • Letter |

    Hongbing Shen and colleagues report a genome-wide association study for lung cancer in individuals of Han Chinese ancestry. The authors identify two new lung cancer susceptibility loci.

    • Zhibin Hu
    • , Chen Wu
    • , Yongyong Shi
    • , Huan Guo
    • , Xueying Zhao
    • , Zhihua Yin
    • , Lei Yang
    • , Juncheng Dai
    • , Lingmin Hu
    • , Wen Tan
    • , Zhiqiang Li
    • , Qifei Deng
    • , Jiucun Wang
    • , Wei Wu
    • , Guangfu Jin
    • , Yue Jiang
    • , Dianke Yu
    • , Guoquan Zhou
    • , Hongyan Chen
    • , Peng Guan
    • , Yijiang Chen
    • , Yongqian Shu
    • , Lin Xu
    • , Xiangyang Liu
    • , Li Liu
    • , Ping Xu
    • , Baohui Han
    • , Chunxue Bai
    • , Yuxia Zhao
    • , Haibo Zhang
    • , Ying Yan
    • , Hongxia Ma
    • , Jiaping Chen
    • , Mingjie Chu
    • , Feng Lu
    • , Zhengdong Zhang
    • , Feng Chen
    • , Xinru Wang
    • , Li Jin
    • , Jiachun Lu
    • , Baosen Zhou
    • , Daru Lu
    • , Tangchun Wu
    • , Dongxin Lin
    •  & Hongbing Shen
  • Letter |

    Kazuaki Chayama and colleagues report a genome-wide association study for progression to hepatocellular carcinoma in individuals with chronic hepatitis C. The authors identify a common variant within DEP2DC that is associated with risk of HCV-induced HCC.

    • Daiki Miki
    • , Hidenori Ochi
    • , C Nelson Hayes
    • , Hiromi Abe
    • , Tadahiko Yoshima
    • , Hiroshi Aikata
    • , Kenji Ikeda
    • , Hiromitsu Kumada
    • , Joji Toyota
    • , Takashi Morizono
    • , Tatsuhiko Tsunoda
    • , Michiaki Kubo
    • , Yusuke Nakamura
    • , Naoyuki Kamatani
    •  & Kazuaki Chayama
  • Letter |

    David Altshuler and colleagues compare strategies to fine map the association of common variants at 9p21 with type 2 diabetes and myocardial infarction. Their study provides an empirical assessment of the performance of targeted sequencing and imputation-based approaches to comprehensively assess genetic variation in disease-associated regions.

    • Jessica Shea
    • , Vineeta Agarwala
    • , Anthony A Philippakis
    • , Jared Maguire
    • , Eric Banks
    • , Mark DePristo
    • , Brian Thomson
    • , Candace Guiducci
    • , Robert C Onofrio
    • , The Myocardial Infarction Genetics Consortium
    • , Sekar Kathiresan
    • , Stacey Gabriel
    • , Noël P Burtt
    • , Mark J Daly
    • , Leif Groop
    •  & David Altshuler
  • Letter |

    Patrick Chinnery and colleagues analyze the effects on mitochondrial DNA of nucleoside analogue anti-retroviral (NRTIs) drugs in patients infected with HIV. The authors find that patients treated with commonly used NRTIs accumulate somatic mitochondrial DNA mutations in a process similar to normal aging.

    • Brendan A I Payne
    • , Ian J Wilson
    • , Charlotte A Hateley
    • , Rita Horvath
    • , Mauro Santibanez-Koref
    • , David C Samuels
    • , D Ashley Price
    •  & Patrick F Chinnery
  • Letter |

    Gavin Kelsey and colleagues report methylation landscapes in mouse oocytes, sperm and blastocysts. They find that the majority of methylated CpG islands in oocytes display incomplete demethylation in preimplantation embryos.

    • Sébastien A Smallwood
    • , Shin-ichi Tomizawa
    • , Felix Krueger
    • , Nico Ruf
    • , Natasha Carli
    • , Anne Segonds-Pichon
    • , Shun Sato
    • , Kenichiro Hata
    • , Simon R Andrews
    •  & Gavin Kelsey

Erratum

  • Erratum |

    • Lusy Handoko
    • , Han Xu
    • , Guoliang Li
    • , Chew Yee Ngan
    • , Elaine Chew
    • , Marie Schnapp
    • , Charlie Wah Heng Lee
    • , Chaopeng Ye
    • , Joanne Lim Hui Ping
    • , Fabianus Mulawadi
    • , Eleanor Wong
    • , Jianpeng Sheng
    • , Yubo Zhang
    • , Thompson Poh
    • , Chee Seng Chan
    • , Galih Kunarso
    • , Atif Shahab
    • , Guillaume Bourque
    • , Valere Cacheux-Rataboul
    • , Wing-Kin Sung
    • , Yijun Ruan
    •  & Chia-Lin Wei

Corrigendum