Volume 52 Issue 7, July 2020

Volume 52 Issue 7

p53 guarding the genome from Cas9

In this issue, Enache, Rendo et al. show that the expression of guide-free Cas9 in human cell lines can lead to DNA damage, thus resulting in p53 activation. This can sometimes result in the emergence or expansion of p53-inactivating mutations. On the cover, p53 is depicted as the ‘watchdog’ of the genome garden. It is trying to bark away Cas9 ‘bunnies’ and prevent them from cutting the DNA. The watchdog and bunnies are based on the crystal structures of p53 and Cas9, respectively.

See Enache et al.

Image: Jeff Day, Oana Enache, Veronica Rendo and Uri Ben-David. Cover Design: Erin Dewalt.

Editorial

  • Editorial |

    When the status quo in science continues to perpetuate ingrained systems of discrimination, inequality and racism, the beneficiaries of these systems must not only reexamine their collective practices but also redress historical injustices through consequential, concrete actions that will lead to change. We cannot focus only on the first steps of listening and learning to build a better, fairer scientific community. We at Nature Genetics fully commit to pledging our energy and efforts toward long-term goals explicitly designed to fundamentally transform how science and its dissemination are conducted.

News & Views

  • News & Views |

    How ‘difficult’ is it for somatic evolution to produce a cell that is capable of leaving the primary tumor and growing in a distant organ? In this issue, Reiter et al. assess genetic diversity across metastatic lesions and identify a tight selective bottleneck preceding distant metastasis.

    • Trevor A. Graham
    •  & Darryl Shibata
  • News & Views |

    Pachytene Piwi-interacting RNAs (piRNAs) are abundant small non-coding RNAs expressed in mammalian germ lines. A new study indicates that, among the diverse pool of piRNA sequences, a small number act as highly selective guides that induce cleavage of coding and non-coding transcripts, thus promoting piRNA generation and regulating gene expression.

    • Alexei A. Aravin

Review Articles

  • Review Article |

    This review discusses major privacy threats relevant to collection and analysis of genomic data in the context of direct-to-consumer applications and provides suggestions for improving the design of privacy-protecting approaches.

    • Luca Bonomi
    • , Yingxiang Huang
    •  & Lucila Ohno-Machado

Letters

  • Letter |

    CTCF is dispensable for transdifferentiation of B cells into induced macrophages despite widespread loss of topologically associating domains. CTCF depletion impairs upregulation of inflammatory genes after endotoxin exposure by destabilizing promoter–enhancer interactions.

    • Grégoire Stik
    • , Enrique Vidal
    • , Mercedes Barrero
    • , Sergi Cuartero
    • , Maria Vila-Casadesús
    • , Julen Mendieta-Esteban
    • , Tian V. Tian
    • , Jinmi Choi
    • , Clara Berenguer
    • , Amaya Abad
    • , Beatrice Borsari
    • , François le Dily
    • , Patrick Cramer
    • , Marc A. Marti-Renom
    • , Ralph Stadhouders
    •  & Thomas Graf
  • Letter |

    Cas9 expression induces DNA damage and activates the p53 pathway, and it can lead to the selection of cells with p53-inactivating mutations. Cas9 is less active in wild-type TP53 cell lines than in TP53-mutant cell lines.

    • Oana M. Enache
    • , Veronica Rendo
    • , Mai Abdusamad
    • , Daniel Lam
    • , Desiree Davison
    • , Sangita Pal
    • , Naomi Currimjee
    • , Julian Hess
    • , Sasha Pantel
    • , Anwesha Nag
    • , Aaron R. Thorner
    • , John G. Doench
    • , Francisca Vazquez
    • , Rameen Beroukhim
    • , Todd R. Golub
    •  & Uri Ben-David
  • Letter |

    Genome-wide analysis in 212,453 Japanese individuals identifies loci associated with 42 diseases. Comparative analysis with European populations identifies East Asian–specific associations.

    • Kazuyoshi Ishigaki
    • , Masato Akiyama
    • , Masahiro Kanai
    • , Atsushi Takahashi
    • , Eiryo Kawakami
    • , Hiroki Sugishita
    • , Saori Sakaue
    • , Nana Matoba
    • , Siew-Kee Low
    • , Yukinori Okada
    • , Chikashi Terao
    • , Tiffany Amariuta
    • , Steven Gazal
    • , Yuta Kochi
    • , Momoko Horikoshi
    • , Ken Suzuki
    • , Kaoru Ito
    • , Satoshi Koyama
    • , Kouichi Ozaki
    • , Shumpei Niida
    • , Yasushi Sakata
    • , Yasuhiko Sakata
    • , Takashi Kohno
    • , Kouya Shiraishi
    • , Yukihide Momozawa
    • , Makoto Hirata
    • , Koichi Matsuda
    • , Masashi Ikeda
    • , Nakao Iwata
    • , Shiro Ikegawa
    • , Ikuyo Kou
    • , Toshihiro Tanaka
    • , Hidewaki Nakagawa
    • , Akari Suzuki
    • , Tomomitsu Hirota
    • , Mayumi Tamari
    • , Kazuaki Chayama
    • , Daiki Miki
    • , Masaki Mori
    • , Satoshi Nagayama
    • , Yataro Daigo
    • , Yoshio Miki
    • , Toyomasa Katagiri
    • , Osamu Ogawa
    • , Wataru Obara
    • , Hidemi Ito
    • , Teruhiko Yoshida
    • , Issei Imoto
    • , Takashi Takahashi
    • , Chizu Tanikawa
    • , Takao Suzuki
    • , Nobuaki Sinozaki
    • , Shiro Minami
    • , Hiroki Yamaguchi
    • , Satoshi Asai
    • , Yasuo Takahashi
    • , Ken Yamaji
    • , Kazuhisa Takahashi
    • , Tomoaki Fujioka
    • , Ryo Takata
    • , Hideki Yanai
    • , Akihide Masumoto
    • , Yukihiro Koretsune
    • , Hiromu Kutsumi
    • , Masahiko Higashiyama
    • , Shigeo Murayama
    • , Naoko Minegishi
    • , Kichiya Suzuki
    • , Kozo Tanno
    • , Atsushi Shimizu
    • , Taiki Yamaji
    • , Motoki Iwasaki
    • , Norie Sawada
    • , Hirokazu Uemura
    • , Keitaro Tanaka
    • , Mariko Naito
    • , Makoto Sasaki
    • , Kenji Wakai
    • , Shoichiro Tsugane
    • , Masayuki Yamamoto
    • , Kazuhiko Yamamoto
    • , Yoshinori Murakami
    • , Yusuke Nakamura
    • , Soumya Raychaudhuri
    • , Johji Inazawa
    • , Toshimasa Yamauchi
    • , Takashi Kadowaki
    • , Michiaki Kubo
    •  & Yoichiro Kamatani

Articles

  • Article |

    Genome-wide association meta-analyses among 1.4 million individuals identify 318 new risk loci for type 2 diabetes and provide insight into the contribution of these risk variants to diabetes-related vascular outcomes.

    • Marijana Vujkovic
    • , Jacob M. Keaton
    • , Julie A. Lynch
    • , Donald R. Miller
    • , Jin Zhou
    • , Catherine Tcheandjieu
    • , Jennifer E. Huffman
    • , Themistocles L. Assimes
    • , Kimberly Lorenz
    • , Xiang Zhu
    • , Austin T. Hilliard
    • , Renae L. Judy
    • , Jie Huang
    • , Kyung M. Lee
    • , Derek Klarin
    • , Saiju Pyarajan
    • , John Danesh
    • , Olle Melander
    • , Asif Rasheed
    • , Nadeem H. Mallick
    • , Shahid Hameed
    • , Irshad H. Qureshi
    • , Muhammad Naeem Afzal
    • , Uzma Malik
    • , Anjum Jalal
    • , Shahid Abbas
    • , Xin Sheng
    • , Long Gao
    • , Klaus H. Kaestner
    • , Katalin Susztak
    • , Yan V. Sun
    • , Scott L. DuVall
    • , Kelly Cho
    • , Jennifer S. Lee
    • , J. Michael Gaziano
    • , Lawrence S. Phillips
    • , James B. Meigs
    • , Peter D. Reaven
    • , Peter W. Wilson
    • , Todd L. Edwards
    • , Daniel J. Rader
    • , Scott M. Damrauer
    • , Christopher J. O’Donnell
    • , Philip S. Tsao
    • , Mark A. Atkinson
    • , Al C. Powers
    • , Ali Naji
    • , Klaus H. Kaestner
    • , Goncalo R. Abecasis
    • , Aris Baras
    • , Michael N. Cantor
    • , Giovanni Coppola
    • , Aris N. Economides
    • , Luca A. Lotta
    • , John D. Overton
    • , Jeffrey G. Reid
    • , Alan R. Shuldiner
    • , Christina Beechert
    • , Caitlin Forsythe
    • , Erin D. Fuller
    • , Zhenhua Gu
    • , Michael Lattari
    • , Alexander E. Lopez
    • , Thomas D. Schleicher
    • , Maria Sotiropoulos Padilla
    • , Karina Toledo
    • , Louis Widom
    • , Sarah E. Wolf
    • , Manasi Pradhan
    • , Kia Manoochehri
    • , Ricardo H. Ulloa
    • , Xiaodong Bai
    • , Suganthi Balasubramanian
    • , Leland Barnard
    • , Andrew L. Blumenfeld
    • , Gisu Eom
    • , Lukas Habegger
    • , Alicia Hawes
    • , Shareef Khalid
    • , Evan K. Maxwell
    • , William J. Salerno
    • , Jeffrey C. Staples
    • , Ashish Yadav
    • , Marcus B. Jones
    • , Lyndon J. Mitnaul
    • , Samuel M. Aguayo
    • , Sunil K. Ahuja
    • , Zuhair K. Ballas
    • , Sujata Bhushan
    • , Edward J. Boyko
    • , David M. Cohen
    • , John Concato
    • , Joseph I. Constans
    • , Louis J. Dellitalia
    • , Joseph M. Fayad
    • , Ronald S. Fernando
    • , Hermes J. Florez
    • , Melinda A. Gaddy
    • , Saib S. Gappy
    • , Gretchen Gibson
    • , Michael Godschalk
    • , Jennifer A. Greco
    • , Samir Gupta
    • , Salvador Gutierrez
    • , Kimberly D. Hammer
    • , Mark B. Hamner
    • , John B. Harley
    • , Adriana M. Hung
    • , Mostaqul Huq
    • , Robin A. Hurley
    • , Pran R. Iruvanti
    • , Douglas J. Ivins
    • , Frank J. Jacono
    • , Darshana N. Jhala
    • , Laurence S. Kaminsky
    • , Scott Kinlay
    • , Jon B. Klein
    • , Suthat Liangpunsakul
    • , Jack H. Lichy
    • , Stephen M. Mastorides
    • , Roy O. Mathew
    • , Kristin M. Mattocks
    • , Rachel McArdle
    • , Paul N. Meyer
    • , Laurence J. Meyer
    • , Jonathan P. Moorman
    • , Timothy R. Morgan
    • , Maureen Murdoch
    • , Xuan-Mai T. Nguyen
    • , Olaoluwa O. Okusaga
    • , Kris-Ann K. Oursler
    • , Nora R. Ratcliffe
    • , Michael I. Rauchman
    • , R. Brooks Robey
    • , George W. Ross
    • , Richard J. Servatius
    • , Satish C. Sharma
    • , Scott E. Sherman
    • , Elif Sonel
    • , Peruvemba Sriram
    • , Todd Stapley
    • , Robert T. Striker
    • , Neeraj Tandon
    • , Gerardo Villareal
    • , Agnes S. Wallbom
    • , John M. Wells
    • , Jeffrey C. Whittle
    • , Mary A. Whooley
    • , Junzhe Xu
    • , Shing-Shing Yeh
    • , Michaela Aslan
    • , Jessica V. Brewer
    • , Mary T. Brophy
    • , Todd Connor
    • , Dean P. Argyres
    • , Nhan V. Do
    • , Elizabeth R. Hauser
    • , Donald E. Humphries
    • , Luis E. Selva
    • , Shahpoor Shayan
    • , Brady Stephens
    • , Stacey B. Whitbourne
    • , Hongyu Zhao
    • , Jennifer Moser
    • , Jean C. Beckham
    • , Jim L. Breeling
    • , J. P. Casas Romero
    • , Grant D. Huang
    • , Rachel B. Ramoni
    • , Saiju Pyarajan
    • , Yan V. Sun
    • , Kelly Cho
    • , Peter W. Wilson
    • , Christopher J. O’Donnell
    • , Philip S. Tsao
    • , Kyong-Mi Chang
    • , J. Michael Gaziano
    • , Sumitra Muralidhar
    • , Kyong-Mi Chang
    • , Benjamin F. Voight
    •  & Danish Saleheen
  • Article |

    Analysis of metastases using a mathematical framework and multi-region sampling data shows that lymph node metastases have higher levels of intratumor heterogeneity than distant metastases, and that these form via different evolutionary mechanisms.

    • Johannes G. Reiter
    • , Wei-Ting Hung
    • , I-Hsiu Lee
    • , Shriya Nagpal
    • , Peter Giunta
    • , Sebastian Degner
    • , Gang Liu
    • , Emma C. E. Wassenaar
    • , William R. Jeck
    • , Martin S. Taylor
    • , Alexander A. Farahani
    • , Hetal D. Marble
    • , Simon Knott
    • , Onno Kranenburg
    • , Jochen K. Lennerz
    •  & Kamila Naxerova
  • Article |

    Analysis with alleles encoding pharmacologically degradable Mediator subunits shows that Mediator acts as a global coactivator that facilitates transcription globally but is acutely required for cell-type-specific gene regulatory circuits.

    • Martin G. Jaeger
    • , Björn Schwalb
    • , Sebastian D. Mackowiak
    • , Taras Velychko
    • , Alexander Hanzl
    • , Hana Imrichova
    • , Matthias Brand
    • , Benedikt Agerer
    • , Someth Chorn
    • , Behnam Nabet
    • , Fleur M. Ferguson
    • , André C. Müller
    • , Andreas Bergthaler
    • , Nathanael S. Gray
    • , James E. Bradner
    • , Christoph Bock
    • , Denes Hnisz
    • , Patrick Cramer
    •  & Georg E. Winter

Amendments & Corrections