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  • Naming human genes
    Nat. Genet. (IF 27.603) Pub Date : 2020-08-03

    Gene nomenclature can be complicated, and the official naming of genes requires rational standards to avoid confusion and to maximize clarity. The HUGO Gene Nomenclature Committee has released updated guidelines for the naming of human genes, and we encourage the community to adopt these recommendations.

    更新日期:2020-08-03
  • Guidelines for human gene nomenclature
    Nat. Genet. (IF 27.603) Pub Date : 2020-08-03
    Elspeth A. Bruford; Bryony Braschi; Paul Denny; Tamsin E. M. Jones; Ruth L. Seal; Susan Tweedie

    Standardized gene naming is crucial for effective communication about genes, and as genomics becomes increasingly important in health care, the need for a consistent language to refer to human genes becomes ever more essential. Here, we present the current HUGO Gene Nomenclature Committee (HGNC) guidelines for naming not only protein-coding genes but also RNA genes and pseudogenes, and we outline the

    更新日期:2020-08-03
  • TADs without borders
    Nat. Genet. (IF 27.603) Pub Date : 2020-08-03
    Irene Farabella; Marc A. Marti-Renom

    Genomes are highly organized in space and time. Compartments, topologically associating domains (TADs) and loops are three dimensional (3D) genome features that have been extensively studied. Among these three levels of organization, TADs have sparked the most debate. New microscopy data shed light on how TADs and their leaky borders contribute to gene regulation.

    更新日期:2020-08-03
  • Analysis of Ugandan cervical carcinomas identifies human papillomavirus clade–specific epigenome and transcriptome landscapes
    Nat. Genet. (IF 27.603) Pub Date : 2020-08-03
    Alessia Gagliardi; Vanessa L. Porter; Zusheng Zong; Reanne Bowlby; Emma Titmuss; Constance Namirembe; Nicholas B. Griner; Hilary Petrello; Jay Bowen; Simon K. Chan; Luka Culibrk; Teresa M. Darragh; Mark H. Stoler; Thomas C. Wright; Patee Gesuwan; Maureen A. Dyer; Yussanne Ma; Karen L. Mungall; Steven J. M. Jones; Carolyn Nakisige; Karen Novik; Jackson Orem; Martin Origa; Julie M. Gastier-Foster; Robert

    Cervical cancer is the most common cancer affecting sub-Saharan African women and is prevalent among HIV-positive (HIV+) individuals. No comprehensive profiling of cancer genomes, transcriptomes or epigenomes has been performed in this population thus far. We characterized 118 tumors from Ugandan patients, of whom 72 were HIV+, and performed extended mutation analysis on an additional 89 tumors. We

    更新日期:2020-08-03
  • DNA mismatch repair promotes APOBEC3-mediated diffuse hypermutation in human cancers
    Nat. Genet. (IF 27.603) Pub Date : 2020-08-03
    David Mas-Ponte; Fran Supek

    Certain mutagens, including the APOBEC3 (A3) cytosine deaminase enzymes, can create multiple genetic changes in a single event. Activity of A3s results in striking ‘mutation showers’ occurring near DNA breakpoints; however, less is known about the mechanisms underlying the majority of A3 mutations. We classified the diverse patterns of clustered mutagenesis in tumor genomes, which identified a new

    更新日期:2020-08-03
  • Landscape of G-quadruplex DNA structural regions in breast cancer
    Nat. Genet. (IF 27.603) Pub Date : 2020-08-03
    Robert Hänsel-Hertsch; Angela Simeone; Abigail Shea; Winnie W. I. Hui; Katherine G. Zyner; Giovanni Marsico; Oscar M. Rueda; Alejandra Bruna; Alistair Martin; Xiaoyun Zhang; Santosh Adhikari; David Tannahill; Carlos Caldas; Shankar Balasubramanian

    Response and resistance to anticancer therapies vary due to intertumor and intratumor heterogeneity1. Here, we map differentially enriched G-quadruplex (G4) DNA structure-forming regions (∆G4Rs) in 22 breast cancer patient-derived tumor xenograft (PDTX) models. ∆G4Rs are associated with the promoters of highly amplified genes showing high expression, and with somatic single-nucleotide variants. Differences

    更新日期:2020-08-03
  • European maize genomes highlight intraspecies variation in repeat and gene content
    Nat. Genet. (IF 27.603) Pub Date : 2020-07-27
    Georg Haberer; Nadia Kamal; Eva Bauer; Heidrun Gundlach; Iris Fischer; Michael A. Seidel; Manuel Spannagl; Caroline Marcon; Alevtina Ruban; Claude Urbany; Adnane Nemri; Frank Hochholdinger; Milena Ouzunova; Andreas Houben; Chris-Carolin Schön; Klaus F. X. Mayer

    The diversity of maize (Zea mays) is the backbone of modern heterotic patterns and hybrid breeding. Historically, US farmers exploited this variability to establish today’s highly productive Corn Belt inbred lines from blends of dent and flint germplasm pools. Here, we report de novo genome sequences of four European flint lines assembled to pseudomolecules with scaffold N50 ranging from 6.1 to 10

    更新日期:2020-07-27
  • APOBEC3-dependent kataegis and TREX1-driven chromothripsis during telomere crisis
    Nat. Genet. (IF 27.603) Pub Date : 2020-07-27
    John Maciejowski; Aikaterini Chatzipli; Alexandra Dananberg; Kevan Chu; Eleonore Toufektchan; Leszek J. Klimczak; Dmitry A. Gordenin; Peter J. Campbell; Titia de Lange

    Chromothripsis and kataegis are frequently observed in cancer and may arise from telomere crisis, a period of genome instability during tumorigenesis when depletion of the telomere reserve generates unstable dicentric chromosomes1,2,3,4,5. Here we examine the mechanism underlying chromothripsis and kataegis by using an in vitro telomere crisis model. We show that the cytoplasmic exonuclease TREX1,

    更新日期:2020-07-27
  • Cross-species chromatin interactions drive transcriptional rewiring in Epstein–Barr virus–positive gastric adenocarcinoma
    Nat. Genet. (IF 27.603) Pub Date : 2020-07-27
    Atsushi Okabe; Kie Kyon Huang; Keisuke Matsusaka; Masaki Fukuyo; Manjie Xing; Xuewen Ong; Takayuki Hoshii; Genki Usui; Motoaki Seki; Yasunobu Mano; Bahityar Rahmutulla; Teru Kanda; Takayoshi Suzuki; Sun Young Rha; Tetsuo Ushiku; Masashi Fukayama; Patrick Tan; Atsushi Kaneda

    Epstein–Barr virus (EBV) is associated with several human malignancies including 8–10% of gastric cancers (GCs). Genome-wide analysis of 3D chromatin topologies across GC lines, primary tissue and normal gastric samples revealed chromatin domains specific to EBV-positive GC, exhibiting heterochromatin-to-euchromatin transitions and long-range human–viral interactions with non-integrated EBV episomes

    更新日期:2020-07-27
  • Characterizing the ecological and evolutionary dynamics of cancer
    Nat. Genet. (IF 27.603) Pub Date : 2020-07-27
    Nastaran Zahir; Ruping Sun; Daniel Gallahan; Robert A. Gatenby; Christina Curtis

    Tumor initiation and progression are somatic evolutionary processes driven by the accumulation of genetic alterations, some of which confer selective fitness advantages to the host cell. This gene-centric model has shaped the field of cancer biology and advanced understanding of cancer pathophysiology. Importantly, however, each genotype encodes diverse phenotypic traits that permit acclimation to

    更新日期:2020-07-27
  • Prostate cancer reactivates developmental epigenomic programs during metastatic progression
    Nat. Genet. (IF 27.603) Pub Date : 2020-07-20
    Mark M. Pomerantz; Xintao Qiu; Yanyun Zhu; David Y. Takeda; Wenting Pan; Sylvan C. Baca; Alexander Gusev; Keegan D. Korthauer; Tesa M. Severson; Gavin Ha; Srinivas R. Viswanathan; Ji-Heui Seo; Holly M. Nguyen; Baohui Zhang; Bogdan Pasaniuc; Claudia Giambartolomei; Sarah A. Alaiwi; Connor A. Bell; Edward P. O’Connor; Matthew S. Chabot; David R. Stillman; Rosina Lis; Alba Font-Tello; Lewyn Li; Paloma

    Epigenetic processes govern prostate cancer (PCa) biology, as evidenced by the dependency of PCa cells on the androgen receptor (AR), a prostate master transcription factor. We generated 268 epigenomic datasets spanning two state transitions—from normal prostate epithelium to localized PCa to metastases—in specimens derived from human tissue. We discovered that reprogrammed AR sites in metastatic PCa

    更新日期:2020-07-20
  • Imprecise DNMT1 activity coupled with neighbor-guided correction enables robust yet flexible epigenetic inheritance
    Nat. Genet. (IF 27.603) Pub Date : 2020-07-20
    Qiujun Wang; Guang Yu; Xuan Ming; Weikun Xia; Xiguang Xu; Yu Zhang; Wenhao Zhang; Yuanyuan Li; Chunyi Huang; Hehuang Xie; Bing Zhu; Wei Xie

    The epigenome, including DNA methylation, is stably propagated during mitotic division. However, single-cell clonal expansion produces heterogeneous methylomes, thus raising the question of how the DNA methylome remains stable despite constant epigenetic drift. Here, we report that a clonal population of DNA (cytosine-5)-methyltransferase 1 (DNMT1)-only cells produces a heterogeneous methylome, which

    更新日期:2020-07-20
  • The DNA methylation landscape of advanced prostate cancer
    Nat. Genet. (IF 27.603) Pub Date : 2020-07-13
    Shuang G. Zhao; William S. Chen; Haolong Li; Adam Foye; Meng Zhang; Martin Sjöström; Rahul Aggarwal; Denise Playdle; Arnold Liao; Joshi J. Alumkal; Rajdeep Das; Jonathan Chou; Junjie T. Hua; Travis J. Barnard; Adina M. Bailey; Eric D. Chow; Marc D. Perry; Ha X. Dang; Rendong Yang; Ruhollah Moussavi-Baygi; Li Zhang; Mohammed Alshalalfa; S. Laura Chang; Kathleen E. Houlahan; Yu-Jia Shiah; Tomasz M. Beer;

    Although DNA methylation is a key regulator of gene expression, the comprehensive methylation landscape of metastatic cancer has never been defined. Through whole-genome bisulfite sequencing paired with deep whole-genome and transcriptome sequencing of 100 castration-resistant prostate metastases, we discovered alterations affecting driver genes that were detectable only with integrated whole-genome

    更新日期:2020-07-13
  • Racism and the status quo
    Nat. Genet. (IF 27.603) Pub Date : 2020-07-06

    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

    更新日期:2020-07-06
  • Navigating the path to distant metastasis
    Nat. Genet. (IF 27.603) Pub Date : 2020-07-06
    Trevor A. Graham; Darryl Shibata

    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.

    更新日期:2020-07-06
  • RNA is essential for PRC2 chromatin occupancy and function in human pluripotent stem cells
    Nat. Genet. (IF 27.603) Pub Date : 2020-07-06
    Yicheng Long; Taeyoung Hwang; Anne R. Gooding; Karen J. Goodrich; John L. Rinn; Thomas R. Cech

    Many chromatin-binding proteins and protein complexes that regulate transcription also bind RNA. One of these, Polycomb repressive complex 2 (PRC2), deposits the H3K27me3 mark of facultative heterochromatin and is required for stem cell differentiation. PRC2 binds RNAs broadly in vivo and in vitro. Yet, the biological importance of this RNA binding remains unsettled. Here, we tackle this question in

    更新日期:2020-07-06
  • Discovery of regulatory noncoding variants in individual cancer genomes by using cis-X
    Nat. Genet. (IF 27.603) Pub Date : 2020-07-06
    Yu Liu; Chunliang Li; Shuhong Shen; Xiaolong Chen; Karol Szlachta; Michael N. Edmonson; Ying Shao; Xiaotu Ma; Judith Hyle; Shaela Wright; Bensheng Ju; Michael C. Rusch; Yanling Liu; Benshang Li; Michael Macias; Liqing Tian; John Easton; Maoxiang Qian; Jun J. Yang; Shaoyan Hu; A. Thomas Look; Jinghui Zhang

    We developed cis-X, a computational method for discovering regulatory noncoding variants in cancer by integrating whole-genome and transcriptome sequencing data from a single cancer sample. cis-X first finds aberrantly cis-activated genes that exhibit allele-specific expression accompanied by an elevated outlier expression. It then searches for causal noncoding variants that may introduce aberrant

    更新日期:2020-07-06
  • Pachytene piRNAs as beneficial regulators or a defense system gone rogue
    Nat. Genet. (IF 27.603) Pub Date : 2020-06-29
    Alexei A. Aravin

    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.

    更新日期:2020-06-29
  • The evolutionarily conserved piRNA-producing locus pi6 is required for male mouse fertility
    Nat. Genet. (IF 27.603) Pub Date : 2020-06-29
    Pei-Hsuan Wu; Yu Fu; Katharine Cecchini; Deniz M. Özata; Amena Arif; Tianxiong Yu; Cansu Colpan; Ildar Gainetdinov; Zhiping Weng; Phillip D. Zamore

    Pachytene PIWI-interacting RNAs (piRNAs), which comprise >80% of small RNAs in the adult mouse testis, have been proposed to bind and regulate target RNAs like microRNAs, cleave targets like short interfering RNAs or lack biological function altogether. Although piRNA pathway protein mutants are male sterile, no biological function has been identified for any mammalian piRNA-producing locus. Here,

    更新日期:2020-06-29
  • High-definition likelihood inference of genetic correlations across human complex traits
    Nat. Genet. (IF 27.603) Pub Date : 2020-06-29
    Zheng Ning; Yudi Pawitan; Xia Shen

    Genetic correlation is a central parameter for understanding shared genetic architecture between complex traits. By using summary statistics from genome-wide association studies (GWAS), linkage disequilibrium score regression (LDSC) was developed for unbiased estimation of genetic correlations. Although easy to use, LDSC only partially utilizes LD information. By fully accounting for LD across the

    更新日期:2020-06-29
  • Privacy challenges and research opportunities for genomic data sharing
    Nat. Genet. (IF 27.603) Pub Date : 2020-06-29
    Luca Bonomi; Yingxiang Huang; Lucila Ohno-Machado

    The sharing of genomic data holds great promise in advancing precision medicine and providing personalized treatments and other types of interventions. However, these opportunities come with privacy concerns, and data misuse could potentially lead to privacy infringement for individuals and their blood relatives. With the rapid growth and increased availability of genomic datasets, understanding the

    更新日期:2020-06-29
  • Genetic analyses support the contribution of mRNA N 6 -methyladenosine (m 6 A) modification to human disease heritability
    Nat. Genet. (IF 27.603) Pub Date : 2020-06-29
    Zijie Zhang; Kaixuan Luo; Zhongyu Zou; Maguanyun Qiu; Jiakun Tian; Laura Sieh; Hailing Shi; Yuxin Zou; Gao Wang; Jean Morrison; Allen C. Zhu; Min Qiao; Zhongshan Li; Matthew Stephens; Xin He; Chuan He

    N6-methyladenosine (m6A) plays important roles in regulating messenger RNA processing. Despite rapid progress in this field, little is known about the genetic determinants of m6A modification and their role in common diseases. In this study, we mapped the quantitative trait loci (QTLs) of m6A peaks in 60 Yoruba (YRI) lymphoblastoid cell lines. We found that m6A QTLs are largely independent of expression

    更新日期:2020-06-29
  • Single-cell analysis of clonal maintenance of transcriptional and epigenetic states in cancer cells
    Nat. Genet. (IF 27.603) Pub Date : 2020-06-29
    Zohar Meir; Zohar Mukamel; Elad Chomsky; Aviezer Lifshitz; Amos Tanay

    Propagation of clonal regulatory programs contributes to cancer development. It is poorly understood how epigenetic mechanisms interact with genetic drivers to shape this process. Here, we combine single-cell analysis of transcription and DNA methylation with a Luria–Delbrück experimental design to demonstrate the existence of clonally stable epigenetic memory in multiple types of cancer cells. Longitudinal

    更新日期:2020-06-29
  • Genomic analyses implicate noncoding de novo variants in congenital heart disease
    Nat. Genet. (IF 27.603) Pub Date : 2020-06-29
    Felix Richter; Sarah U. Morton; Seong Won Kim; Alexander Kitaygorodsky; Lauren K. Wasson; Kathleen M. Chen; Jian Zhou; Hongjian Qi; Nihir Patel; Steven R. DePalma; Michael Parfenov; Jason Homsy; Joshua M. Gorham; Kathryn B. Manheimer; Matthew Velinder; Andrew Farrell; Gabor Marth; Eric E. Schadt; Jonathan R. Kaltman; Jane W. Newburger; Alessandro Giardini; Elizabeth Goldmuntz; Martina Brueckner; Richard

    A genetic etiology is identified for one-third of patients with congenital heart disease (CHD), with 8% of cases attributable to coding de novo variants (DNVs). To assess the contribution of noncoding DNVs to CHD, we compared genome sequences from 749 CHD probands and their parents with those from 1,611 unaffected trios. Neural network prediction of noncoding DNV transcriptional impact identified a

    更新日期:2020-06-29
  • Author Correction: Cas9 activates the p53 pathway and selects for p53-inactivating mutations
    Nat. Genet. (IF 27.603) Pub Date : 2020-06-25
    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

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    更新日期:2020-06-25
  • Cohesin promotes stochastic domain intermingling to ensure proper regulation of boundary-proximal genes.
    Nat. Genet. (IF 27.603) Pub Date : 2020-06-22
    Jennifer M Luppino,Daniel S Park,Son C Nguyen,Yemin Lan,Zhuxuan Xu,Rebecca Yunker,Eric F Joyce

    The human genome can be segmented into topologically associating domains (TADs), which have been proposed to spatially sequester genes and regulatory elements through chromatin looping. Interactions between TADs have also been suggested, presumably because of variable boundary positions across individual cells. However, the nature, extent and consequence of these dynamic boundaries remain unclear.

    更新日期:2020-06-23
  • Author Correction: A transcriptomic analysis of the phylum Nematoda.
    Nat. Genet. (IF 27.603) Pub Date : 2020-06-15
    John Parkinson,Makedonka Mitreva,Claire Whitton,Marian Thomson,Jennifer Daub,John Martin,Ralf Schmid,Neil Hall,Bart Barrell,Robert H Waterston,James P McCarter,Mark L Blaxter

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    更新日期:2020-06-15
  • Recurrent inversion toggling and great ape genome evolution.
    Nat. Genet. (IF 27.603) Pub Date : 2020-06-15
    David Porubsky,Ashley D Sanders,Wolfram Höps,PingHsun Hsieh,Arvis Sulovari,Ruiyang Li,Ludovica Mercuri,Melanie Sorensen,Shwetha C Murali,David Gordon,Stuart Cantsilieris,Alex A Pollen,Mario Ventura,Francesca Antonacci,Tobias Marschall,Jan O Korbel,Evan E Eichler

    Inversions play an important role in disease and evolution but are difficult to characterize because their breakpoints map to large repeats. We increased by sixfold the number (n = 1,069) of previously reported great ape inversions by using single-cell DNA template strand and long-read sequencing. We find that the X chromosome is most enriched (2.5-fold) for inversions, on the basis of its size and

    更新日期:2020-06-15
  • Discovery of 318 new risk loci for type 2 diabetes and related vascular outcomes among 1.4 million participants in a multi-ancestry meta-analysis.
    Nat. Genet. (IF 27.603) Pub Date : 2020-06-15
    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

    We investigated type 2 diabetes (T2D) genetic susceptibility via multi-ancestry meta-analysis of 228,499 cases and 1,178,783 controls in the Million Veteran Program (MVP), DIAMANTE, Biobank Japan and other studies. We report 568 associations, including 286 autosomal, 7 X-chromosomal and 25 identified in ancestry-specific analyses that were previously unreported. Transcriptome-wide association analysis

    更新日期:2020-06-15
  • TETs compete with DNMT3 activity in pluripotent cells at thousands of methylated somatic enhancers.
    Nat. Genet. (IF 27.603) Pub Date : 2020-06-08
    Jocelyn Charlton,Eunmi J Jung,Alexandra L Mattei,Nina Bailly,Jing Liao,Eric J Martin,Pay Giesselmann,Björn Brändl,Elena K Stamenova,Franz-Josef Müller,Evangelos Kiskinis,Andreas Gnirke,Zachary D Smith,Alexander Meissner

    Mammalian cells stably maintain high levels of DNA methylation despite expressing both positive (DNMT3A/B) and negative (TET1-3) regulators. Here, we analyzed the independent and combined effects of these regulators on the DNA methylation landscape using a panel of knockout human embryonic stem cell (ESC) lines. The greatest impact on global methylation levels was observed in DNMT3-deficient cells

    更新日期:2020-06-08
  • Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases.
    Nat. Genet. (IF 27.603) Pub Date : 2020-06-08
    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

    The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P < 9.58 × 10−9). East Asian–specific missense variants

    更新日期:2020-06-08
  • CTCF is dispensable for immune cell transdifferentiation but facilitates an acute inflammatory response.
    Nat. Genet. (IF 27.603) Pub Date : 2020-06-08
    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

    Three-dimensional organization of the genome is important for transcriptional regulation1,2,3,4,5,6,7. In mammals, CTCF and the cohesin complex create submegabase structures with elevated internal chromatin contact frequencies, called topologically associating domains (TADs)8,9,10,11,12. Although TADs can contribute to transcriptional regulation, ablation of TAD organization by disrupting CTCF or the

    更新日期:2020-06-08
  • DNMT3A and TET2 mutations reshape hematopoiesis in opposing ways.
    Nat. Genet. (IF 27.603) Pub Date : 2020-06-05
    Isaac F López-Moyado,Anjana Rao

    TET2 and DNMT3A mutations lead to similar long-term outcomes in blood cancers despite the antagonistic biochemical functions of their encoded proteins. A new study highlights the opposing effects of TET2 and DNMT3A mutations in shaping the early erythroid or myeloid bias of hematopoietic progenitors.

    更新日期:2020-06-05
  • Going virtual.
    Nat. Genet. (IF 27.603) Pub Date : 2020-06-05

    One of the many consequences of the global COVID-19 pandemic is the need for the scientific community to adapt to the cancellation of conferences and events because of travel restrictions and social-distancing guidelines. We have seen a very swift conversion to online meetings, which have allowed for this established form of science communication to continue and opened new avenues for innovation in

    更新日期:2020-06-05
  • Exploring and visualizing large-scale genetic associations by using PheWeb.
    Nat. Genet. (IF 27.603) Pub Date : 2020-06-01
    Sarah A Gagliano Taliun,Peter VandeHaar,Andrew P Boughton,Ryan P Welch,Daniel Taliun,Ellen M Schmidt,Wei Zhou,Jonas B Nielsen,Cristen J Willer,Seunggeun Lee,Lars G Fritsche,Michael Boehnke,Gonçalo R Abecasis

    更新日期:2020-06-01
  • Selective Mediator dependence of cell-type-specifying transcription.
    Nat. Genet. (IF 27.603) Pub Date : 2020-06-01
    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

    The Mediator complex directs signals from DNA-binding transcription factors to RNA polymerase II (Pol II). Despite this pivotal position, mechanistic understanding of Mediator in human cells remains incomplete. Here we quantified Mediator-controlled Pol II kinetics by coupling rapid subunit degradation with orthogonal experimental readouts. In agreement with a model of condensate-driven transcription

    更新日期:2020-06-01
  • Unraveling tumor-immune heterogeneity in advanced ovarian cancer uncovers immunogenic effect of chemotherapy.
    Nat. Genet. (IF 27.603) Pub Date : 2020-06-01
    Alejandro Jiménez-Sánchez,Paulina Cybulska,Katherine LaVigne Mager,Simon Koplev,Oliver Cast,Dominique-Laurent Couturier,Danish Memon,Pier Selenica,Ines Nikolovski,Yousef Mazaheri,Yonina Bykov,Felipe C Geyer,Geoff Macintyre,Lena Morrill Gavarró,Ruben M Drews,Michael B Gill,Anastasios D Papanastasiou,Ramon E Sosa,Robert A Soslow,Tyler Walther,Ronglai Shen,Dennis S Chi,Kay J Park,Travis Hollmann,Jorge

    In metastatic cancer, the degree of heterogeneity of the tumor microenvironment (TME) and its molecular underpinnings remain largely unstudied. To characterize the tumor–immune interface at baseline and during neoadjuvant chemotherapy (NACT) in high-grade serous ovarian cancer (HGSOC), we performed immunogenomic analysis of treatment-naive and paired samples from before and after treatment with chemotherapy

    更新日期:2020-06-01
  • Publisher Correction: Mendelian randomization accounting for correlated and uncorrelated pleiotropic effects using genome-wide summary statistics.
    Nat. Genet. (IF 27.603) Pub Date : 2020-05-29
    Jean Morrison,Nicholas Knoblauch,Joseph H Marcus,Matthew Stephens,Xin He

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    更新日期:2020-05-29
  • Author Correction: Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes.
    Nat. Genet. (IF 27.603) Pub Date : 2020-05-26
    Andrea Cortese,Yi Zhu,Adriana P Rebelo,Sara Negri,Steve Courel,Lisa Abreu,Chelsea J Bacon,Yunhong Bai,Dana M Bis-Brewer,Enrico Bugiardini,Elena Buglo,Matt C Danzi,Shawna M E Feely,Alkyoni Athanasiou-Fragkouli,Nourelhoda A Haridy,,Rosario Isasi,Alaa Khan,Matilde Laurà,Stefania Magri,Menelaos Pipis,Chiara Pisciotta,Eric Powell,Alexander M Rossor,Paola Saveri,Janet E Sowden,Stefano Tozza,Jana Vandrovcova

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    更新日期:2020-05-26
  • Mendelian randomization accounting for correlated and uncorrelated pleiotropic effects using genome-wide summary statistics.
    Nat. Genet. (IF 27.603) Pub Date : 2020-05-25
    Jean Morrison,Nicholas Knoblauch,Joseph H Marcus,Matthew Stephens,Xin He

    Mendelian randomization (MR) is a valuable tool for detecting causal effects by using genetic variant associations. Opportunities to apply MR are growing rapidly with the increasing number of genome-wide association studies (GWAS). However, existing MR methods rely on strong assumptions that are often violated, leading to false positives. Correlated horizontal pleiotropy, which arises when variants

    更新日期:2020-05-25
  • Lineage-dependent gene expression programs influence the immune landscape of colorectal cancer.
    Nat. Genet. (IF 27.603) Pub Date : 2020-05-25
    Hae-Ock Lee,Yourae Hong,Hakki Emre Etlioglu,Yong Beom Cho,Valentina Pomella,Ben Van den Bosch,Jasper Vanhecke,Sara Verbandt,Hyekyung Hong,Jae-Woong Min,Nayoung Kim,Hye Hyeon Eum,Junbin Qian,Bram Boeckx,Diether Lambrechts,Petros Tsantoulis,Gert De Hertogh,Woosung Chung,Taeseob Lee,Minae An,Hyun-Tae Shin,Je-Gun Joung,Min-Hyeok Jung,Gunhwan Ko,Pratyaksha Wirapati,Seok Hyung Kim,Hee Cheol Kim,Seong Hyeon

    Immunotherapy for metastatic colorectal cancer is effective only for mismatch repair-deficient tumors with high microsatellite instability that demonstrate immune infiltration, suggesting that tumor cells can determine their immune microenvironment. To understand this cross-talk, we analyzed the transcriptome of 91,103 unsorted single cells from 23 Korean and 6 Belgian patients. Cancer cells displayed

    更新日期:2020-05-25
  • Lymph node metastases develop through a wider evolutionary bottleneck than distant metastases.
    Nat. Genet. (IF 27.603) Pub Date : 2020-05-25
    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

    Genetic diversity among metastases is poorly understood but contains important information about disease evolution at secondary sites. Here we investigate inter- and intra-lesion heterogeneity for two types of metastases that associate with different clinical outcomes: lymph node and distant organ metastases in human colorectal cancer. We develop a rigorous mathematical framework for quantifying metastatic

    更新日期:2020-05-25
  • Spatial competition shapes the dynamic mutational landscape of normal esophageal epithelium.
    Nat. Genet. (IF 27.603) Pub Date : 2020-05-18
    Bartomeu Colom,Maria P Alcolea,Gabriel Piedrafita,Michael W J Hall,Agnieszka Wabik,Stefan C Dentro,Joanna C Fowler,Albert Herms,Charlotte King,Swee Hoe Ong,Roshan K Sood,Moritz Gerstung,Inigo Martincorena,Benjamin A Hall,Philip H Jones

    During aging, progenitor cells acquire mutations, which may generate clones that colonize the surrounding tissue. By middle age, normal human tissues, including the esophageal epithelium (EE), become a patchwork of mutant clones. Despite their relevance for understanding aging and cancer, the processes that underpin mutational selection in normal tissues remain poorly understood. Here, we investigated

    更新日期:2020-05-18
  • Quantifying genetic effects on disease mediated by assayed gene expression levels.
    Nat. Genet. (IF 27.603) Pub Date : 2020-05-18
    Douglas W Yao,Luke J O'Connor,Alkes L Price,Alexander Gusev

    Disease variants identified by genome-wide association studies (GWAS) tend to overlap with expression quantitative trait loci (eQTLs), but it remains unclear whether this overlap is driven by gene expression levels 'mediating' genetic effects on disease. Here, we introduce a new method, mediated expression score regression (MESC), to estimate disease heritability mediated by the cis genetic component

    更新日期:2020-05-18
  • Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.
    Nat. Genet. (IF 27.603) Pub Date : 2020-05-18
    Haoyu Zhang,Thomas U Ahearn,Julie Lecarpentier,Daniel Barnes,Jonathan Beesley,Guanghao Qi,Xia Jiang,Tracy A O'Mara,Ni Zhao,Manjeet K Bolla,Alison M Dunning,Joe Dennis,Qin Wang,Zumuruda Abu Ful,Kristiina Aittomäki,Irene L Andrulis,Hoda Anton-Culver,Volker Arndt,Kristan J Aronson,Banu K Arun,Paul L Auer,Jacopo Azzollini,Daniel Barrowdale,Heiko Becher,Matthias W Beckmann,Sabine Behrens,Javier Benitez

    Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity

    更新日期:2020-05-18
  • Cas9 activates the p53 pathway and selects for p53-inactivating mutations.
    Nat. Genet. (IF 27.603) Pub Date : 2020-05-18
    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

    Cas9 is commonly introduced into cell lines to enable CRISPR-Cas9-mediated genome editing. Here, we studied the genetic and transcriptional consequences of Cas9 expression itself. Gene expression profiling of 165 pairs of human cancer cell lines and their Cas9-expressing derivatives revealed upregulation of the p53 pathway upon introduction of Cas9, specifically in wild-type TP53 (TP53-WT) cell lines

    更新日期:2020-05-18
  • Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases.
    Nat. Genet. (IF 27.603) Pub Date : 2020-05-18
    Zheng Hu,Zan Li,Zhicheng Ma,Christina Curtis

    Metastasis is the primary cause of cancer-related deaths, but the natural history, clonal evolution and impact of treatment are poorly understood. We analyzed whole-exome sequencing (WES) data from 457 paired primary tumor and metastatic samples from 136 patients with breast, colorectal and lung cancer, including untreated (n = 99) and treated (n = 100) metastases. Treated metastases often harbored

    更新日期:2020-05-18
  • Clonal competition in a confined space.
    Nat. Genet. (IF 27.603) Pub Date : 2020-05-18
    Kamila Naxerova

    Many normal tissues are populated by clonal expansions that compete for space. Colom et al. now show that mutant clones keep other mutant clones in check by effectively annulling one another’s advantages.

    更新日期:2020-05-18
  • Scalable generalized linear mixed model for region-based association tests in large biobanks and cohorts.
    Nat. Genet. (IF 27.603) Pub Date : 2020-05-18
    Wei Zhou,Zhangchen Zhao,Jonas B Nielsen,Lars G Fritsche,Jonathon LeFaive,Sarah A Gagliano Taliun,Wenjian Bi,Maiken E Gabrielsen,Mark J Daly,Benjamin M Neale,Kristian Hveem,Goncalo R Abecasis,Cristen J Willer,Seunggeun Lee

    With very large sample sizes, biobanks provide an exciting opportunity to identify genetic components of complex traits. To analyze rare variants, region-based multiple-variant aggregate tests are commonly used to increase power for association tests. However, because of the substantial computational cost, existing region-based tests cannot analyze hundreds of thousands of samples while accounting

    更新日期:2020-05-18
  • Publisher Correction: Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing.
    Nat. Genet. (IF 27.603) Pub Date : 2020-05-13
    Isidro Cortés-Ciriano,Jake June-Koo Lee,Ruibin Xi,Dhawal Jain,Youngsook L Jung,Lixing Yang,Dmitry Gordenin,Leszek J Klimczak,Cheng-Zhong Zhang,David S Pellman,,Peter J Park,

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    更新日期:2020-05-13
  • Reply to: Evaluating two different models of peanut's origin.
    Nat. Genet. (IF 27.603) Pub Date : 2020-05-11
    Weijian Zhuang,Xiyin Wang,Andrew H Paterson,Hua Chen,Meng Yang,Chong Zhang,Pengchuan Sun,Yixiong Zheng,Lihui Wang,Wenping Xie,Wenting Chu,Huiwen Fu,Rajeev K Varshney

    更新日期:2020-05-11
  • Evaluating two different models of peanut's origin.
    Nat. Genet. (IF 27.603) Pub Date : 2020-05-11
    David J Bertioli,Brian Abernathy,Guillermo Seijo,Josh Clevenger,Steven B Cannon

    更新日期:2020-05-11
  • Uncoupling histone H3K4 trimethylation from developmental gene expression via an equilibrium of COMPASS, Polycomb and DNA methylation.
    Nat. Genet. (IF 27.603) Pub Date : 2020-05-11
    Delphine Douillet,Christie C Sze,Caila Ryan,Andrea Piunti,Avani P Shah,Michal Ugarenko,Stacy A Marshall,Emily J Rendleman,Didi Zha,Kathryn A Helmin,Zibo Zhao,Kaixiang Cao,Marc A Morgan,Benjamin D Singer,Elizabeth T Bartom,Edwin R Smith,Ali Shilatifard

    The COMPASS protein family catalyzes histone H3 Lys 4 (H3K4) methylation and its members are essential for regulating gene expression. MLL2/COMPASS methylates H3K4 on many developmental genes and bivalent clusters. To understand MLL2-dependent transcriptional regulation, we performed a CRISPR-based screen with an MLL2-dependent gene as a reporter in mouse embryonic stem cells. We found that MLL2 functions

    更新日期:2020-05-11
  • Tracking genetic discrimination.
    Nat. Genet. (IF 27.603) Pub Date : 2020-05-01

    The promise of personalized medicine lies in the tailored treatment of individual patients, a process requiring detailed phenotypic and genetic information. Although the widespread collection of such data can help to advance the implementation of precision healthcare, the genomic sequencing data being amassed also include private information that could potentially be used as a basis for genetic discrimination

    更新日期:2020-05-06
  • Enhancer-promoter interactions and transcription.
    Nat. Genet. (IF 27.603) Pub Date : 2020-05-01
    Douglas R Higgs

    A new study addresses whether transcription of enhancers and the resulting enhancer RNAs (eRNAs) play a role in mediating long-range interactions between enhancers and promoters. Studying the immunoglobulin heavy chain (Igh) locus, the authors find that transcription of the enhancers per se is required to establish but not maintain these interactions, and this mechanism may apply to a subset of other

    更新日期:2020-05-06
  • Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes.
    Nat. Genet. (IF 27.603) Pub Date : 2020-05-04
    Andrea Cortese,Yi Zhu,Adriana P Rebelo,Sara Negri,Steve Courel,Lisa Abreu,Chelsea J Bacon,Yunhong Bai,Dana M Bis-Brewer,Enrico Bugiardini,Elena Buglo,Matt C Danzi,Shawna M E Feely,Alkyoni Athanasiou-Fragkouli,Nourelhoda A Haridy,,Rosario Isasi,Alaa Khan,Matilde Laurà,Stefania Magri,Menelaos Pipis,Chiara Pisciotta,Eric Powell,Alexander M Rossor,Paola Saveri,Janet E Sowden,Stefano Tozza,Jana Vandrovcova

    Here we report biallelic mutations in the sorbitol dehydrogenase gene (SORD) as the most frequent recessive form of hereditary neuropathy. We identified 45 individuals from 38 families across multiple ancestries carrying the nonsense c.757delG (p.Ala253GlnfsTer27) variant in SORD, in either a homozygous or compound heterozygous state. SORD is an enzyme that converts sorbitol into fructose in the two-step

    更新日期:2020-05-04
  • Elevated sorbitol underlies a heritable neuropathy.
    Nat. Genet. (IF 27.603) Pub Date : 2020-05-01
    Eva Morava

    A new study identifies sorbitol dehydrogenase (SORD) deficiency as a slowly progressive hereditary motor axonopathy caused by a genetic defect in the second step of the polyol pathway, thus leading to elevated tissue and blood sorbitol. SORD deficiency is the most common recessive cause of neuropathy, for which therapeutic intervention with aldose reductase inhibitors may have potential.

    更新日期:2020-05-04
  • Author Correction: Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation.
    Nat. Genet. (IF 27.603) Pub Date : 2020-05-01
    Aaheli Roy Choudhury,Zhenyu Ju,Meta W Djojosubroto,Andrea Schienke,Andre Lechel,Sonja Schaetzlein,Hong Jiang,Anna Stepczynska,Chunfang Wang,Jan Buer,Han-Woong Lee,Thomas von Zglinicki,Arnold Ganser,Peter Schirmacher,Hiromitsu Nakauchi,K Lenhard Rudolph

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    更新日期:2020-04-30
  • Author Correction: Comprehensive molecular characterization of mitochondrial genomes in human cancers.
    Nat. Genet. (IF 27.603) Pub Date : 2020-04-27
    Yuan Yuan,Young Seok Ju,Youngwook Kim,Jun Li,Yumeng Wang,Christopher J Yoon,Yang Yang,Inigo Martincorena,Chad J Creighton,John N Weinstein,Yanxun Xu,Leng Han,Hyung-Lae Kim,Hidewaki Nakagawa,Keunchil Park,Peter J Campbell,Han Liang,

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    更新日期:2020-04-27
  • Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson's disease.
    Nat. Genet. (IF 27.603) Pub Date : 2020-04-27
    Julien Bryois,Nathan G Skene,Thomas Folkmann Hansen,Lisette J A Kogelman,Hunna J Watson,Zijing Liu,,,,Leo Brueggeman,Gerome Breen,Cynthia M Bulik,Ernest Arenas,Jens Hjerling-Leffler,Patrick F Sullivan

    Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders

    更新日期:2020-04-27
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