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  • Loosening the grip on nuclear cGAS
    Nat. Genet. (IF 27.603) Pub Date : 2020-11-23
    Fiachra Humphries; Katherine A. Fitzgerald

    Maintaining ignorance to self-nucleic acids can prevent inflammatory diseases such as Aicardi–Goutières syndrome (AGS). A new study finds that mutations in LSM11 and RNU7-1, which encode components of the histone messenger RNA–preprocessing complex, cause AGS by loosening the binding of cyclic GMP–AMP synthase (cGAS) to nucleosomes, thus enabling cGAS activation and induction of type I interferons

    更新日期:2020-11-23
  • Integrated molecular drivers coordinate biological and clinical states in melanoma
    Nat. Genet. (IF 27.603) Pub Date : 2020-11-23
    Jake R. Conway; Felix Dietlein; Amaro Taylor-Weiner; Saud AlDubayan; Natalie Vokes; Tanya Keenan; Brendan Reardon; Meng Xiao He; Claire A. Margolis; Jason L. Weirather; Rizwan Haq; Bastian Schilling; F. Stephen Hodi; Dirk Schadendorf; David Liu; Eliezer M. Van Allen

    We performed harmonized molecular and clinical analysis on 1,048 melanomas and discovered markedly different global genomic properties among subtypes (BRAF, (N)RAS, NF1, triple wild-type (TWT)), subtype-specific preferences for secondary driver genes and active mutational processes previously unreported in melanoma. Secondary driver genes significantly enriched in specific subtypes reflected preferential

    更新日期:2020-11-23
  • Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
    Nat. Genet. (IF 27.603) Pub Date : 2020-11-23
    Praveen Surendran; Elena V. Feofanova; Najim Lahrouchi; Ioanna Ntalla; Savita Karthikeyan; James Cook; Lingyan Chen; Borbala Mifsud; Chen Yao; Aldi T. Kraja; James H. Cartwright; Jacklyn N. Hellwege; Ayush Giri; Vinicius Tragante; Gudmar Thorleifsson; Dajiang J. Liu; Bram P. Prins; Isobel D. Stewart; Claudia P. Cabrera; James M. Eales; Artur Akbarov; Paul L. Auer; Lawrence F. Bielak; Joshua C. Bis;

    Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10−8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide

    更新日期:2020-11-23
  • cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing
    Nat. Genet. (IF 27.603) Pub Date : 2020-11-23
    Carolina Uggenti; Alice Lepelley; Marine Depp; Andrew P. Badrock; Mathieu P. Rodero; Marie-Thérèse El-Daher; Gillian I. Rice; Somdutta Dhir; Ann P. Wheeler; Ashish Dhir; Waad Albawardi; Marie-Louise Frémond; Luis Seabra; Jennifer Doig; Natalie Blair; Maria José Martin-Niclos; Erika Della Mina; Alejandro Rubio-Roldán; Jose L. García-Pérez; Duncan Sproul; Jan Rehwinkel; Jonny Hertzog; Anne Boland-Auge;

    Inappropriate stimulation or defective negative regulation of the type I interferon response can lead to autoinflammation. In genetically uncharacterized cases of the type I interferonopathy Aicardi–Goutières syndrome, we identified biallelic mutations in LSM11 and RNU7-1, which encode components of the replication-dependent histone pre-mRNA–processing complex. Mutations were associated with the misprocessing

    更新日期:2020-11-23
  • Common variants in signaling transcription-factor-binding sites drive phenotypic variability in red blood cell traits
    Nat. Genet. (IF 27.603) Pub Date : 2020-11-23
    Avik Choudhuri; Eirini Trompouki; Brian J. Abraham; Leandro M. Colli; Kian Hong Kock; William Mallard; Min-Lee Yang; Divya S. Vinjamur; Alireza Ghamari; Audrey Sporrij; Karen Hoi; Barbara Hummel; Sonja Boatman; Victoria Chan; Sierra Tseng; Satish K. Nandakumar; Song Yang; Asher Lichtig; Michael Superdock; Seraj N. Grimes; Teresa V. Bowman; Yi Zhou; Shinichiro Takahashi; Roby Joehanes; Alan B. Cantor;

    Genome-wide association studies identify genomic variants associated with human traits and diseases. Most trait-associated variants are located within cell-type-specific enhancers, but the molecular mechanisms governing phenotypic variation are less well understood. Here, we show that many enhancer variants associated with red blood cell (RBC) traits map to enhancers that are co-bound by lineage-specific

    更新日期:2020-11-23
  • Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors
    Nat. Genet. (IF 27.603) Pub Date : 2020-11-16
    Mark K. Bakker; Rick A. A. van der Spek; Wouter van Rheenen; Sandrine Morel; Romain Bourcier; Isabel C. Hostettler; Varinder S. Alg; Kristel R. van Eijk; Masaru Koido; Masato Akiyama; Chikashi Terao; Koichi Matsuda; Robin G. Walters; Kuang Lin; Liming Li; Iona Y. Millwood; Zhengming Chen; Guy A. Rouleau; Sirui Zhou; Kristiina Rannikmäe; Cathie L. M. Sudlow; Henry Houlden; Leonard H. van den Berg; Christian

    Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain

    更新日期:2020-11-16
  • Functionally informed fine-mapping and polygenic localization of complex trait heritability
    Nat. Genet. (IF 27.603) Pub Date : 2020-11-16
    Omer Weissbrod; Farhad Hormozdiari; Christian Benner; Ran Cui; Jacob Ulirsch; Steven Gazal; Armin P. Schoech; Bryce van de Geijn; Yakir Reshef; Carla Márquez-Luna; Luke O’Connor; Matti Pirinen; Hilary K. Finucane; Alkes L. Price

    Fine-mapping aims to identify causal variants impacting complex traits. We propose PolyFun, a computationally scalable framework to improve fine-mapping accuracy by leveraging functional annotations across the entire genome—not just genome-wide-significant loci—to specify prior probabilities for fine-mapping methods such as SuSiE or FINEMAP. In simulations, PolyFun + SuSiE and PolyFun + FINEMAP were

    更新日期:2020-11-16
  • MLL4-associated condensates counterbalance Polycomb-mediated nuclear mechanical stress in Kabuki syndrome
    Nat. Genet. (IF 27.603) Pub Date : 2020-11-09
    Alessandra Fasciani; Sarah D’Annunzio; Vittoria Poli; Luca Fagnocchi; Sven Beyes; Daniela Michelatti; Francesco Corazza; Laura Antonelli; Francesco Gregoretti; Gennaro Oliva; Romina Belli; Daniele Peroni; Enrico Domenici; Samuel Zambrano; Daniela Intartaglia; Carmine Settembre; Ivan Conte; Claudia Testi; Panagiotis Vergyris; Giancarlo Ruocco; Alessio Zippo

    The genetic elements required to tune gene expression are partitioned in active and repressive nuclear condensates. Chromatin compartments include transcriptional clusters whose dynamic establishment and functioning depend on multivalent interactions occurring among transcription factors, cofactors and basal transcriptional machinery. However, how chromatin players contribute to the assembly of transcriptional

    更新日期:2020-11-09
  • José Luis Gómez-Skarmeta (1966–2020)
    Nat. Genet. (IF 27.603) Pub Date : 2020-11-04
    Ozren Bogdanovic; Manuel Irimia

    On 16 September 2020, when the news of José Luis Gómez-Skarmeta’s untimely passing broke, the scientific community was left in dismay.

    更新日期:2020-11-04
  • BAHCC1 binds H3K27me3 via a conserved BAH module to mediate gene silencing and oncogenesis
    Nat. Genet. (IF 27.603) Pub Date : 2020-11-02
    Huitao Fan; Jiuwei Lu; Yiran Guo; Dongxu Li; Zhi-Min Zhang; Yi-Hsuan Tsai; Wen-Chieh Pi; Jeong Hyun Ahn; Weida Gong; Yu Xiang; David F. Allison; Huimin Geng; Shenghui He; Yarui Diao; Wei-Yi Chen; Brian D. Strahl; Ling Cai; Jikui Song; Gang Greg Wang

    Trimethylated histone H3 lysine 27 (H3K27me3) regulates gene repression, cell-fate determination and differentiation. We report that a conserved bromo-adjacent homology (BAH) module of BAHCC1 (BAHCC1BAH) ‘recognizes’ H3K27me3 specifically and enforces silencing of H3K27me3-demarcated genes in mammalian cells. Biochemical, structural and integrated chromatin immunoprecipitation-sequencing-based analyses

    更新日期:2020-11-02
  • Phased diploid genome assemblies and pan-genomes provide insights into the genetic history of apple domestication
    Nat. Genet. (IF 27.603) Pub Date : 2020-11-02
    Xuepeng Sun; Chen Jiao; Heidi Schwaninger; C. Thomas Chao; Yumin Ma; Naibin Duan; Awais Khan; Seunghyun Ban; Kenong Xu; Lailiang Cheng; Gan-Yuan Zhong; Zhangjun Fei

    Domestication of the apple was mainly driven by interspecific hybridization. In the present study, we report the haplotype-resolved genomes of the cultivated apple (Malus domestica cv. Gala) and its two major wild progenitors, M. sieversii and M. sylvestris. Substantial variations are identified between the two haplotypes of each genome. Inference of genome ancestry identifies ~23% of the Gala genome

    更新日期:2020-11-02
  • Personal perspective: bootless
    Nat. Genet. (IF 27.603) Pub Date : 2020-10-30
    Russell J. Ledet

    Given an opportunity to chronicle the experience of traversing America as a Black man, I elect to convey a less frequently told vantage point. This is the perspective of the ‘accomplished’ bootless.

    更新日期:2020-10-30
  • Evolutionary dependencies show paths to cancer development
    Nat. Genet. (IF 27.603) Pub Date : 2020-10-30
    Martin S. Taylor

    Patterns of co-occurring and mutually exclusive mutations reveal synergistic interactions among cancer driver genes. A new study functionally confirms these interactions and builds the pairwise relationships into networks of pathway disruption that have better predictive power than specific mutations alone.

    更新日期:2020-10-30
  • Are carcinogens direct mutagens?
    Nat. Genet. (IF 27.603) Pub Date : 2020-10-30
    Nuria Lopez-Bigas; Abel Gonzalez-Perez

    In a classical view of carcinogenesis, carcinogens directly cause mutations. In this issue, Riva et al. explore the effects of 20 known or suspected human carcinogens and find discernible mutational signatures for only three of them.

    更新日期:2020-10-30
  • Assembly of whole-chromosome pseudomolecules for polyploid plant genomes using outbred mapping populations
    Nat. Genet. (IF 27.603) Pub Date : 2020-10-30
    Chenxi Zhou; Bode Olukolu; Dorcus C. Gemenet; Shan Wu; Wolfgang Gruneberg; Minh Duc Cao; Zhangjun Fei; Zhao-Bang Zeng; Andrew W. George; Awais Khan; G. Craig Yencho; Lachlan J. M. Coin

    Despite advances in sequencing technologies, assembly of complex plant genomes remains elusive due to polyploidy and high repeat content. Here we report PolyGembler for grouping and ordering contigs into pseudomolecules by genetic linkage analysis. Our approach also provides an accurate method with which to detect and fix assembly errors. Using simulated data, we demonstrate that our approach is of

    更新日期:2020-10-30
  • Pan-cancer single-cell RNA-seq identifies recurring programs of cellular heterogeneity
    Nat. Genet. (IF 27.603) Pub Date : 2020-10-30
    Gabriela S. Kinker; Alissa C. Greenwald; Rotem Tal; Zhanna Orlova; Michael S. Cuoco; James M. McFarland; Allison Warren; Christopher Rodman; Jennifer A. Roth; Samantha A. Bender; Bhavna Kumar; James W. Rocco; Pedro A. C. M. Fernandes; Christopher C. Mader; Hadas Keren-Shaul; Alexander Plotnikov; Haim Barr; Aviad Tsherniak; Orit Rozenblatt-Rosen; Valery Krizhanovsky; Sidharth V. Puram; Aviv Regev; Itay

    Cultured cell lines are the workhorse of cancer research, but the extent to which they recapitulate the heterogeneity observed among malignant cells in tumors is unclear. Here we used multiplexed single-cell RNA-seq to profile 198 cancer cell lines from 22 cancer types. We identified 12 expression programs that are recurrently heterogeneous within multiple cancer cell lines. These programs are associated

    更新日期:2020-10-30
  • The critical roles of somatic mutations and environmental tumor-promoting agents in cancer risk
    Nat. Genet. (IF 27.603) Pub Date : 2020-10-26
    Allan Balmain

    Cancer is driven by genomic mutations in ‘cancer driver’ genes, which have essential roles in tumor development. These mutations may be caused by exposure to mutagens in the environment or by endogenous DNA-replication errors in tissue stem cells. Recent observations of abundant mutations, including cancer driver mutations, in histologically normal human tissues suggest that mutations alone are not

    更新日期:2020-10-28
  • Cancer therapy shapes the fitness landscape of clonal hematopoiesis
    Nat. Genet. (IF 27.603) Pub Date : 2020-10-26
    Kelly L. Bolton; Ryan N. Ptashkin; Teng Gao; Lior Braunstein; Sean M. Devlin; Daniel Kelly; Minal Patel; Antonin Berthon; Aijazuddin Syed; Mariko Yabe; Catherine C. Coombs; Nicole M. Caltabellotta; Mike Walsh; Kenneth Offit; Zsofia Stadler; Diana Mandelker; Jessica Schulman; Akshar Patel; John Philip; Elsa Bernard; Gunes Gundem; Juan E. Arango Ossa; Max Levine; Juan S. Medina Martinez; Noushin Farnoud;

    Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched

    更新日期:2020-10-28
  • Triticum population sequencing provides insights into wheat adaptation
    Nat. Genet. (IF 27.603) Pub Date : 2020-10-26
    Yao Zhou; Xuebo Zhao; Yiwen Li; Jun Xu; Aoyue Bi; Lipeng Kang; Daxing Xu; Haofeng Chen; Ying Wang; Yuan-ge Wang; Sanyang Liu; Chengzhi Jiao; Hongfeng Lu; Jing Wang; Changbin Yin; Yuling Jiao; Fei Lu

    Bread wheat expanded its habitat from a core area of the Fertile Crescent to global environments within ~10,000 years. The genetic mechanisms of this remarkable evolutionary success are not well understood. By whole-genome sequencing of populations from 25 subspecies within the genera Triticum and Aegilops, we identified composite introgression from wild populations contributing to a substantial portion

    更新日期:2020-10-28
  • Single-cell epigenomic analyses implicate candidate causal variants at inherited risk loci for Alzheimer’s and Parkinson’s diseases
    Nat. Genet. (IF 27.603) Pub Date : 2020-10-26
    M. Ryan Corces; Anna Shcherbina; Soumya Kundu; Michael J. Gloudemans; Laure Frésard; Jeffrey M. Granja; Bryan H. Louie; Tiffany Eulalio; Shadi Shams; S. Tansu Bagdatli; Maxwell R. Mumbach; Boxiang Liu; Kathleen S. Montine; William J. Greenleaf; Anshul Kundaje; Stephen B. Montgomery; Howard Y. Chang; Thomas J. Montine

    Genome-wide association studies of neurological diseases have identified thousands of variants associated with disease phenotypes. However, most of these variants do not alter coding sequences, making it difficult to assign their function. Here, we present a multi-omic epigenetic atlas of the adult human brain through profiling of single-cell chromatin accessibility landscapes and three-dimensional

    更新日期:2020-10-28
  • Publisher Correction: A genome-wide search for asthma susceptibility loci in ethnically diverse populations
    Nat. Genet. (IF 27.603) Pub Date : 2020-10-22

    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:2020-10-28
  • CHESS enables quantitative comparison of chromatin contact data and automatic feature extraction
    Nat. Genet. (IF 27.603) Pub Date : 2020-10-19
    Silvia Galan; Nick Machnik; Kai Kruse; Noelia Díaz; Marc A. Marti-Renom; Juan M. Vaquerizas

    Dynamic changes in the three-dimensional (3D) organization of chromatin are associated with central biological processes, such as transcription, replication and development. Therefore, the comprehensive identification and quantification of these changes is fundamental to understanding of evolutionary and regulatory mechanisms. Here, we present Comparison of Hi-C Experiments using Structural Similarity

    更新日期:2020-10-19
  • Interferons and viruses induce a novel truncated ACE2 isoform and not the full-length SARS-CoV-2 receptor
    Nat. Genet. (IF 27.603) Pub Date : 2020-10-19
    Olusegun O. Onabajo; A. Rouf Banday; Megan L. Stanifer; Wusheng Yan; Adeola Obajemu; Deanna M. Santer; Oscar Florez-Vargas; Helen Piontkivska; Joselin M. Vargas; Timothy J. Ring; Carmon Kee; Patricio Doldan; D. Lorne Tyrrell; Juan L. Mendoza; Steeve Boulant; Ludmila Prokunina-Olsson

    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19, utilizes angiotensin-converting enzyme 2 (ACE2) for entry into target cells. ACE2 has been proposed as an interferon-stimulated gene (ISG). Thus, interferon-induced variability in ACE2 expression levels could be important for susceptibility to COVID-19 or its outcomes. Here, we report the discovery of a novel, transcriptionally

    更新日期:2020-10-19
  • Tissue-specific and interferon-inducible expression of nonfunctional ACE2 through endogenous retroelement co-option
    Nat. Genet. (IF 27.603) Pub Date : 2020-10-19
    Kevin W. Ng; Jan Attig; William Bolland; George R. Young; Jack Major; Antoni G. Wrobel; Steve Gamblin; Andreas Wack; George Kassiotis

    Angiotensin-converting enzyme 2 (ACE2) is an entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and a regulator of several physiological processes. ACE2 has recently been proposed to be interferon (IFN) inducible, suggesting that SARS-CoV-2 may exploit this phenomenon to enhance viral spread and questioning the efficacy of IFN treatment in coronavirus disease 2019. Using

    更新日期:2020-10-19
  • Regulation of single-cell genome organization into TADs and chromatin nanodomains
    Nat. Genet. (IF 27.603) Pub Date : 2020-10-19
    Quentin Szabo; Axelle Donjon; Ivana Jerković; Giorgio L. Papadopoulos; Thierry Cheutin; Boyan Bonev; Elphège P. Nora; Benoit G. Bruneau; Frédéric Bantignies; Giacomo Cavalli

    The genome folds into a hierarchy of three-dimensional structures within the nucleus. At the sub-megabase scale, chromosomes form topologically associating domains (TADs)1,2,3,4. However, how TADs fold in single cells is elusive. Here, we reveal TAD features inaccessible to cell population analysis by using super-resolution microscopy. TAD structures and physical insulation associated with their borders

    更新日期:2020-10-19
  • Evidence for secondary-variant genetic burden and non-random distribution across biological modules in a recessive ciliopathy
    Nat. Genet. (IF 27.603) Pub Date : 2020-10-12
    Maria Kousi; Onuralp Söylemez; Aysegül Ozanturk; Niki Mourtzi; Sebastian Akle; Irwin Jungreis; Jean Muller; Christopher A. Cassa; Harrison Brand; Jill Anne Mokry; Maxim Y. Wolf; Azita Sadeghpour; Kelsey McFadden; Richard A. Lewis; Michael E. Talkowski; Hélène Dollfus; Manolis Kellis; Erica E. Davis; Shamil R. Sunyaev; Nicholas Katsanis

    The influence of genetic background on driver mutations is well established; however, the mechanisms by which the background interacts with Mendelian loci remain unclear. We performed a systematic secondary-variant burden analysis of two independent cohorts of patients with Bardet–Biedl syndrome (BBS) with known recessive biallelic pathogenic mutations in one of 17 BBS genes for each individual. We

    更新日期:2020-10-12
  • Author Correction: An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer’s disease
    Nat. Genet. (IF 27.603) Pub Date : 2020-10-08
    Raffaella Nativio; Yemin Lan; Greg Donahue; Simone Sidoli; Amit Berson; Ananth R. Srinivasan; Oksana Shcherbakova; Alexandre Amlie-Wolf; Ji Nie; Xiaolong Cui; Chuan He; Li-San Wang; Benjamin A. Garcia; John Q. Trojanowski; Nancy M. Bonini; Shelley L. Berger

    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:2020-10-08
  • Author Correction: Treating medical data as a durable asset
    Nat. Genet. (IF 27.603) Pub Date : 2020-10-08
    Amalio Telenti; Xiaoqian Jiang

    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:2020-10-08
  • Population-specific and trans-ancestry genome-wide analyses identify distinct and shared genetic risk loci for coronary artery disease
    Nat. Genet. (IF 27.603) Pub Date : 2020-10-05
    Satoshi Koyama; Kaoru Ito; Chikashi Terao; Masato Akiyama; Momoko Horikoshi; Yukihide Momozawa; Hiroshi Matsunaga; Hirotaka Ieki; Kouichi Ozaki; Yoshihiro Onouchi; Atsushi Takahashi; Seitaro Nomura; Hiroyuki Morita; Hiroshi Akazawa; Changhoon Kim; Jeong-sun Seo; Koichiro Higasa; Motoki Iwasaki; Taiki Yamaji; Norie Sawada; Shoichiro Tsugane; Teruhide Koyama; Hiroaki Ikezaki; Naoyuki Takashima; Keitaro

    To elucidate the genetics of coronary artery disease (CAD) in the Japanese population, we conducted a large-scale genome-wide association study of 168,228 individuals of Japanese ancestry (25,892 cases and 142,336 controls) with genotype imputation using a newly developed reference panel of Japanese haplotypes including 1,781 CAD cases and 2,636 controls. We detected eight new susceptibility loci and

    更新日期:2020-10-05
  • Somatic mutation distributions in cancer genomes vary with three-dimensional chromatin structure
    Nat. Genet. (IF 27.603) Pub Date : 2020-10-05
    Kadir C. Akdemir; Victoria T. Le; Justin M. Kim; Sarah Killcoyne; Devin A. King; Ya-Ping Lin; Yanyan Tian; Akira Inoue; Samirkumar B. Amin; Frederick S. Robinson; Manjunath Nimmakayalu; Rafael E. Herrera; Erica J. Lynn; Kin Chan; Sahil Seth; Leszek J. Klimczak; Moritz Gerstung; Dmitry A. Gordenin; John O’Brien; Lei Li; Yonathan Lissanu Deribe; Roel G. Verhaak; Peter J. Campbell; Rebecca Fitzgerald;

    Somatic mutations in driver genes may ultimately lead to the development of cancer. Understanding how somatic mutations accumulate in cancer genomes and the underlying factors that generate somatic mutations is therefore crucial for developing novel therapeutic strategies. To understand the interplay between spatial genome organization and specific mutational processes, we studied 3,000 tumor–normal-pair

    更新日期:2020-10-05
  • A unified framework for joint-tissue transcriptome-wide association and Mendelian randomization analysis
    Nat. Genet. (IF 27.603) Pub Date : 2020-10-05
    Dan Zhou; Yi Jiang; Xue Zhong; Nancy J. Cox; Chunyu Liu; Eric R. Gamazon

    Here, we present a joint-tissue imputation (JTI) approach and a Mendelian randomization framework for causal inference, MR-JTI. JTI borrows information across transcriptomes of different tissues, leveraging shared genetic regulation, to improve prediction performance in a tissue-dependent manner. Notably, JTI includes the single-tissue imputation method PrediXcan as a special case and outperforms other

    更新日期:2020-10-05
  • Highly interconnected enhancer communities control lineage-determining genes in human mesenchymal stem cells
    Nat. Genet. (IF 27.603) Pub Date : 2020-10-05
    Jesper G. S. Madsen; Maria S. Madsen; Alexander Rauch; Sofie Traynor; Elvira L. Van Hauwaert; Anders K. Haakonsson; Biola M. Javierre; Mette Hyldahl; Peter Fraser; Susanne Mandrup

    Adipocyte differentiation is driven by waves of transcriptional regulators that reprogram the enhancer landscape and change the wiring of the promoter interactome. Here, we use high-throughput chromosome conformation enhancer capture to interrogate the role of enhancer-to-enhancer interactions during differentiation of human mesenchymal stem cells. We find that enhancers form an elaborate network that

    更新日期:2020-10-05
  • Stories in the DNA
    Nat. Genet. (IF 27.603) Pub Date : 2020-09-30

    Genetic tools can help uncover evolutionary histories, migration patterns and admixture events of domesticated animals and their wild ancestors. The genetic window into the past can help shape breeding strategies and inform animal agricultural practices that should lead to a more resilient and sustainable future.

    更新日期:2020-09-30
  • Targeting LSD1 and FOXA1 in prostate cancer
    Nat. Genet. (IF 27.603) Pub Date : 2020-09-30
    Soleilmane Omarjee; Jason S. Carroll

    FOXA1 is a key pioneer factor in androgen-receptor activity but has been an elusive drug target. A new study shows that inhibition of the associated cofactor LSD1 modifies the methylation state of FOXA1, thus resulting in chromatin dissociation and tumor inhibition, even in models of treatment-resistant prostate cancer.

    更新日期:2020-09-30
  • Setting new boundaries with transcription and CTCF
    Nat. Genet. (IF 27.603) Pub Date : 2020-09-30
    Erika C. Anderson; Elphège P. Nora

    How do boundary elements divide chromosomes into domains? A new study uses random genomic insertions to show how small genomic fragments can shape chromatin folding through the interplay of loop extrusion and compartmentalization. Spoiler: context matters.

    更新日期:2020-09-30
  • The mosaic genome of indigenous African cattle as a unique genetic resource for African pastoralism
    Nat. Genet. (IF 27.603) Pub Date : 2020-09-28
    Kwondo Kim; Taehyung Kwon; Tadelle Dessie; DongAhn Yoo; Okeyo Ally Mwai; Jisung Jang; Samsun Sung; SaetByeol Lee; Bashir Salim; Jaehoon Jung; Heesu Jeong; Getinet Mekuriaw Tarekegn; Abdulfatai Tijjani; Dajeong Lim; Seoae Cho; Sung Jong Oh; Hak-Kyo Lee; Jaemin Kim; Choongwon Jeong; Stephen Kemp; Olivier Hanotte; Heebal Kim

    Cattle pastoralism plays a central role in human livelihood in Africa. However, the genetic history of its success remains unknown. Here, through whole-genome sequence analysis of 172 indigenous African cattle from 16 breeds representative of the main cattle groups, we identify a major taurine × indicine cattle admixture event dated to circa 750–1,050 yr ago, which has shaped the genome of today’s

    更新日期:2020-09-28
  • Haplotype-resolved genome analyses of a heterozygous diploid potato
    Nat. Genet. (IF 27.603) Pub Date : 2020-09-28
    Qian Zhou; Dié Tang; Wu Huang; Zhongmin Yang; Yu Zhang; John P. Hamilton; Richard G. F. Visser; Christian W. B. Bachem; C. Robin Buell; Zhonghua Zhang; Chunzhi Zhang; Sanwen Huang

    Potato (Solanum tuberosum L.) is the most important tuber crop worldwide. Efforts are underway to transform the crop from a clonally propagated tetraploid into a seed-propagated, inbred-line-based hybrid, but this process requires a better understanding of potato genome. Here, we report the 1.67-Gb haplotype-resolved assembly of a diploid potato, RH89-039-16, using a combination of multiple sequencing

    更新日期:2020-09-28
  • The mutational signature profile of known and suspected human carcinogens in mice
    Nat. Genet. (IF 27.603) Pub Date : 2020-09-28
    Laura Riva; Arun R. Pandiri; Yun Rose Li; Alastair Droop; James Hewinson; Michael A. Quail; Vivek Iyer; Rebecca Shepherd; Ronald A. Herbert; Peter J. Campbell; Robert C. Sills; Ludmil B. Alexandrov; Allan Balmain; David J. Adams

    Epidemiological studies have identified many environmental agents that appear to significantly increase cancer risk in human populations. By analyzing tumor genomes from mice chronically exposed to 1 of 20 known or suspected human carcinogens, we reveal that most agents do not generate distinct mutational signatures or increase mutation burden, with most mutations, including driver mutations, resulting

    更新日期:2020-09-28
  • Mutations disrupting neuritogenesis genes confer risk for cerebral palsy
    Nat. Genet. (IF 27.603) Pub Date : 2020-09-28
    Sheng Chih Jin; Sara A. Lewis; Somayeh Bakhtiari; Xue Zeng; Michael C. Sierant; Sheetal Shetty; Sandra M. Nordlie; Aureliane Elie; Mark A. Corbett; Bethany Y. Norton; Clare L. van Eyk; Shozeb Haider; Brandon S. Guida; Helen Magee; James Liu; Stephen Pastore; John B. Vincent; Janice Brunstrom-Hernandez; Antigone Papavasileiou; Michael C. Fahey; Jesia G. Berry; Kelly Harper; Chongchen Zhou; Junhui Zhang;

    In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent–offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies

    更新日期:2020-09-28
  • Discovering functional evolutionary dependencies in human cancers
    Nat. Genet. (IF 27.603) Pub Date : 2020-09-28
    Marco Mina; Arvind Iyer; Daniele Tavernari; Franck Raynaud; Giovanni Ciriello

    Cancer cells retain genomic alterations that provide a selective advantage. The prediction and validation of advantageous alterations are major challenges in cancer genomics. Moreover, it is crucial to understand how the coexistence of specific alterations alters response to genetic and therapeutic perturbations. In the present study, we inferred functional alterations and preferentially selected combinations

    更新日期:2020-09-28
  • Analysis of wild tomato introgression lines elucidates the genetic basis of transcriptome and metabolome variation underlying fruit traits and pathogen response
    Nat. Genet. (IF 27.603) Pub Date : 2020-09-28
    Jędrzej Szymański; Samuel Bocobza; Sayantan Panda; Prashant Sonawane; Pablo D. Cárdenas; Justin Lashbrooke; Avinash Kamble; Nir Shahaf; Sagit Meir; Arnaud Bovy; Jules Beekwilder; Yury Tikunov; Irene Romero de la Fuente; Dani Zamir; Ilana Rogachev; Asaph Aharoni

    Wild tomato species represent a rich gene pool for numerous desirable traits lost during domestication. Here, we exploited an introgression population representing wild desert-adapted species and a domesticated cultivar to establish the genetic basis of gene expression and chemical variation accompanying the transfer of wild-species-associated fruit traits. Transcriptome and metabolome analysis of

    更新日期:2020-09-28
  • An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer’s disease
    Nat. Genet. (IF 27.603) Pub Date : 2020-09-28
    Raffaella Nativio; Yemin Lan; Greg Donahue; Simone Sidoli; Amit Berson; Ananth R. Srinivasan; Oksana Shcherbakova; Alexandre Amlie-Wolf; Ji Nie; Xiaolong Cui; Chuan He; Li-San Wang; Benjamin A. Garcia; John Q. Trojanowski; Nancy M. Bonini; Shelley L. Berger

    Protein aggregation is the hallmark of neurodegeneration, but the molecular mechanisms underlying late-onset Alzheimer’s disease (AD) are unclear. Here we integrated transcriptomic, proteomic and epigenomic analyses of postmortem human brains to identify molecular pathways involved in AD. RNA sequencing analysis revealed upregulation of transcription- and chromatin-related genes, including the histone

    更新日期:2020-09-28
  • Transcription imparts architecture, function and logic to enhancer units.
    Nat. Genet. (IF 27.603) Pub Date : 2020-09-21
    Nathaniel D Tippens,Jin Liang,Alden King-Yung Leung,Shayne D Wierbowski,Abdullah Ozer,James G Booth,John T Lis,Haiyuan Yu

    Distal enhancers play pivotal roles in development and disease yet remain one of the least understood regulatory elements. We used massively parallel reporter assays to perform functional comparisons of two leading enhancer models and find that gene-distal transcription start sites are robust predictors of active enhancers with higher resolution than histone modifications. We show that active enhancer

    更新日期:2020-09-21
  • Author Correction: WNT signaling and AHCTF1 promote oncogenic MYC expression through super-enhancer-mediated gene gating.
    Nat. Genet. (IF 27.603) Pub Date : 2020-09-18
    Barbara A Scholz,Noriyuki Sumida,Carolina Diettrich Mallet de Lima,Ilyas Chachoua,Mirco Martino,Ilias Tzelepis,Andrej Nikoshkov,Honglei Zhao,Rashid Mehmood,Emmanouil G Sifakis,Deeksha Bhartiya,Anita Göndör,Rolf Ohlsson

    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:2020-09-20
  • Author Correction: Complex genetic signatures in immune cells underlie autoimmunity and inform therapy.
    Nat. Genet. (IF 27.603) Pub Date : 2020-09-18
    Valeria Orrù,Maristella Steri,Carlo Sidore,Michele Marongiu,Valentina Serra,Stefania Olla,Gabriella Sole,Sandra Lai,Mariano Dei,Antonella Mulas,Francesca Virdis,Maria Grazia Piras,Monia Lobina,Mara Marongiu,Maristella Pitzalis,Francesca Deidda,Annalisa Loizedda,Stefano Onano,Magdalena Zoledziewska,Stephen Sawcer,Marcella Devoto,Myriam Gorospe,Gonçalo R Abecasis,Matteo Floris,Mauro Pala,David Schlessinger

    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:2020-09-20
  • Author Correction: Exploring the coronavirus pandemic with the WashU Virus Genome Browser.
    Nat. Genet. (IF 27.603) Pub Date : 2020-09-16
    Jennifer A Flynn,Deepak Purushotham,Mayank N K Choudhary,Xiaoyu Zhuo,Changxu Fan,Gavriel Matt,Daofeng Li,Ting Wang

    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:2020-09-16
  • Treating medical data as a durable asset.
    Nat. Genet. (IF 27.603) Pub Date : 2020-09-14
    Amalio Telenti,Xiaoqian Jiang

    Access to medical data is central for conducting research on genomics. However, to tap these metadata (observable traits and phenotypes, diagnoses and medication, and labels), researchers must grapple with the complex and sensitive nature of the information. In this Perspective, we argue that, at this exciting time for genomics and artificial intelligence, several critical aspects of data generation

    更新日期:2020-09-14
  • Complex genetic signatures in immune cells underlie autoimmunity and inform therapy.
    Nat. Genet. (IF 27.603) Pub Date : 2020-09-14
    Valeria Orrù,Maristella Steri,Carlo Sidore,Michele Marongiu,Valentina Serra,Stefania Olla,Gabriella Sole,Sandra Lai,Mariano Dei,Antonella Mulas,Francesca Virdis,Maria Grazia Piras,Monia Lobina,Mara Marongiu,Maristella Pitzalis,Francesca Deidda,Annalisa Loizedda,Stefano Onano,Magdalena Zoledziewska,Stephen Sawcer,Marcella Devoto,Myriam Gorospe,Gonçalo R Abecasis,Matteo Floris,Mauro Pala,David Schlessinger

    We report on the influence of ~22 million variants on 731 immune cell traits in a cohort of 3,757 Sardinians. We detected 122 significant (P < 1.28 × 10−11) independent association signals for 459 cell traits at 69 loci (52 of them novel) identifying several molecules and mechanisms involved in cell regulation. Furthermore, 53 signals at 36 loci overlapped with previously reported disease-associated

    更新日期:2020-09-14
  • NSD1-deposited H3K36me2 directs de novo methylation in the mouse male germline and counteracts Polycomb-associated silencing.
    Nat. Genet. (IF 27.603) Pub Date : 2020-09-14
    Kenjiro Shirane,Fumihito Miura,Takashi Ito,Matthew C Lorincz

    De novo DNA methylation (DNAme) in mammalian germ cells is dependent on DNMT3A and DNMT3L. However, oocytes and spermatozoa show distinct patterns of DNAme. In mouse oocytes, de novo DNAme requires the lysine methyltransferase (KMTase) SETD2, which deposits H3K36me3. We show here that SETD2 is dispensable for de novo DNAme in the male germline. Instead, the lysine methyltransferase NSD1, which broadly

    更新日期:2020-09-14
  • Evolutionary dynamics of neoantigens in growing tumors.
    Nat. Genet. (IF 27.603) Pub Date : 2020-09-14
    Eszter Lakatos,Marc J Williams,Ryan O Schenck,William C H Cross,Jacob Househam,Luis Zapata,Benjamin Werner,Chandler Gatenbee,Mark Robertson-Tessi,Chris P Barnes,Alexander R A Anderson,Andrea Sottoriva,Trevor A Graham

    Cancers accumulate mutations that lead to neoantigens, novel peptides that elicit an immune response, and consequently undergo evolutionary selection. Here we establish how negative selection shapes the clonality of neoantigens in a growing cancer by constructing a mathematical model of neoantigen evolution. The model predicts that, without immune escape, tumor neoantigens are either clonal or at low

    更新日期:2020-09-14
  • Author Correction: PGBD5 promotes site-specific oncogenic mutations in human tumors.
    Nat. Genet. (IF 27.603) Pub Date : 2020-09-11
    Anton G Henssen,Richard Koche,Jiali Zhuang,Eileen Jiang,Casie Reed,Amy Eisenberg,Eric Still,Ian C MacArthur,Elias Rodríguez-Fos,Santiago Gonzalez,Montserrat Puiggròs,Andrew N Blackford,Christopher E Mason,Elisa de Stanchina,Mithat Gönen,Anne-Katrin Emde,Minita Shah,Kanika Arora,Catherine Reeves,Nicholas D Socci,Elizabeth Perlman,Cristina R Antonescu,Charles W M Roberts,Hanno Steen,Elizabeth Mullen

    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:2020-09-12
  • Exploring the coronavirus pandemic with the WashU Virus Genome Browser.
    Nat. Genet. (IF 27.603) Pub Date : 2020-09-09
    Jennifer A Flynn,Deepak Purushotham,Mayank N K Choudhary,Xiaoyu Zhuo,Changxu Fan,Gavriel Matt,Daofeng Li,Ting Wang

    The WashU Virus Genome Browser is a web-based portal for efficient visualization of viral ‘omics’ data in the context of a variety of annotation tracks and host infection responses. The browser features both a phylogenetic-tree-based view and a genomic-coordinate, track-based view in which users can analyze the sequence features of viral genomes, sequence diversity among viral strains, genomic sites

    更新日期:2020-09-10
  • Exploring the structural distribution of genetic variation in SARS-CoV-2 with the COVID-3D online resource.
    Nat. Genet. (IF 27.603) Pub Date : 2020-09-09
    Stephanie Portelli,Moshe Olshansky,Carlos H M Rodrigues,Elston N D'Souza,Yoochan Myung,Michael Silk,Azadeh Alavi,Douglas E V Pires,David B Ascher

    The emergence of the COVID-19 pandemic has spurred a global rush to uncover basic biological mechanisms to inform effective vaccine and drug development. Despite the novelty of the virus, global sequencing efforts have already identified genomic variation across isolates. To enable easy exploration and spatial visualization of the potential implications of SARS-CoV-2 mutations in infection, host immunity

    更新日期:2020-09-10
  • The UCSC SARS-CoV-2 Genome Browser.
    Nat. Genet. (IF 27.603) Pub Date : 2020-09-09
    Jason D Fernandes,Angie S Hinrichs,Hiram Clawson,Jairo Navarro Gonzalez,Brian T Lee,Luis R Nassar,Brian J Raney,Kate R Rosenbloom,Santrupti Nerli,Arjun A Rao,Daniel Schmelter,Alastair Fyfe,Nathan Maulding,Ann S Zweig,Todd M Lowe,Manuel Ares,Russ Corbet-Detig,W James Kent,David Haussler,Maximilian Haeussler

    The UCSC SARS-CoV-2 Genome Browser (https://genome.ucsc.edu/covid19.html) is an adaptation of our popular genome-browser visualization tool for this virus, containing many annotation tracks and new features, including conservation with similar viruses, immune epitopes, RT–PCR and sequencing primers and CRISPR guides. We invite all investigators to contribute to this resource to accelerate research

    更新日期:2020-09-10
  • Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases.
    Nat. Genet. (IF 27.603) Pub Date : 2020-09-07
    Jie Zheng,Valeriia Haberland,Denis Baird,Venexia Walker,Philip C Haycock,Mark R Hurle,Alex Gutteridge,Pau Erola,Yi Liu,Shan Luo,Jamie Robinson,Tom G Richardson,James R Staley,Benjamin Elsworth,Stephen Burgess,Benjamin B Sun,John Danesh,Heiko Runz,Joseph C Maranville,Hannah M Martin,James Yarmolinsky,Charles Laurin,Michael V Holmes,Jimmy Z Liu,Karol Estrada,Rita Santos,Linda McCarthy,Dawn Waterworth

    The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma protein levels. Here we estimated the effects of 1,002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130

    更新日期:2020-09-08
  • Author Correction: A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer.
    Nat. Genet. (IF 27.603) Pub Date : 2020-09-03
    Andrea Lunardi,Ugo Ala,Mirjam T Epping,Leonardo Salmena,John G Clohessy,Kaitlyn A Webster,Guocan Wang,Roberta Mazzucchelli,Maristella Bianconi,Edward C Stack,Rosina Lis,Akash Patnaik,Lewis C Cantley,Glenn Bubley,Carlos Cordon-Cardo,William L Gerald,Rodolfo Montironi,Sabina Signoretti,Massimo Loda,Caterina Nardella,Pier Paolo Pandolfi

    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:2020-09-03
  • RNA post-transcriptional modification speaks to chromatin.
    Nat. Genet. (IF 27.603) Pub Date : 2020-09-02
    Dalen Chan,Pedro J Batista

    The role of N6-methyladenosine (m6A) is still not fully understood. Two new studies advance understanding of this RNA modification. One shows that m6A modification of nascent messenger RNA promotes transcription by recruiting the histone H3 K9 demethylase KDM3B. Another study identifies genetic variants that affect m6A deposition and human disease.

    更新日期:2020-09-02
  • RNA closing the Polycomb circle.
    Nat. Genet. (IF 27.603) Pub Date : 2020-09-02
    Ivano Mocavini,Luciano Di Croce

    Binding of RNA to the gene expression regulator Polycomb repressive complex 2 (PRC2) has been proposed to antagonize PRC2’s chromatin recruitment. A new study now shows that RNA is in fact critical for correct recruitment of PRC2 at its target genes in human pluripotent stem cells and suggests that interplay of PRC2 and RNA can fine-tune PRC2’s regulatory role.

    更新日期:2020-09-02