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  •   Esophageal cancer mutational signatures around the world
    Nat. Genet. (IF 38.33) Pub Date : 2021-10-21
    Marios Giannakis, Ulrike Peters

    Mutational signatures can shed light onto mechanisms of carcinogenesis and reveal the mutagenic impact of novel and established environmental risk factors. A new study examines the mutational spectra of esophageal squamous cell cancer together with exposure information in regions of high and low incidence of the disease, and demonstrates both the limitations and potential of mutational signature analyses

  •   Automated CUT&Tag profiling of chromatin heterogeneity in mixed-lineage leukemia
    Nat. Genet. (IF 38.33) Pub Date : 2021-10-18
    Derek H. Janssens, Michael P. Meers, Steven J. Wu, Ekaterina Babaeva, Soheil Meshinchi, Jay F. Sarthy, Kami Ahmad, Steven Henikoff

    Acute myeloid and lymphoid leukemias often harbor chromosomal translocations involving the KMT2A gene, encoding the KMT2A lysine methyltransferase (also known as mixed-lineage leukemia-1), and produce in-frame fusions of KMT2A to other chromatin-regulatory proteins. Here we map fusion-specific targets across the genome for diverse KMT2A oncofusion proteins in cell lines and patient samples. By modifying

  •   Mutational signatures in esophageal squamous cell carcinoma from eight countries with varying incidence
    Nat. Genet. (IF 38.33) Pub Date : 2021-10-18
    Sarah Moody, Sergey Senkin, S. M. Ashiqul Islam, Jingwei Wang, Dariush Nasrollahzadeh, Ricardo Cortez Cardoso Penha, Stephen Fitzgerald, Erik N. Bergstrom, Joshua Atkins, Yudou He, Azhar Khandekar, Karl Smith-Byrne, Christine Carreira, Valerie Gaborieau, Calli Latimer, Emily Thomas, Irina Abnizova, Pauline E. Bucciarelli, David Jones, Jon W. Teague, Behnoush Abedi-Ardekani, Stefano Serra, Jean-Yves

    Esophageal squamous cell carcinoma (ESCC) shows remarkable variation in incidence that is not fully explained by known lifestyle and environmental risk factors. It has been speculated that an unknown exogenous exposure(s) could be responsible. Here we combine the fields of mutational signature analysis with cancer epidemiology to study 552 ESCC genomes from eight countries with varying incidence rates

  •   The dynamic, combinatorial cis-regulatory lexicon of epidermal differentiation
    Nat. Genet. (IF 38.33) Pub Date : 2021-10-14
    Daniel S. Kim, Viviana I. Risca, David L. Reynolds, James Chappell, Adam J. Rubin, Namyoung Jung, Laura K. H. Donohue, Vanessa Lopez-Pajares, Arwa Kathiria, Minyi Shi, Zhixin Zhao, Harsh Deep, Mahfuza Sharmin, Deepti Rao, Shin Lin, Howard Y. Chang, Michael P. Snyder, William J. Greenleaf, Anshul Kundaje, Paul A. Khavari

    Transcription factors bind DNA sequence motif vocabularies in cis-regulatory elements (CREs) to modulate chromatin state and gene expression during cell state transitions. A quantitative understanding of how motif lexicons influence dynamic regulatory activity has been elusive due to the combinatorial nature of the cis-regulatory code. To address this, we undertook multiomic data profiling of chromatin

  •   Renal plasticity revealed through reversal of polycystic kidney disease in mice
    Nat. Genet. (IF 38.33) Pub Date : 2021-10-11
    Ke Dong, Chao Zhang, Xin Tian, Daniel Coman, Fahmeed Hyder, Ming Ma, Stefan Somlo

    Initiation of cyst formation in autosomal dominant polycystic kidney disease (ADPKD) occurs when kidney tubule cells are rendered null for either PKD1 or PKD2 by somatic ‘second hit’ mutations. Subsequent cyst progression remodels the organ through changes in tubule cell shape, proliferation and secretion. The kidney develops inflammation and fibrosis. We constructed a mouse model in which adult inactivation

  •   BRD4 orchestrates genome folding to promote neural crest differentiation
    Nat. Genet. (IF 38.33) Pub Date : 2021-10-05
    Ricardo Linares-Saldana, Wonho Kim, Nikhita A. Bolar, Haoyue Zhang, Bailey A. Koch-Bojalad, Sora Yoon, Parisha P. Shah, Ashley Karnay, Daniel S. Park, Jennifer M. Luppino, Son C. Nguyen, Arun Padmanabhan, Cheryl L. Smith, Andrey Poleshko, Qiaohong Wang, Li Li, Deepak Srivastava, Golnaz Vahedi, Gwang Hyeon Eom, Gerd A. Blobel, Eric F. Joyce, Rajan Jain

    Higher-order chromatin structure regulates gene expression, and mutations in proteins mediating genome folding underlie developmental disorders known as cohesinopathies. However, the relationship between three-dimensional genome organization and embryonic development remains unclear. Here we define a role for bromodomain-containing protein 4 (BRD4) in genome folding, and leverage it to understand the

  •   Polygenic basis and biomedical consequences of telomere length variation
    Nat. Genet. (IF 38.33) Pub Date : 2021-10-05
    Veryan Codd, Qingning Wang, Elias Allara, Crispin Musicha, Stephen Kaptoge, Svetlana Stoma, Tao Jiang, Stephen E. Hamby, Peter S. Braund, Vasiliki Bountziouka, Charley A. Budgeon, Matthew Denniff, Chloe Swinfield, Manolo Papakonstantinou, Shilpi Sheth, Dominika E. Nanus, Sophie C. Warner, Minxian Wang, Amit V. Khera, James Eales, Willem H. Ouwehand, John R. Thompson, Emanuele Di Angelantonio, Angela

    Telomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence. Here we characterize the genetic architecture of naturally occurring variation in leukocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized UK Biobank participants. We identified 197 independent sentinel variants associated with LTL

  •   A high-resolution HLA reference panel capturing global population diversity enables multi-ancestry fine-mapping in HIV host response
    Nat. Genet. (IF 38.33) Pub Date : 2021-10-05
    Yang Luo, Masahiro Kanai, Wanson Choi, Xinyi Li, Saori Sakaue, Kenichi Yamamoto, Kotaro Ogawa, Maria Gutierrez-Arcelus, Peter K. Gregersen, Philip E. Stuart, James T. Elder, Lukas Forer, Sebastian Schönherr, Christian Fuchsberger, Albert V. Smith, Jacques Fellay, Mary Carrington, David W. Haas, Xiuqing Guo, Nicholette D. Palmer, Yii-Der Ida Chen, Jerome I. Rotter, Kent D. Taylor, Stephen S. Rich, Adolfo

    Fine-mapping to plausible causal variation may be more effective in multi-ancestry cohorts, particularly in the MHC, which has population-specific structure. To enable such studies, we constructed a large (n = 21,546) HLA reference panel spanning five global populations based on whole-genome sequences. Despite population-specific long-range haplotypes, we demonstrated accurate imputation at G-group

  •   Epigenomic contributions to tumor cell heterogeneity and plasticity
    Nat. Genet. (IF 38.33) Pub Date : 2021-10-04
    Radhika Mathur, Joseph F. Costello

    Heterogeneity in brain tumors has been viewed through many lenses—from microscopes and experimental models to ‘omic’ analysis at the tissue and single-cell levels. Two studies now characterize patterns of DNA methylation and gene expression in single cells to reveal epigenomic underpinnings of cellular heterogeneity and plasticity in exquisite detail, including mechanistic insight into cellular transitions

  •   Author Correction: Genetics of 35 blood and urine biomarkers in the UK Biobank.
    Nat. Genet. (IF 38.33) Pub Date : 2021-10-04
    Nasa Sinnott-Armstrong,Yosuke Tanigawa,David Amar,Nina Mars,Christian Benner,Matthew Aguirre,Guhan Ram Venkataraman,Michael Wainberg,Hanna M Ollila,Tuomo Kiiskinen,Aki S Havulinna,James P Pirruccello,Junyang Qian,Anna Shcherbina,,Fatima Rodriguez,Themistocles L Assimes,Vineeta Agarwala,Robert Tibshirani,Trevor Hastie,Samuli Ripatti,Jonathan K Pritchard,Mark J Daly,Manuel A Rivas

  •   Epigenetic encoding, heritability and plasticity of glioma transcriptional cell states
    Nat. Genet. (IF 38.33) Pub Date : 2021-09-30
    Ronan Chaligne, Federico Gaiti, Dana Silverbush, Joshua S. Schiffman, Hannah R. Weisman, Lloyd Kluegel, Simon Gritsch, Sunil D. Deochand, L. Nicolas Gonzalez Castro, Alyssa R. Richman, Johanna Klughammer, Tommaso Biancalani, Christoph Muus, Caroline Sheridan, Alicia Alonso, Franco Izzo, Jane Park, Orit Rozenblatt-Rosen, Aviv Regev, Mario L. Suvà, Dan A. Landau

    Single-cell RNA sequencing has revealed extensive transcriptional cell state diversity in cancer, often observed independently of genetic heterogeneity, raising the central question of how malignant cell states are encoded epigenetically. To address this, here we performed multiomics single-cell profiling—integrating DNA methylation, transcriptome and genotype within the same cells—of diffuse gliomas

  •   Increased somatic mutation burdens in normal human cells due to defective DNA polymerases
    Nat. Genet. (IF 38.33) Pub Date : 2021-09-30
    Philip S. Robinson, Tim H. H. Coorens, Claire Palles, Emily Mitchell, Federico Abascal, Sigurgeir Olafsson, Bernard C. H. Lee, Andrew R. J. Lawson, Henry Lee-Six, Luiza Moore, Mathijs A. Sanders, James Hewinson, Lynn Martin, Claudia M. A. Pinna, Sara Galavotti, Raheleh Rahbari, Peter J. Campbell, Iñigo Martincorena, Ian Tomlinson, Michael R. Stratton

    Mutation accumulation in somatic cells contributes to cancer development and is proposed as a cause of aging. DNA polymerases Pol ε and Pol δ replicate DNA during cell division. However, in some cancers, defective proofreading due to acquired POLE/POLD1 exonuclease domain mutations causes markedly elevated somatic mutation burdens with distinctive mutational signatures. Germline POLE/POLD1 mutations

  •   Single-cell multimodal glioma analyses identify epigenetic regulators of cellular plasticity and environmental stress response
    Nat. Genet. (IF 38.33) Pub Date : 2021-09-30
    Kevin C. Johnson, Kevin J. Anderson, Elise T. Courtois, Amit D. Gujar, Floris P. Barthel, Frederick S. Varn, Diane Luo, Martine Seignon, Eunhee Yi, Hoon Kim, Marcos R. H. Estecio, Dacheng Zhao, Ming Tang, Nicholas E. Navin, Rahul Maurya, Chew Yee Ngan, Niels Verburg, Philip C. de Witt Hamer, Ketan Bulsara, Michael L. Samuels, Sunit Das, Paul Robson, Roel G. W. Verhaak

    Glioma intratumoral heterogeneity enables adaptation to challenging microenvironments and contributes to therapeutic resistance. We integrated 914 single-cell DNA methylomes, 55,284 single-cell transcriptomes and bulk multi-omic profiles across 11 adult IDH mutant or IDH wild-type gliomas to delineate sources of intratumoral heterogeneity. We showed that local DNA methylation disorder is associated

  •   Parallel subgenome structure and divergent expression evolution of allo-tetraploid common carp and goldfish
    Nat. Genet. (IF 38.33) Pub Date : 2021-09-30
    Jiong-Tang Li, Qi Wang, Mei-Di Huang Yang, Qing-Song Li, Ming-Shu Cui, Zai-Jie Dong, Hong-Wei Wang, Ju-Hua Yu, Yu-Jie Zhao, Chen-Ru Yang, Ya-Xin Wang, Xiao-Qing Sun, Yan Zhang, Ran Zhao, Zhi-Ying Jia, Xi-Yin Wang

    How two subgenomes in allo-tetraploids adapt to coexistence and coordinate through structure and expression evolution requires extensive studies. In the present study, we report an improved genome assembly of allo-tetraploid common carp, an updated genome annotation of allo-tetraploid goldfish and the chromosome-scale assemblies of a progenitor-like diploid Puntius tetrazona and an outgroup diploid

  •   A cross-population atlas of genetic associations for 220 human phenotypes
    Nat. Genet. (IF 38.33) Pub Date : 2021-09-30
    Saori Sakaue, Masahiro Kanai, Yosuke Tanigawa, Juha Karjalainen, Mitja Kurki, Seizo Koshiba, Akira Narita, Takahiro Konuma, Kenichi Yamamoto, Masato Akiyama, Kazuyoshi Ishigaki, Akari Suzuki, Ken Suzuki, Wataru Obara, Ken Yamaji, Kazuhisa Takahashi, Satoshi Asai, Yasuo Takahashi, Takao Suzuki, Nobuaki Shinozaki, Hiroki Yamaguchi, Shiro Minami, Shigeo Murayama, Kozo Yoshimori, Satoshi Nagayama, Daisuke

    Current genome-wide association studies do not yet capture sufficient diversity in populations and scope of phenotypes. To expand an atlas of genetic associations in non-European populations, we conducted 220 deep-phenotype genome-wide association studies (diseases, biomarkers and medication usage) in BioBank Japan (n = 179,000), by incorporating past medical history and text-mining of electronic medical

  •   The first wave of the COVID-19 epidemic in Spain was associated with early introductions and fast spread of a dominating genetic variant
    Nat. Genet. (IF 38.33) Pub Date : 2021-09-30
    Mariana G. López, Álvaro Chiner-Oms, Darío García de Viedma, Paula Ruiz-Rodriguez, Maria Alma Bracho, Irving Cancino-Muñoz, Giuseppe D’Auria, Griselda de Marco, Neris García-González, Galo Adrian Goig, Inmaculada Gómez-Navarro, Santiago Jiménez-Serrano, Llúcia Martinez-Priego, Paula Ruiz-Hueso, Lidia Ruiz-Roldán, Manuela Torres-Puente, Juan Alberola, Eliseo Albert, Maitane Aranzamendi Zaldumbide, María

    The coronavirus disease 2019 (COVID-19) pandemic has affected the world radically since 2020. Spain was one of the European countries with the highest incidence during the first wave. As a part of a consortium to monitor and study the evolution of the epidemic, we sequenced 2,170 samples, diagnosed mostly before lockdown measures. Here, we identified at least 500 introductions from multiple international

  •   Mutational synergy during leukemia induction remodels chromatin accessibility, histone modifications and three-dimensional DNA topology to alter gene expression
    Nat. Genet. (IF 38.33) Pub Date : 2021-09-23
    Haiyang Yun, Nisha Narayan, Shabana Vohra, George Giotopoulos, Annalisa Mupo, Pedro Madrigal, Daniel Sasca, David Lara-Astiaso, Sarah J. Horton, Shuchi Agrawal-Singh, Eshwar Meduri, Faisal Basheer, Ludovica Marando, Malgorzata Gozdecka, Oliver M. Dovey, Aracely Castillo-Venzor, Xiaonan Wang, Paolo Gallipoli, Carsten Müller-Tidow, Cameron S. Osborne, George S. Vassiliou, Brian J. P. Huntly

    Altered transcription is a cardinal feature of acute myeloid leukemia (AML); however, exactly how mutations synergize to remodel the epigenetic landscape and rewire three-dimensional DNA topology is unknown. Here, we apply an integrated genomic approach to a murine allelic series that models the two most common mutations in AML: Flt3-ITD and Npm1c. We then deconvolute the contribution of each mutation

  •   Author Correction: Direct characterization of cis-regulatory elements and functional dissection of complex genetic associations using HCR-FlowFISH.
    Nat. Genet. (IF 38.33) Pub Date : 2021-10-01
    Steven K Reilly,Sager J Gosai,Alan Gutierrez,Ava Mackay-Smith,Jacob C Ulirsch,Masahiro Kanai,Kousuke Mouri,Daniel Berenzy,Susan Kales,Gina M Butler,Adrianne Gladden-Young,Redwan M Bhuiyan,Michael L Stitzel,Hilary K Finucane,Pardis C Sabeti,Ryan Tewhey

  •   Embracing communication
    Nat. Genet. (IF 38.33) Pub Date : 2021-09-07

    Although it should be a given that scholarly communication must be clear and accurate, researchers, particularly those in the field of human genetics, can also promote the responsible reporting of their findings to a broader public audience in ways that heighten understanding and reduce misinterpretation.

  •   A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease
    Nat. Genet. (IF 38.33) Pub Date : 2021-09-07
    Douglas P. Wightman, Iris E. Jansen, Jeanne E. Savage, Alexey A. Shadrin, Shahram Bahrami, Dominic Holland, Arvid Rongve, Sigrid Børte, Bendik S. Winsvold, Ole Kristian Drange, Amy E. Martinsen, Anne Heidi Skogholt, Cristen Willer, Geir Bråthen, Ingunn Bosnes, Jonas Bille Nielsen, Lars G. Fritsche, Laurent F. Thomas, Linda M. Pedersen, Maiken E. Gabrielsen, Marianne Bakke Johnsen, Tore Wergeland Meisingset

    Late-onset Alzheimer’s disease is a prevalent age-related polygenic disease that accounts for 50–70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer’s disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer’s disease. This study highlights microglia

  •   Sex differences in genetic architecture in the UK Biobank
    Nat. Genet. (IF 38.33) Pub Date : 2021-09-07
    Elena Bernabeu, Oriol Canela-Xandri, Konrad Rawlik, Andrea Talenti, James Prendergast, Albert Tenesa

    Males and females present differences in complex traits and in the risk of a wide array of diseases. Genotype by sex (GxS) interactions are thought to account for some of these differences. However, the extent and basis of GxS are poorly understood. In the present study, we provide insights into both the scope and the mechanism of GxS across the genome of about 450,000 individuals of European ancestry

  •   FoGS provides a public FAQ repository for social and behavioral genomic discoveries
    Nat. Genet. (IF 38.33) Pub Date : 2021-09-06
    Daphne Oluwaseun Martschenko, Benjamin W. Domingue, Lucas J. Matthews, Sam Trejo

    Here we introduce ‘FAQs on Genomic Studies’ (FoGS), an open-access repository of explanatory documents that accompany genomic analyses in social and behavioral genomics. For fields such as social and behavioral genomics that are shaped by an ugly history and uncertain future, socially and ethically responsible research and research communication are crucial. FoGS amplifies one such approach towards

  •   Genomic and evolutionary classification of lung cancer in never smokers
    Nat. Genet. (IF 38.33) Pub Date : 2021-09-06
    Tongwu Zhang, Philippe Joubert, Naser Ansari-Pour, Wei Zhao, Phuc H. Hoang, Rachel Lokanga, Aaron L. Moye, Jennifer Rosenbaum, Abel Gonzalez-Perez, Francisco Martínez-Jiménez, Andrea Castro, Lucia Anna Muscarella, Paul Hofman, Dario Consonni, Angela C. Pesatori, Michael Kebede, Mengying Li, Bonnie E. Gould Rothberg, Iliana Peneva, Matthew B. Schabath, Maria Luana Poeta, Manuela Costantini, Daniela

    Lung cancer in never smokers (LCINS) is a common cause of cancer mortality but its genomic landscape is poorly characterized. Here high-coverage whole-genome sequencing of 232 LCINS showed 3 subtypes defined by copy number aberrations. The dominant subtype (piano), which is rare in lung cancer in smokers, features somatic UBA1 mutations, germline AR variants and stem cell-like properties, including

  •   A single-cell and spatially resolved atlas of human breast cancers
    Nat. Genet. (IF 38.33) Pub Date : 2021-09-06
    Sunny Z. Wu, Ghamdan Al-Eryani, Daniel Lee Roden, Simon Junankar, Kate Harvey, Alma Andersson, Aatish Thennavan, Chenfei Wang, James R. Torpy, Nenad Bartonicek, Taopeng Wang, Ludvig Larsson, Dominik Kaczorowski, Neil I. Weisenfeld, Cedric R. Uytingco, Jennifer G. Chew, Zachary W. Bent, Chia-Ling Chan, Vikkitharan Gnanasambandapillai, Charles-Antoine Dutertre, Laurence Gluch, Mun N. Hui, Jane Beith

    Breast cancers are complex cellular ecosystems where heterotypic interactions play central roles in disease progression and response to therapy. However, our knowledge of their cellular composition and organization is limited. Here we present a single-cell and spatially resolved transcriptomics analysis of human breast cancers. We developed a single-cell method of intrinsic subtype classification (SCSubtype)

  •   Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation
    Nat. Genet. (IF 38.33) Pub Date : 2021-09-06
    Josine L. Min, Gibran Hemani, Eilis Hannon, Koen F. Dekkers, Juan Castillo-Fernandez, René Luijk, Elena Carnero-Montoro, Daniel J. Lawson, Kimberley Burrows, Matthew Suderman, Andrew D. Bretherick, Tom G. Richardson, Johanna Klughammer, Valentina Iotchkova, Gemma Sharp, Ahmad Al Khleifat, Aleksey Shatunov, Alfredo Iacoangeli, Wendy L. McArdle, Karen M. Ho, Ashish Kumar, Cilla Söderhäll, Carolina Soriano-Tárraga

    Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs,

  •   A compendium of uniformly processed human gene expression and splicing quantitative trait loci
    Nat. Genet. (IF 38.33) Pub Date : 2021-09-06
    Nurlan Kerimov, James D. Hayhurst, Kateryna Peikova, Jonathan R. Manning, Peter Walter, Liis Kolberg, Marija Samoviča, Manoj Pandian Sakthivel, Ivan Kuzmin, Stephen J. Trevanion, Tony Burdett, Simon Jupp, Helen Parkinson, Irene Papatheodorou, Andrew D. Yates, Daniel R. Zerbino, Kaur Alasoo

    Many gene expression quantitative trait locus (eQTL) studies have published their summary statistics, which can be used to gain insight into complex human traits by downstream analyses, such as fine mapping and co-localization. However, technical differences between these datasets are a barrier to their widespread use. Consequently, target genes for most genome-wide association study (GWAS) signals

  •   Genomic insights into the origin, domestication and diversification of Brassica juncea
    Nat. Genet. (IF 38.33) Pub Date : 2021-09-06
    Lei Kang, Lunwen Qian, Ming Zheng, Liyang Chen, Hao Chen, Liu Yang, Liang You, Bin Yang, Mingli Yan, Yuanguo Gu, Tianyi Wang, Sarah-Veronica Schiessl, Hong An, Paul Blischak, Xianjun Liu, Hongfeng Lu, Dawei Zhang, Yong Rao, Donghai Jia, Dinggang Zhou, Huagui Xiao, Yonggang Wang, Xinghua Xiong, Annaliese S. Mason, J. Chris Pires, Rod J. Snowdon, Wei Hua, Zhongsong Liu

    Despite early domestication around 3000 BC, the evolutionary history of the ancient allotetraploid species Brassica juncea (L.) Czern & Coss remains uncertain. Here, we report a chromosome-scale de novo assembly of a yellow-seeded B. juncea genome by integrating long-read and short-read sequencing, optical mapping and Hi-C technologies. Nuclear and organelle phylogenies of 480 accessions worldwide

  •   Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression
    Nat. Genet. (IF 38.33) Pub Date : 2021-09-02
    Urmo Võsa, Annique Claringbould, Harm-Jan Westra, Marc Jan Bonder, Patrick Deelen, Biao Zeng, Holger Kirsten, Ashis Saha, Roman Kreuzhuber, Seyhan Yazar, Harm Brugge, Roy Oelen, Dylan H. de Vries, Monique G. P. van der Wijst, Silva Kasela, Natalia Pervjakova, Isabel Alves, Marie-Julie Favé, Mawussé Agbessi, Mark W. Christiansen, Rick Jansen, Ilkka Seppälä, Lin Tong, Alexander Teumer, Katharina Schramm

    Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in

  •   RNA demethylation for increased crop yields.
    Nat. Genet. (IF 38.33) Pub Date : 2021-09-01
    Ornob Alam

  •   The bowfin genome illuminates the developmental evolution of ray-finned fishes
    Nat. Genet. (IF 38.33) Pub Date : 2021-08-30
    Andrew W. Thompson, M. Brent Hawkins, Elise Parey, Dustin J. Wcisel, Tatsuya Ota, Kazuhiko Kawasaki, Emily Funk, Mauricio Losilla, Olivia E. Fitch, Qiaowei Pan, Romain Feron, Alexandra Louis, Jérôme Montfort, Marine Milhes, Brett L. Racicot, Kevin L. Childs, Quenton Fontenot, Allyse Ferrara, Solomon R. David, Amy R. McCune, Alex Dornburg, Jeffrey A. Yoder, Yann Guiguen, Hugues Roest Crollius, Camille

    The bowfin (Amia calva) is a ray-finned fish that possesses a unique suite of ancestral and derived phenotypes, which are key to understanding vertebrate evolution. The phylogenetic position of bowfin as a representative of neopterygian fishes, its archetypical body plan and its unduplicated and slowly evolving genome make bowfin a central species for the genomic exploration of ray-finned fishes. Here

  •   Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause
    Nat. Genet. (IF 38.33) Pub Date : 2021-08-12
    Zhou, Junhua, Azizan, Elena A. B., Cabrera, Claudia P., Fernandes-Rosa, Fabio L., Boulkroun, Sheerazed, Argentesi, Giulia, Cottrell, Emily, Amar, Laurence, Wu, Xilin, O’Toole, Sam, Goodchild, Emily, Marker, Alison, Senanayake, Russell, Garg, Sumedha, Åkerström, Tobias, Backman, Samuel, Jordan, Suzanne, Polubothu, Satyamaanasa, Berney, Daniel M., Gluck, Anna, Lines, Kate E., Thakker, Rajesh V., Tuthill

    Most aldosterone-producing adenomas (APAs) have gain-of-function somatic mutations of ion channels or transporters. However, their frequency in aldosterone-producing cell clusters of normal adrenal gland suggests a requirement for codriver mutations in APAs. Here we identified gain-of-function mutations in both CTNNB1 and GNA11 by whole-exome sequencing of 3/41 APAs. Further sequencing of known CTNNB1-mutant

  •   Mapping the genetic architecture of human traits to cell types in the kidney identifies mechanisms of disease and potential treatments
    Nat. Genet. (IF 38.33) Pub Date : 2021-08-12
    Sheng, Xin, Guan, Yuting, Ma, Ziyuan, Wu, Junnan, Liu, Hongbo, Qiu, Chengxiang, Vitale, Steven, Miao, Zhen, Seasock, Matthew J., Palmer, Matthew, Shin, Myung K., Duffin, Kevin L., Pullen, Steven S., Edwards, Todd L., Hellwege, Jacklyn N., Hung, Adriana M., Li, Mingyao, Voight, Benjamin F., Coffman, Thomas M., Brown, Christopher D., Susztak, Katalin

    The functional interpretation of genome-wide association studies (GWAS) is challenging due to the cell-type-dependent influences of genetic variants. Here, we generated comprehensive maps of expression quantitative trait loci (eQTLs) for 659 microdissected human kidney samples and identified cell-type-eQTLs by mapping interactions between cell type abundances and genotypes. By partitioning heritability

  •   High-quality genome assembly and resequencing of modern cotton cultivars provide resources for crop improvement
    Nat. Genet. (IF 38.33) Pub Date : 2021-08-09
    Ma, Zhiying, Zhang, Yan, Wu, Liqiang, Zhang, Guiyin, Sun, Zhengwen, Li, Zhikun, Jiang, Yafei, Ke, Huifeng, Chen, Bin, Liu, Zhengwen, Gu, Qishen, Wang, Zhicheng, Wang, Guoning, Yang, Jun, Wu, Jinhua, Yan, Yuanyuan, Meng, Chengsheng, Li, Lihua, Li, Xiuxin, Mo, Shaojing, Wu, Nan, Ma, Limei, Chen, Liting, Zhang, Man, Si, Aijun, Yang, Zhanwu, Wang, Nan, Wu, Lizhu, Zhang, Dongmei, Cui, Yanru, Cui, Jing,

    Cotton produces natural fiber for the textile industry. The genetic effects of genomic structural variations underlying agronomic traits remain unclear. Here, we generate two high-quality genomes of Gossypium hirsutum cv. NDM8 and Gossypium barbadense acc. Pima90, and identify large-scale structural variations in the two species and 1,081 G. hirsutum accessions. The density of structural variations

  •   Activation of γ-globin gene expression by GATA1 and NF-Y in hereditary persistence of fetal hemoglobin
    Nat. Genet. (IF 38.33) Pub Date : 2021-08-02
    Doerfler, Phillip A., Feng, Ruopeng, Li, Yichao, Palmer, Lance E., Porter, Shaina N., Bell, Henry W., Crossley, Merlin, Pruett-Miller, Shondra M., Cheng, Yong, Weiss, Mitchell J.

    Hereditary persistence of fetal hemoglobin (HPFH) ameliorates β-hemoglobinopathies by inhibiting the developmental switch from γ-globin (HBG1/HBG2) to β-globin (HBB) gene expression. Some forms of HPFH are associated with γ-globin promoter variants that either disrupt binding motifs for transcriptional repressors or create new motifs for transcriptional activators. How these variants sustain γ-globin

  •   Metastable epialleles are stable in their instability
    Nat. Genet. (IF 38.33) Pub Date : 2021-07-29
    Bourc’his, Deborah

    Metastable epialleles refer to loci with variable methylation states among individuals without underlying genetic differences. Although these loci have generally been assumed to be vulnerable to environmental influence, a new study reports their remarkable metastable epigenetic robustness toward a range of physiological, chemical and dietary disruptions in mammals.

  •   The distribution of common-variant effect sizes
    Nat. Genet. (IF 38.33) Pub Date : 2021-07-29
    O’Connor, Luke J.

    The genetic effect-size distribution of a disease describes the number of risk variants, the range of their effect sizes and sample sizes that will be required to discover them. Accurate estimation has been a challenge. Here I propose Fourier Mixture Regression (FMR), validating that it accurately estimates real and simulated effect-size distributions. Applied to summary statistics for ten diseases

  •   Direct characterization of cis-regulatory elements and functional dissection of complex genetic associations using HCR–FlowFISH
    Nat. Genet. (IF 38.33) Pub Date : 2021-07-29
    Reilly, Steven K., Gosai, Sager J., Gutierrez, Alan, Mackay-Smith, Ava, Ulirsch, Jacob C., Kanai, Masahiro, Mouri, Kousuke, Berenzy, Daniel, Kales, Susan, Butler, Gina M., Gladden-Young, Adrianne, Bhuiyan, Redwan M., Stitzel, Michael L., Finucane, Hilary K., Sabeti, Pardis C., Tewhey, Ryan

    Effective interpretation of genome function and genetic variation requires a shift from epigenetic mapping of cis-regulatory elements (CREs) to characterization of endogenous function. We developed hybridization chain reaction fluorescence in situ hybridization coupled with flow cytometry (HCR–FlowFISH), a broadly applicable approach to characterize CRISPR-perturbed CREs via accurate quantification

  •   Variably methylated retrotransposons are refractory to a range of environmental perturbations
    Nat. Genet. (IF 38.33) Pub Date : 2021-07-29
    Bertozzi, Tessa M., Becker, Jessica L., Blake, Georgina E. T., Bansal, Amita, Nguyen, Duy K., Fernandez-Twinn, Denise S., Ozanne, Susan E., Bartolomei, Marisa S., Simmons, Rebecca A., Watson, Erica D., Ferguson-Smith, Anne C.

    The agouti viable yellow (Avy) allele is an insertional mutation in the mouse genome caused by a variably methylated intracisternal A particle (VM-IAP) retrotransposon. Avy expressivity is sensitive to a range of early-life chemical exposures and nutritional interventions, suggesting that environmental perturbations can have long-lasting effects on the methylome. However, the extent to which VM-IAP

  •   Recent ultra-rare inherited variants implicate new autism candidate risk genes
    Nat. Genet. (IF 38.33) Pub Date : 2021-07-26
    Amy B. Wilfert, Tychele N. Turner, Shwetha C. Murali, PingHsun Hsieh, Arvis Sulovari, Tianyun Wang, Bradley P. Coe, Hui Guo, Kendra Hoekzema, Trygve E. Bakken, Lara H. Winterkorn, Uday S. Evani, Marta Byrska-Bishop, Rachel K. Earl, Raphael A. Bernier, Michael C. Zody, Evan E. Eichler

    Autism is a highly heritable complex disorder in which de novo mutation (DNM) variation contributes significantly to risk. Using whole-genome sequencing data from 3,474 families, we investigate another source of large-effect risk variation, ultra-rare variants. We report and replicate a transmission disequilibrium of private, likely gene-disruptive (LGD) variants in probands but find that 95% of this

  •   Simultaneous disruption of PRC2 and enhancer function underlies histone H3.3-K27M oncogenic activity in human hindbrain neural stem cells
    Nat. Genet. (IF 38.33) Pub Date : 2021-07-22
    Gerard L. Brien, Raul Bardini Bressan, Craig Monger, Dáire Gannon, Eimear Lagan, Anthony M. Doherty, Evan Healy, Hannah Neikes, Darren J. Fitzpatrick, Orla Deevy, Vivien Grant, Maria-Angeles Marqués-Torrejón, Neza Alfazema, Steven M. Pollard, Adrian P. Bracken

    Driver mutations in genes encoding histone H3 proteins resulting in p.Lys27Met substitutions (H3-K27M) are frequent in pediatric midline brain tumors. However, the precise mechanisms by which H3-K27M causes tumor initiation remain unclear. Here, we use human hindbrain neural stem cells to model the consequences of H3.3-K27M on the epigenomic landscape in a relevant developmental context. Genome-wide

  •   Shedding light on the genetics of fetal growth
    Nat. Genet. (IF 38.33) Pub Date : 2021-07-19
    David M. Evans, Rachel M. Freathy

    Genome-wide association studies have identified genetic variants in maternal and fetal genomes associated with early-life growth traits but have been limited by the paucity of large-scale family-based cohorts that would enable the resolution of informative transmissions between parents and their offspring. A new study uses extensive pedigree data from the Icelandic population to identify genetic effects

  •   Distinction between the effects of parental and fetal genomes on fetal growth
    Nat. Genet. (IF 38.33) Pub Date : 2021-07-19
    Thorhildur Juliusdottir, Valgerdur Steinthorsdottir, Lilja Stefansdottir, Gardar Sveinbjornsson, Erna V. Ivarsdottir, Rosa B. Thorolfsdottir, Jon K. Sigurdsson, Vinicius Tragante, Kristjan E. Hjorleifsson, Anna Helgadottir, Michael L. Frigge, Gudmundur Thorgeirsson, Rafn Benediktsson, Emil L. Sigurdsson, David O. Arnar, Thora Steingrimsdottir, Ingileif Jonsdottir, Hilma Holm, Daniel F. Gudbjartsson

    Birth weight is a common measure of fetal growth that is associated with a range of health outcomes. It is directly affected by the fetal genome and indirectly by the maternal genome. We performed genome-wide association studies on birth weight in the genomes of the child and parents and further analyzed birth length and ponderal index, yielding a total of 243 fetal growth variants. We clustered those

  •   Stephen T. Warren 1953–2021
    Nat. Genet. (IF 38.33) Pub Date : 2021-07-15
    David L. Nelson

    Stephen T. Warren was a key contributor to the 1991 discovery of an unstable trinucleotide repeat that expands in families and causes loss of function in fragile X syndrome.

  •   A call for direct sequencing of full-length RNAs to identify all modifications
    Nat. Genet. (IF 38.33) Pub Date : 2021-07-15
    Juan D. Alfonzo, Jessica A. Brown, Peter H. Byers, Vivian G. Cheung, Richard J. Maraia, Robert L. Ross

    For most organisms, DNA sequences are available, but the complete RNA sequences are not. Here, we call for technologies to sequence full-length RNAs with all their modifications.

  •   Haplotype-resolved genome assembly provides insights into evolutionary history of the tea plant Camellia sinensis
    Nat. Genet. (IF 38.33) Pub Date : 2021-07-15
    Xingtan Zhang, Shuai Chen, Longqing Shi, Daping Gong, Shengcheng Zhang, Qian Zhao, Dongliang Zhan, Liette Vasseur, Yibin Wang, Jiaxin Yu, Zhenyang Liao, Xindan Xu, Rui Qi, Wenling Wang, Yunran Ma, Pengjie Wang, Naixing Ye, Dongna Ma, Yan Shi, Haifeng Wang, Xiaokai Ma, Xiangrui Kong, Jing Lin, Liufeng Wei, Yaying Ma, Ruoyu Li, Guiping Hu, Haifang He, Lin Zhang, Ray Ming, Gang Wang, Haibao Tang, Minsheng

    Tea is an important global beverage crop and is largely clonally propagated. Despite previous studies on the species, its genetic and evolutionary history deserves further research. Here, we present a haplotype-resolved assembly of an Oolong tea cultivar, Tieguanyin. Analysis of allele-specific expression suggests a potential mechanism in response to mutation load during long-term clonal propagation

  •   p53 convergently activates Dux/DUX4 in embryonic stem cells and in facioscapulohumeral muscular dystrophy cell models
    Nat. Genet. (IF 38.33) Pub Date : 2021-07-15
    Edward J. Grow, Bradley D. Weaver, Christina M. Smith, Jingtao Guo, Paula Stein, Sean C. Shadle, Peter G. Hendrickson, Nicholas E. Johnson, Russell J. Butterfield, Roberta Menafra, Susan L. Kloet, Silvère M. van der Maarel, Carmen J. Williams, Bradley R. Cairns

    In mammalian embryos, proper zygotic genome activation (ZGA) underlies totipotent development. Double homeobox (DUX)-family factors participate in ZGA, and mouse Dux is required for forming cultured two-cell (2C)-like cells. Remarkably, in mouse embryonic stem cells, Dux is activated by the tumor suppressor p53, and Dux expression promotes differentiation into expanded-fate cell types. Long-read sequencing

  •   Genome-scale screens identify factors regulating tumor cell responses to natural killer cells
    Nat. Genet. (IF 38.33) Pub Date : 2021-07-12
    Michal Sheffer, Emily Lowry, Nicky Beelen, Minasri Borah, Suha Naffar-Abu Amara, Chris C. Mader, Jennifer A. Roth, Aviad Tsherniak, Samuel S. Freeman, Olga Dashevsky, Sara Gandolfi, Samantha Bender, Jordan G. Bryan, Cong Zhu, Li Wang, Ifrah Tariq, Govinda M. Kamath, Ricardo De Matos Simoes, Eugen Dhimolea, Channing Yu, Yiguo Hu, Olli Dufva, Marios Giannakis, Vasilis Syrgkanis, Ernest Fraenkel, Todd

    To systematically define molecular features in human tumor cells that determine their degree of sensitivity to human allogeneic natural killer (NK) cells, we quantified the NK cell responsiveness of hundreds of molecularly annotated ‘DNA-barcoded’ solid tumor cell lines in multiplexed format and applied genome-scale CRISPR-based gene-editing screens in several solid tumor cell lines, to functionally

  •   SWI/SNF complexes as determinants of R-loop metabolism
    Nat. Genet. (IF 38.33) Pub Date : 2021-07-09
    Abdulkadir Abakir, Alexey Ruzov

    R-loops—nucleic acid structures composed of an RNA:DNA hybrid and displaced single-stranded DNA—are abundant in the genome and may impair progression of the replication fork, thus leading to accumulation of DNA damage and genome instability. A new study demonstrates that SWI/SNF chromatin-remodeling complexes are instrumental in resolving such R-loop-mediated transcription–replication conflicts, highlighting

  •   Single-nucleus chromatin accessibility and transcriptomic characterization of Alzheimer’s disease
    Nat. Genet. (IF 38.33) Pub Date : 2021-07-08
    Samuel Morabito, Emily Miyoshi, Neethu Michael, Saba Shahin, Alessandra Cadete Martini, Elizabeth Head, Justine Silva, Kelsey Leavy, Mari Perez-Rosendahl, Vivek Swarup

    The gene-regulatory landscape of the brain is highly dynamic in health and disease, coordinating a menagerie of biological processes across distinct cell types. Here, we present a multi-omic single-nucleus study of 191,890 nuclei in late-stage Alzheimer’s disease (AD), accessible through our web portal, profiling chromatin accessibility and gene expression in the same biological samples and uncovering

  •   Whole-exome imputation within UK Biobank powers rare coding variant association and fine-mapping analyses
    Nat. Genet. (IF 38.33) Pub Date : 2021-07-05
    Alison R. Barton, Maxwell A. Sherman, Ronen E. Mukamel, Po-Ru Loh

    Exome association studies to date have generally been underpowered to systematically evaluate the phenotypic impact of very rare coding variants. We leveraged extensive haplotype sharing between 49,960 exome-sequenced UK Biobank participants and the remainder of the cohort (total n ≈ 500,000) to impute exome-wide variants with accuracy R2 > 0.5 down to minor allele frequency (MAF) ~0.00005. Association

  •   Genetic drivers of m6A methylation in human brain, lung, heart and muscle
    Nat. Genet. (IF 38.33) Pub Date : 2021-07-01
    Xushen Xiong, Lei Hou, Yongjin P. Park, Benoit Molinie, Richard I. Gregory, Manolis Kellis

    The most prevalent post-transcriptional mRNA modification, N6-methyladenosine (m6A), plays diverse RNA-regulatory roles, but its genetic control in human tissues remains uncharted. Here we report 129 transcriptome-wide m6A profiles, covering 91 individuals and 4 tissues (brain, lung, muscle and heart) from GTEx/eGTEx. We integrate these with interindividual genetic and expression variation, revealing

  •   Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome
    Nat. Genet. (IF 38.33) Pub Date : 2021-07-01
    Margot A. Cousin, Blake A. Creighton, Keith A. Breau, Rebecca C. Spillmann, Erin Torti, Sruthi Dontu, Swarnendu Tripathi, Deepa Ajit, Reginald J. Edwards, Simone Afriyie, Julia C. Bay, Kathryn M. Harper, Alvaro A. Beltran, Lorena J. Munoz, Liset Falcon Rodriguez, Michael C. Stankewich, Richard E. Person, Yue Si, Elizabeth A. Normand, Amy Blevins, Alison S. May, Louise Bier, Vimla Aggarwal, Grazia M

    SPTBN1 encodes βII-spectrin, the ubiquitously expressed β-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal βII-spectrin have defects in cortical organization, developmental delay and behavioral deficiencies. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous SPTBN1

  •   Reconstructing single-cell karyotype alterations in colorectal cancer identifies punctuated and gradual diversification patterns
    Nat. Genet. (IF 38.33) Pub Date : 2021-07-01
    Yannik Bollen, Ellen Stelloo, Petra van Leenen, Myrna van den Bos, Bas Ponsioen, Bingxin Lu, Markus J. van Roosmalen, Ana C. F. Bolhaqueiro, Christopher Kimberley, Maximilian Mossner, William C. H. Cross, Nicolle J. M. Besselink, Bastiaan van der Roest, Sander Boymans, Koen C. Oost, Sippe G. de Vries, Holger Rehmann, Edwin Cuppen, Susanne M. A. Lens, Geert J. P. L. Kops, Wigard P. Kloosterman, Leon

    Central to tumor evolution is the generation of genetic diversity. However, the extent and patterns by which de novo karyotype alterations emerge and propagate within human tumors are not well understood, especially at single-cell resolution. Here, we present 3D Live-Seq—a protocol that integrates live-cell imaging of tumor organoid outgrowth and whole-genome sequencing of each imaged cell to reconstruct

  •   Advancing human genetics research and drug discovery through exome sequencing of the UK Biobank
    Nat. Genet. (IF 38.33) Pub Date : 2021-06-28
    Joseph D. Szustakowski, Suganthi Balasubramanian, Erika Kvikstad, Shareef Khalid, Paola G. Bronson, Ariella Sasson, Emily Wong, Daren Liu, J. Wade Davis, Carolina Haefliger, A. Katrina Loomis, Rajesh Mikkilineni, Hyun Ji Noh, Samir Wadhawan, Xiaodong Bai, Alicia Hawes, Olga Krasheninina, Ricardo Ulloa, Alex E. Lopez, Erin N. Smith, Jeffrey F. Waring, Christopher D. Whelan, Ellen A. Tsai, John D. Overton

    The UK Biobank Exome Sequencing Consortium (UKB-ESC) is a private–public partnership between the UK Biobank (UKB) and eight biopharmaceutical companies that will complete the sequencing of exomes for all ~500,000 UKB participants. Here, we describe the early results from ~200,000 UKB participants and the features of this project that enabled its success. The biopharmaceutical industry has increasingly

  •   Orphan CpG islands amplify poised enhancer regulatory activity and determine target gene responsiveness
    Nat. Genet. (IF 38.33) Pub Date : 2021-06-28
    Tomas Pachano, Víctor Sánchez-Gaya, Thais Ealo, Maria Mariner-Faulí, Tore Bleckwehl, Helena G. Asenjo, Patricia Respuela, Sara Cruz-Molina, María Muñoz-San Martín, Endika Haro, Wilfred F. J. van IJcken, David Landeira, Alvaro Rada-Iglesias

    CpG islands (CGIs) represent a widespread feature of vertebrate genomes, being associated with ~70% of all gene promoters. CGIs control transcription initiation by conferring nearby promoters with unique chromatin properties. In addition, there are thousands of distal or orphan CGIs (oCGIs) whose functional relevance is barely known. Here we show that oCGIs are an essential component of poised enhancers

  •   The HIF complex recruits the histone methyltransferase SET1B to activate specific hypoxia-inducible genes
    Nat. Genet. (IF 38.33) Pub Date : 2021-06-21
    Brian M. Ortmann, Natalie Burrows, Ian T. Lobb, Esther Arnaiz, Niek Wit, Peter S. J. Bailey, Louise H. Jordon, Olivia Lombardi, Ana Peñalver, James McCaffrey, Rachel Seear, David R. Mole, Peter J. Ratcliffe, Patrick H. Maxwell, James A. Nathan

    Hypoxia-inducible transcription factors (HIFs) are fundamental to cellular adaptation to low oxygen levels, but it is unclear how they interact with chromatin and activate their target genes. Here, we use genome-wide mutagenesis to identify genes involved in HIF transcriptional activity, and define a requirement for the histone H3 lysine 4 (H3K4) methyltransferase SET1B. SET1B loss leads to a selective

  •   A unified framework identifies new links between plasma lipids and diseases from electronic medical records across large-scale cohorts
    Nat. Genet. (IF 38.33) Pub Date : 2021-06-17
    Yogasudha Veturi, Anastasia Lucas, Yuki Bradford, Daniel Hui, Scott Dudek, Elizabeth Theusch, Anurag Verma, Jason E. Miller, Iftikhar Kullo, Hakon Hakonarson, Patrick Sleiman, Daniel Schaid, Charles M. Stein, Digna R. Velez Edwards, QiPing Feng, Wei-Qi Wei, Marisa W. Medina, Ronald M. Krauss, Thomas J. Hoffmann, Neil Risch, Benjamin F. Voight, Daniel J. Rader, Marylyn D. Ritchie

    Plasma lipids are known heritable risk factors for cardiovascular disease, but increasing evidence also supports shared genetics with diseases of other organ systems. We devised a comprehensive three-phase framework to identify new lipid-associated genes and study the relationships among lipids, genotypes, gene expression and hundreds of complex human diseases from the Electronic Medical Records and

  •   PHYTOCHROME-INTERACTING FACTORs trigger environmentally responsive chromatin dynamics in plants
    Nat. Genet. (IF 38.33) Pub Date : 2021-06-17
    Björn C. Willige, Mark Zander, Chan Yul Yoo, Amy Phan, Renee M. Garza, Shelly A. Trigg, Yupeng He, Joseph R. Nery, Huaming Chen, Meng Chen, Joseph R. Ecker, Joanne Chory

    The interplay between light receptors and PHYTOCHROME-INTERACTING FACTORs (PIFs) serves as a regulatory hub that perceives and integrates environmental cues into transcriptional networks of plants1,2. Although occupancy of the histone variant H2A.Z and acetylation of histone H3 have emerged as regulators of environmentally responsive gene networks, how these epigenomic features interface with PIF activity

  •   Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes
    Nat. Genet. (IF 38.33) Pub Date : 2021-06-14
    Catherine C. Robertson, Jamie R. J. Inshaw, Suna Onengut-Gumuscu, Wei-Min Chen, David Flores Santa Cruz, Hanzhi Yang, Antony J. Cutler, Daniel J. M. Crouch, Emily Farber, S. Louis Bridges, Jeffrey C. Edberg, Robert P. Kimberly, Jane H. Buckner, Panos Deloukas, Jasmin Divers, Dana Dabelea, Jean M. Lawrence, Santica Marcovina, Amy S. Shah, Carla J. Greenbaum, Mark A. Atkinson, Peter K. Gregersen, Jorge

    We report the largest and most diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 78 genome-wide-significant (P < 5 × 10−8) regions, including 36 that are new. We define credible sets of T1D-associated variants and show that they are enriched in immune-cell accessible chromatin, particularly CD4+ effector T cells. Using chromatin-accessibility profiling of CD4+ T

  •   CRISPR–Cas9 can cause chromothripsis
    Nat. Genet. (IF 38.33) Pub Date : 2021-06-08
    Fyodor D. Urnov

    Genome editing with CRISPR–Cas9 is beginning to be used clinically; promising results to date inspire hope for broad medical impact and mindfulness about safety. A new study shows that when Cas9 cuts its target, a fraction of the time, the target chromosome experiences a breakage process known as chromothripsis, thus prompting efforts to understand the potential negative consequences of this phenomenon

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