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  •   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 : 2021-09-08
    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

  •   Going home: the challenges and rewards of genetics research in Mexico
    Nat. Genet. (IF 38.33) Pub Date : 2021-06-07
    Carla Daniela Robles-Espinoza

    The decision to move back home was very appealing but still took substantial thought.

  •   Three-dimensional folding dynamics of the Xenopus tropicalis genome
    Nat. Genet. (IF 38.33) Pub Date : 2021-06-07
    Longjian Niu, Wei Shen, Zhaoying Shi, Yongjun Tan, Na He, Jing Wan, Jialei Sun, Yuedong Zhang, Yingzhang Huang, Wenjing Wang, Chao Fang, Jiashuo Li, Piaopiao Zheng, Edwin Cheung, Yonglong Chen, Li Li, Chunhui Hou

    Animal interphase chromosomes are organized into topologically associating domains (TADs). How TADs are formed is not fully understood. Here, we combined high-throughput chromosome conformation capture and gene silencing to obtain insights into TAD dynamics in Xenopus tropicalis embryos. First, TAD establishment in X. tropicalis is similar to that in mice and flies and does not depend on zygotic genome

  •   Scrutinizing disease states and regulation in human microglia
    Nat. Genet. (IF 38.33) Pub Date : 2021-06-03
    Kevin W. Kelley, Sergiu P. Pașca

    Single-cell and bulk transcriptomics of adult human microglia from a population of individuals reveals activated states across several brain disorders and maps Alzheimer’s disease variants to microglia-enriched genes.

  •   Rapid genotype imputation from sequence with reference panels
    Nat. Genet. (IF 38.33) Pub Date : 2021-06-03
    Robert W. Davies, Marek Kucka, Dingwen Su, Sinan Shi, Maeve Flanagan, Christopher M. Cunniff, Yingguang Frank Chan, Simon Myers

    Inexpensive genotyping methods are essential to modern genomics. Here we present QUILT, which performs diploid genotype imputation using low-coverage whole-genome sequence data. QUILT employs Gibbs sampling to partition reads into maternal and paternal sets, facilitating rapid haploid imputation using large reference panels. We show this partitioning to be accurate over many megabases, enabling highly

  •   A map of transcriptional heterogeneity and regulatory variation in human microglia
    Nat. Genet. (IF 38.33) Pub Date : 2021-06-03
    Adam M. H. Young, Natsuhiko Kumasaka, Fiona Calvert, Timothy R. Hammond, Andrew Knights, Nikolaos Panousis, Jun Sung Park, Jeremy Schwartzentruber, Jimmy Liu, Kousik Kundu, Michael Segel, Natalia A. Murphy, Christopher E. McMurran, Harry Bulstrode, Jason Correia, Karol P. Budohoski, Alexis Joannides, Mathew R. Guilfoyle, Rikin Trivedi, Ramez Kirollos, Robert Morris, Matthew R. Garnett, Ivan Timofeev

    Microglia, the tissue-resident macrophages of the central nervous system (CNS), play critical roles in immune defense, development and homeostasis. However, isolating microglia from humans in large numbers is challenging. Here, we profiled gene expression variation in primary human microglia isolated from 141 patients undergoing neurosurgery. Using single-cell and bulk RNA sequencing, we identify how

  •   Author Correction: The NCI Genomic Data Commons.
    Nat. Genet. (IF 38.33) Pub Date : 2021-06-01
    Allison P Heath,Vincent Ferretti,Stuti Agrawal,Maksim An,James C Angelakos,Renuka Arya,Rosita Bajari,Bilal Baqar,Justin H B Barnowski,Jeffrey Burt,Ann Catton,Brandon F Chan,Fay Chu,Kim Cullion,Tanja Davidsen,Phuong-My Do,Christian Dompierre,Martin L Ferguson,Michael S Fitzsimons,Michael Ford,Miyuki Fukuma,Sharon Gaheen,Gajanan L Ganji,Tzintzuni I Garcia,Sameera S George,Daniela S Gerhard,Francois Gerthoffert

  •   The trans-ancestral genomic architecture of glycemic traits
    Nat. Genet. (IF 38.33) Pub Date : 2021-05-31
    Ji Chen, Cassandra N. Spracklen, Gaëlle Marenne, Arushi Varshney, Laura J. Corbin, Jian’an Luan, Sara M. Willems, Ying Wu, Xiaoshuai Zhang, Momoko Horikoshi, Thibaud S. Boutin, Reedik Mägi, Johannes Waage, Ruifang Li-Gao, Kei Hang Katie Chan, Jie Yao, Mila D. Anasanti, Audrey Y. Chu, Annique Claringbould, Jani Heikkinen, Jaeyoung Hong, Jouke-Jan Hottenga, Shaofeng Huo, Marika A. Kaakinen, Tin Louie

    Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated

  •   Radiotherapy is associated with a deletion signature that contributes to poor outcomes in patients with cancer
    Nat. Genet. (IF 38.33) Pub Date : 2021-05-27
    Emre Kocakavuk, Kevin J. Anderson, Frederick S. Varn, Kevin C. Johnson, Samirkumar B. Amin, Erik. P. Sulman, Martijn P. Lolkema, Floris P. Barthel, Roel G. W. Verhaak

    Ionizing radiation causes DNA damage and is a mainstay for cancer treatment, but understanding of its genomic impact is limited. We analyzed mutational spectra following radiotherapy in 190 paired primary and recurrent gliomas from the Glioma Longitudinal Analysis Consortium and 3,693 post-treatment metastatic tumors from the Hartwig Medical Foundation. We identified radiotherapy-associated significant

  •   Non-additive association analysis using proxy phenotypes identifies novel cattle syndromes
    Nat. Genet. (IF 38.33) Pub Date : 2021-05-27
    Edwardo G. M. Reynolds, Catherine Neeley, Thomas J. Lopdell, Michael Keehan, Keren Dittmer, Chad S. Harland, Christine Couldrey, Thomas J. J. Johnson, Kathryn Tiplady, Gemma Worth, Mark Walker, Stephen R. Davis, Richard G. Sherlock, Katie Carnie, Bevin L. Harris, Carole Charlier, Michel Georges, Richard J. Spelman, Dorian J. Garrick, Mathew D. Littlejohn

    Mammalian species carry ~100 loss-of-function variants per individual1,2, where ~1–5 of these impact essential genes and cause embryonic lethality or severe disease when homozygous3. The functions of the remainder are more difficult to resolve, although the assumption is that these variants impact fitness in less manifest ways. Here we report one of the largest sequence-resolution screens of cattle

  •   Separating measurement and expression models clarifies confusion in single-cell RNA sequencing analysis
    Nat. Genet. (IF 38.33) Pub Date : 2021-05-24
    Abhishek Sarkar, Matthew Stephens

    The high proportion of zeros in typical single-cell RNA sequencing datasets has led to widespread but inconsistent use of terminology such as dropout and missing data. Here, we argue that much of this terminology is unhelpful and confusing, and outline simple ideas to help to reduce confusion. These include: (1) observed single-cell RNA sequencing counts reflect both true gene expression levels and

  •   Computationally efficient whole-genome regression for quantitative and binary traits
    Nat. Genet. (IF 38.33) Pub Date : 2021-05-20
    Joelle Mbatchou, Leland Barnard, Joshua Backman, Anthony Marcketta, Jack A. Kosmicki, Andrey Ziyatdinov, Christian Benner, Colm O’Dushlaine, Mathew Barber, Boris Boutkov, Lukas Habegger, Manuel Ferreira, Aris Baras, Jeffrey Reid, Goncalo Abecasis, Evan Maxwell, Jonathan Marchini

    Genome-wide association analysis of cohorts with thousands of phenotypes is computationally expensive, particularly when accounting for sample relatedness or population structure. Here we present a novel machine-learning method called REGENIE for fitting a whole-genome regression model for quantitative and binary phenotypes that is substantially faster than alternatives in multi-trait analyses while

  •   Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
    Nat. Genet. (IF 38.33) Pub Date : 2021-05-17
    Niamh Mullins, Andreas J. Forstner, Kevin S. O’Connell, Brandon Coombes, Jonathan R. I. Coleman, Zhen Qiao, Thomas D. Als, Tim B. Bigdeli, Sigrid Børte, Julien Bryois, Alexander W. Charney, Ole Kristian Drange, Michael J. Gandal, Saskia P. Hagenaars, Masashi Ikeda, Nolan Kamitaki, Minsoo Kim, Kristi Krebs, Georgia Panagiotaropoulou, Brian M. Schilder, Laura G. Sloofman, Stacy Steinberg, Vassily Trubetskoy

    Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression

  •   An atlas of mitochondrial DNA genotype–phenotype associations in the UK Biobank
    Nat. Genet. (IF 38.33) Pub Date : 2021-05-17
    Ekaterina Yonova-Doing, Claudia Calabrese, Aurora Gomez-Duran, Katherine Schon, Wei Wei, Savita Karthikeyan, Patrick F. Chinnery, Joanna M. M. Howson

    Mitochondrial DNA (mtDNA) variation in common diseases has been underexplored, partly due to a lack of genotype calling and quality-control procedures. Developing an at-scale workflow for mtDNA variant analyses, we show correlations between nuclear and mitochondrial genomic structures within subpopulations of Great Britain and establish a UK Biobank reference atlas of mtDNA–phenotype associations.

  •   CTCF mediates dosage- and sequence-context-dependent transcriptional insulation by forming local chromatin domains
    Nat. Genet. (IF 38.33) Pub Date : 2021-05-17
    Hui Huang, Quan Zhu, Adam Jussila, Yuanyuan Han, Bogdan Bintu, Colin Kern, Mattia Conte, Yanxiao Zhang, Simona Bianco, Andrea M. Chiariello, Miao Yu, Rong Hu, Melodi Tastemel, Ivan Juric, Ming Hu, Mario Nicodemi, Xiaowei Zhuang, Bing Ren

    Insulators play a critical role in spatiotemporal gene regulation in animals. The evolutionarily conserved CCCTC-binding factor (CTCF) is required for insulator function in mammals, but not all of its binding sites act as insulators. Here we explore the sequence requirements of CTCF-mediated transcriptional insulation using a sensitive insulator reporter in mouse embryonic stem cells. We find that

  •   An atlas of alternative polyadenylation quantitative trait loci contributing to complex trait and disease heritability
    Nat. Genet. (IF 38.33) Pub Date : 2021-05-13
    Lei Li, Kai-Lieh Huang, Yipeng Gao, Ya Cui, Gao Wang, Nathan D. Elrod, Yumei Li, Yiling Elaine Chen, Ping Ji, Fanglue Peng, William K. Russell, Eric J. Wagner, Wei Li

    Genome-wide association studies have identified thousands of noncoding variants associated with human traits and diseases. However, the functional interpretation of these variants is a major challenge. Here, we constructed a multi-tissue atlas of human 3′UTR alternative polyadenylation (APA) quantitative trait loci (3′aQTLs), containing approximately 0.4 million common genetic variants associated with

  •   The SWI/SNF chromatin remodeling complex helps resolve R-loop-mediated transcription–replication conflicts
    Nat. Genet. (IF 38.33) Pub Date : 2021-05-13
    Aleix Bayona-Feliu, Sonia Barroso, Sergio Muñoz, Andrés Aguilera

    ATP-dependent chromatin remodelers are commonly mutated in human cancer. Mammalian SWI/SNF complexes comprise three conserved multisubunit chromatin remodelers (cBAF, ncBAF and PBAF) that share the BRG1 (also known as SMARCA4) subunit responsible for the main ATPase activity. BRG1 is the most frequently mutated Snf2-like ATPase in cancer. In the present study, we have investigated the role of SWI/SNF

  •   Two competing mechanisms of DNMT3A recruitment regulate the dynamics of de novo DNA methylation at PRC1-targeted CpG islands
    Nat. Genet. (IF 38.33) Pub Date : 2021-05-13
    Daniel N. Weinberg, Phillip Rosenbaum, Xiao Chen, Douglas Barrows, Cynthia Horth, Matthew R. Marunde, Irina K. Popova, Zachary B. Gillespie, Michael-Christopher Keogh, Chao Lu, Jacek Majewski, C. David Allis

    Precise deposition of CpG methylation is critical for mammalian development and tissue homeostasis and is often dysregulated in human diseases. The localization of de novo DNA methyltransferase DNMT3A is facilitated by its PWWP domain recognizing histone H3 lysine 36 (H3K36) methylation1,2 and is normally depleted at CpG islands (CGIs)3. However, methylation of CGIs regulated by Polycomb repressive

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