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Linking genetic variants to kidney disease via the epigenome Nat. Genet. (IF 38.33) Pub Date : 2022-06-23
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Graph pangenomes find missing heritability Nat. Genet. (IF 38.33) Pub Date : 2022-06-23 David Edwards, Jacqueline Batley
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Single-cell analyses define a continuum of cell state and composition changes in the malignant transformation of polyps to colorectal cancer Nat. Genet. (IF 38.33) Pub Date : 2022-06-20 Winston R. Becker, Stephanie A. Nevins, Derek C. Chen, Roxanne Chiu, Aaron M. Horning, Tuhin K. Guha, Rozelle Laquindanum, Meredith Mills, Hassan Chaib, Uri Ladabaum, Teri Longacre, Jeanne Shen, Edward D. Esplin, Anshul Kundaje, James M. Ford, Christina Curtis, Michael P. Snyder, William J. Greenleaf
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Epigenomic and transcriptomic analyses define core cell types, genes and targetable mechanisms for kidney disease Nat. Genet. (IF 38.33) Pub Date : 2022-06-16 Hongbo Liu, Tomohito Doke, Dong Guo, Xin Sheng, Ziyuan Ma, Joseph Park, Ha My T. Vy, Girish N. Nadkarni, Amin Abedini, Zhen Miao, Matthew Palmer, Benjamin F. Voight, Hongzhe Li, Christopher D. Brown, Marylyn D. Ritchie, Yan Shu, Katalin Susztak
More than 800 million people suffer from kidney disease, yet the mechanism of kidney dysfunction is poorly understood. In the present study, we define the genetic association with kidney function in 1.5 million individuals and identify 878 (126 new) loci. We map the genotype effect on the methylome in 443 kidneys, transcriptome in 686 samples and single-cell open chromatin in 57,229 kidney cells. Heritability
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Allelic imbalance of chromatin accessibility in cancer identifies candidate causal risk variants and their mechanisms Nat. Genet. (IF 38.33) Pub Date : 2022-06-13 Dennis Grishin, Alexander Gusev
While many germline cancer risk variants have been identified through genome-wide association studies (GWAS), the mechanisms by which these variants operate remain largely unknown. Here we used 406 cancer ATAC-Seq samples across 23 cancer types to identify 7,262 germline allele-specific accessibility QTLs (as-aQTLs). Cancer as-aQTLs had stronger enrichment for cancer risk heritability (up to 145 fold)
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Genome-wide association analysis reveals insights into the genetic architecture of right ventricular structure and function Nat. Genet. (IF 38.33) Pub Date : 2022-06-13 Nay Aung, Jose D. Vargas, Chaojie Yang, Kenneth Fung, Mihir M. Sanghvi, Stefan K. Piechnik, Stefan Neubauer, Ani Manichaikul, Jerome I. Rotter, Kent D. Taylor, Joao A. C. Lima, David A. Bluemke, Steven M. Kawut, Steffen E. Petersen, Patricia B. Munroe
Right ventricular (RV) structure and function influence the morbidity and mortality from coronary artery disease (CAD), dilated cardiomyopathy (DCM), pulmonary hypertension and heart failure. Little is known about the genetic basis of RV measurements. Here we perform genome-wide association analyses of four clinically relevant RV phenotypes (RV end-diastolic volume, RV end-systolic volume, RV stroke
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Genetic analysis of right heart structure and function in 40,000 people Nat. Genet. (IF 38.33) Pub Date : 2022-06-13 James P. Pirruccello, Paolo Di Achille, Victor Nauffal, Mahan Nekoui, Samuel F. Friedman, Marcus D. R. Klarqvist, Mark D. Chaffin, Lu-Chen Weng, Jonathan W. Cunningham, Shaan Khurshid, Carolina Roselli, Honghuang Lin, Satoshi Koyama, Kaoru Ito, Yoichiro Kamatani, Issei Komuro, Sean J. Jurgens, Emelia J. Benjamin, Puneet Batra, Pradeep Natarajan, Kenney Ng, Udo Hoffmann, Steven A. Lubitz, Jennifer E
Congenital heart diseases often involve maldevelopment of the evolutionarily recent right heart chamber. To gain insight into right heart structure and function, we fine-tuned deep learning models to recognize the right atrium, right ventricle and pulmonary artery, measuring right heart structures in 40,000 individuals from the UK Biobank with magnetic resonance imaging. Genome-wide association studies
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The missing diversity in human epigenomic studies Nat. Genet. (IF 38.33) Pub Date : 2022-06-09 Charles E. Breeze, Stephan Beck, Sonja I. Berndt, Nora Franceschini
Recent work has highlighted a lack of diversity in genomic studies. However, less attention has been given to epigenomics. Here, we show that epigenomic studies are lacking in diversity and propose several solutions to address this problem.
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Genomic analysis defines clonal relationships of ductal carcinoma in situ and recurrent invasive breast cancer Nat. Genet. (IF 38.33) Pub Date : 2022-06-09 Esther H. Lips, Tapsi Kumar, Anargyros Megalios, Lindy L. Visser, Michael Sheinman, Angelo Fortunato, Vandna Shah, Marlous Hoogstraat, Emi Sei, Diego Mallo, Maria Roman-Escorza, Ahmed A. Ahmed, Mingchu Xu, Alexandra W. van den Belt-Dusebout, Wim Brugman, Anna K. Casasent, Karen Clements, Helen R. Davies, Liping Fu, Anita Grigoriadis, Timothy M. Hardman, Lorraine M. King, Marielle Krete, Petra Kristel
Ductal carcinoma in situ (DCIS) is the most common form of preinvasive breast cancer and, despite treatment, a small fraction (5–10%) of DCIS patients develop subsequent invasive disease. A fundamental biologic question is whether the invasive disease arises from tumor cells in the initial DCIS or represents new unrelated disease. To address this question, we performed genomic analyses on the initial
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Mendelian imputation of parental genotypes improves estimates of direct genetic effects Nat. Genet. (IF 38.33) Pub Date : 2022-06-09 Alexander I. Young, Seyed Moeen Nehzati, Stefania Benonisdottir, Aysu Okbay, Hariharan Jayashankar, Chanwook Lee, David Cesarini, Daniel J. Benjamin, Patrick Turley, Augustine Kong
Effects estimated by genome-wide association studies (GWASs) include effects of alleles in an individual on that individual (direct genetic effects), indirect genetic effects (for example, effects of alleles in parents on offspring through the environment) and bias from confounding. Within-family genetic variation is random, enabling unbiased estimation of direct genetic effects when parents are genotyped
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SMARCE1 deficiency generates a targetable mSWI/SNF dependency in clear cell meningioma Nat. Genet. (IF 38.33) Pub Date : 2022-06-09 Roodolph St. Pierre, Clayton K. Collings, Daniel D. Samé Guerra, Christian J. Widmer, Olubusayo Bolonduro, Nazar Mashtalir, Akshay Sankar, Yu Liang, Wenya Linda Bi, Erica H. Gerkes, Vijaya Ramesh, Jun Qi, Miriam J. Smith, David M. Meredith, Cigall Kadoch
Mammalian SWI/SNF (mSWI/SNF) ATP-dependent chromatin remodeling complexes establish and maintain chromatin accessibility and gene expression, and are frequently perturbed in cancer. Clear cell meningioma (CCM), an aggressive tumor of the central nervous system, is uniformly driven by loss of SMARCE1, an integral subunit of the mSWI/SNF core. Here, we identify a structural role for SMARCE1 in selectively
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Histone gene editing probes functions of H3K27 modifications in mammals Nat. Genet. (IF 38.33) Pub Date : 2022-06-06 Alessandro Scacchetti, Roberto Bonasio
A new study employs CRISPR–Cas9-based base editing for simultaneous mutagenesis of all copies of histone H3 genes in mammals, highlighting the functional importance of H3K27me3 for Polycomb-mediated gene silencing and the dispensability of H3K27ac in transcriptional activation.
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One step closer to linking GWAS SNPs with the right genes Nat. Genet. (IF 38.33) Pub Date : 2022-06-06 Guillaume Lettre
A new study highlights a strategy to link SNPs implicated in human complex traits and diseases with probable causal genes. This method prioritizes genes for functional characterization and helps address questions about the architecture of human phenotypes.
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Increasing diversity in genomics requires investment in equitable partnerships and capacity building Nat. Genet. (IF 38.33) Pub Date : 2022-06-06 Alicia R. Martin, Rocky E. Stroud, Tamrat Abebe, Dickens Akena, Melkam Alemayehu, Lukoye Atwoli, Sinéad B. Chapman, Katelyn Flowers, Bizu Gelaye, Stella Gichuru, Symon M. Kariuki, Sam Kinyanjui, Kristina J. Korte, Nastassja Koen, Karestan C. Koenen, Charles R. J. C. Newton, Ana Maria Olivares, Sam Pollock, Kristianna Post, Ilina Singh, Dan J. Stein, Solomon Teferra, Zukiswa Zingela, Lori B. Chibnik
Calls for diversity in genomics have motivated new global research collaborations across institutions with highly imbalanced resources. We describe practical lessons we have learned so far from designing multidisciplinary international research and capacity-building programs that prioritize equity in two intertwined programs — the NeuroGAP-Psychosis research study and GINGER training program — spanning
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Histone editing elucidates the functional roles of H3K27 methylation and acetylation in mammals Nat. Genet. (IF 38.33) Pub Date : 2022-06-06 Aditya Sankar, Faizaan Mohammad, Arun Kumar Sundaramurthy, Hua Wang, Mads Lerdrup, Tulin Tatar, Kristian Helin
Posttranslational modifications of histones (PTMs) are associated with specific chromatin and gene expression states1,2. Although studies in Drosophila melanogaster have revealed phenotypic associations between chromatin-modifying enzymes and their histone substrates, comparable studies in mammalian models do not exist3,4,5. Here, we use CRISPR base editing in mouse embryonic stem cells (mESCs) to
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Combining SNP-to-gene linking strategies to identify disease genes and assess disease omnigenicity Nat. Genet. (IF 38.33) Pub Date : 2022-06-06 Steven Gazal, Omer Weissbrod, Farhad Hormozdiari, Kushal K. Dey, Joseph Nasser, Karthik A. Jagadeesh, Daniel J. Weiner, Huwenbo Shi, Charles P. Fulco, Luke J. O’Connor, Bogdan Pasaniuc, Jesse M. Engreitz, Alkes L. Price
Disease-associated single-nucleotide polymorphisms (SNPs) generally do not implicate target genes, as most disease SNPs are regulatory. Many SNP-to-gene (S2G) linking strategies have been developed to link regulatory SNPs to the genes that they regulate in cis. Here, we developed a heritability-based framework for evaluating and combining different S2G strategies to optimize their informativeness for
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Genomic insights into the recent chromosome reduction of autopolyploid sugarcane Saccharum spontaneum Nat. Genet. (IF 38.33) Pub Date : 2022-06-02 Qing Zhang, Yiying Qi, Haoran Pan, Haibao Tang, Gang Wang, Xiuting Hua, Yongjun Wang, Lianyu Lin, Zhen Li, Yihan Li, Fan Yu, Zehuai Yu, Yongji Huang, Tianyou Wang, Panpan Ma, Meijie Dou, Zongyi Sun, Yibin Wang, Hengbo Wang, Xingtan Zhang, Wei Yao, Yuntong Wang, Xinlong Liu, Maojun Wang, Jianping Wang, Zuhu Deng, Jingsheng Xu, Qinghui Yang, ZhongJian Liu, Baoshan Chen, Muqing Zhang, Ray Ming, Jisen
Saccharum spontaneum is a founding Saccharum species and exhibits wide variation in ploidy levels. We have assembled a high-quality autopolyploid genome of S. spontaneum Np-X (2n = 4x = 40) into 40 pseudochromosomes across 10 homologous groups, that better elucidates recent chromosome reduction and polyploidization that occurred circa 1.5 million years ago (Mya). One paleo-duplicated chromosomal pair
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Genetic correlates of phenotypic heterogeneity in autism Nat. Genet. (IF 38.33) Pub Date : 2022-06-02 Varun Warrier, Xinhe Zhang, Patrick Reed, Alexandra Havdahl, Tyler M. Moore, Freddy Cliquet, Claire S. Leblond, Thomas Rolland, Anders Rosengren, David H. Rowitch, Matthew E. Hurles, Daniel H. Geschwind, Anders D. Børglum, Elise B. Robinson, Jakob Grove, Hilary C. Martin, Thomas Bourgeron, Simon Baron-Cohen
The substantial phenotypic heterogeneity in autism limits our understanding of its genetic etiology. To address this gap, here we investigated genetic differences between autistic individuals (nmax = 12,893) based on core and associated features of autism, co-occurring developmental disabilities and sex. We conducted a comprehensive factor analysis of core autism features in autistic individuals and
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A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation Nat. Genet. (IF 38.33) Pub Date : 2022-06-02 Marijana Vujkovic, Shweta Ramdas, Kim M. Lorenz, Xiuqing Guo, Rebecca Darlay, Heather J. Cordell, Jing He, Yevgeniy Gindin, Chuhan Chung, Robert P. Myers, Carolin V. Schneider, Joseph Park, Kyung Min Lee, Marina Serper, Rotonya M. Carr, David E. Kaplan, Mary E. Haas, Matthew T. MacLean, Walter R. Witschey, Xiang Zhu, Catherine Tcheandjieu, Rachel L. Kember, Henry R. Kranzler, Anurag Verma, Ayush Giri
Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease. Using a proxy NAFLD definition of chronic elevation of alanine aminotransferase (cALT) levels without other liver diseases, we performed a multiancestry genome-wide association study (GWAS) in the Million Veteran Program (MVP) including 90,408 cALT cases and 128,187 controls. Seventy-seven loci exceeded genome-wide
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A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex Nat. Genet. (IF 38.33) Pub Date : 2022-06-02 Danny Antaki, James Guevara, Adam X. Maihofer, Marieke Klein, Madhusudan Gujral, Jakob Grove, Caitlin E. Carey, Oanh Hong, Maria J. Arranz, Amaia Hervas, Christina Corsello, Keith K. Vaux, Alysson R. Muotri, Lilia M. Iakoucheva, Eric Courchesne, Karen Pierce, Joseph G. Gleeson, Elise B. Robinson, Caroline M. Nievergelt, Jonathan Sebat
The genetic etiology of autism spectrum disorder (ASD) is multifactorial, but how combinations of genetic factors determine risk is unclear. In a large family sample, we show that genetic loads of rare and polygenic risk are inversely correlated in cases and greater in females than in males, consistent with a liability threshold that differs by sex. De novo mutations (DNMs), rare inherited variants
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Publisher Correction: Dual function NFI factors control fetal hemoglobin silencing in adult erythroid cells. Nat. Genet. (IF 38.33) Pub Date : 2022-06-01 Kunhua Qin,Peng Huang,Ruopeng Feng,Cheryl A Keller,Scott A Peslak,Eugene Khandros,Megan S Saari,Xianjiang Lan,Thiyagaraj Mayuranathan,Phillip A Doerfler,Osheiza Abdulmalik,Belinda Giardine,Stella T Chou,Junwei Shi,Ross C Hardison,Mitchell J Weiss,Gerd A Blobel
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A molecular map of T cell activation gives insights into immune disease Nat. Genet. (IF 38.33) Pub Date : 2022-05-30
A study using single-cell transcriptomics and mapping of expression quantitative trait loci (eQTLs) in a dynamic model of CD4+ T cell activation reveals novel, context-specific eQTLs linked to genes associated with immune diseases such as inflammatory bowel disease.
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High heritability of ascending aortic diameter and trans-ancestry prediction of thoracic aortic disease Nat. Genet. (IF 38.33) Pub Date : 2022-05-30 Catherine Tcheandjieu, Ke Xiao, Helio Tejeda, Julie A. Lynch, Sanni Ruotsalainen, Tiffany Bellomo, Madhuri Palnati, Renae Judy, Derek Klarin, Rachel L. Kember, Shefali Verma, Aarno Palotie, Mark Daly, Marylyn Ritchie, Daniel J. Rader, Manuel A. Rivas, Themistocles Assimes, Philip Tsao, Scott Damrauer, James R. Priest
Enlargement of the aorta is an important risk factor for aortic aneurysm and dissection, a leading cause of morbidity in the developed world. Here we performed automated extraction of ascending aortic diameter from cardiac magnetic resonance images of 36,021 individuals from the UK Biobank, followed by genome-wide association. We identified lead variants across 41 loci, including genes related to cardiovascular
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Chromatin profiling of coronary artery illuminates genetic risk for heart disease Nat. Genet. (IF 38.33) Pub Date : 2022-05-26
A large-scale single-nucleus chromatin accessibility profiling study in coronary artery samples from patients with coronary artery disease generated a landscape of the regulatory activity during the disease. These data highlight cell type-specific gene programs that can improve the interpretation of human genome-wide association studies findings for cardiovascular diseases.
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Immune disease risk variants regulate gene expression dynamics during CD4+ T cell activation Nat. Genet. (IF 38.33) Pub Date : 2022-05-26 Blagoje Soskic, Eddie Cano-Gamez, Deborah J. Smyth, Kirsty Ambridge, Ziying Ke, Julie C. Matte, Lara Bossini-Castillo, Joanna Kaplanis, Lucia Ramirez-Navarro, Anna Lorenc, Nikolina Nakic, Jorge Esparza-Gordillo, Wendy Rowan, David Wille, David F. Tough, Paola G. Bronson, Gosia Trynka
During activation, T cells undergo extensive gene expression changes that shape the properties of cells to exert their effector function. Understanding the regulation of this process could help explain how genetic variants predispose to immune diseases. Here, we mapped genetic effects on gene expression (expression quantitative trait loci (eQTLs)) using single-cell transcriptomics. We profiled 655
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Dual function NFI factors control fetal hemoglobin silencing in adult erythroid cells Nat. Genet. (IF 38.33) Pub Date : 2022-05-26 Kunhua Qin, Peng Huang, Ruopeng Feng, Cheryl A. Keller, Scott A. Peslak, Eugene Khandros, Megan S. Saari, Xianjiang Lan, Thiyagaraj Mayuranathan, Phillip A. Doerfler, Osheiza Abdulmalik, Belinda Giardine, Stella T. Chou, Junwei Shi, Ross C. Hardison, Mitchell J. Weiss, Gerd A. Blobel
The mechanisms by which the fetal-type β-globin-like genes HBG1 and HBG2 are silenced in adult erythroid precursor cells remain a fundamental question in human biology and have therapeutic relevance to sickle cell disease and β-thalassemia. Here, we identify via a CRISPR–Cas9 genetic screen two members of the NFI transcription factor family—NFIA and NFIX—as HBG1/2 repressors. NFIA and NFIX are expressed
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Single-nucleus chromatin accessibility profiling highlights regulatory mechanisms of coronary artery disease risk Nat. Genet. (IF 38.33) Pub Date : 2022-05-19 Adam W. Turner, Shengen Shawn Hu, Jose Verdezoto Mosquera, Wei Feng Ma, Chani J. Hodonsky, Doris Wong, Gaëlle Auguste, Yipei Song, Katia Sol-Church, Emily Farber, Soumya Kundu, Anshul Kundaje, Nicolas G. Lopez, Lijiang Ma, Saikat Kumar B. Ghosh, Suna Onengut-Gumuscu, Euan A. Ashley, Thomas Quertermous, Aloke V. Finn, Nicholas J. Leeper, Jason C. Kovacic, Johan L. M. Björkgren, Chongzhi Zang, Clint
Coronary artery disease (CAD) is a complex inflammatory disease involving genetic influences across cell types. Genome-wide association studies have identified over 200 loci associated with CAD, where the majority of risk variants reside in noncoding DNA sequences impacting cis-regulatory elements. Here, we applied single-nucleus assay for transposase-accessible chromatin with sequencing to profile
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Sequence-based modeling of three-dimensional genome architecture from kilobase to chromosome scale Nat. Genet. (IF 38.33) Pub Date : 2022-05-12 Jian Zhou
To learn how genomic sequence influences multiscale three-dimensional (3D) genome architecture, this manuscript presents a sequence-based deep-learning approach, Orca, that predicts directly from sequence the 3D genome architecture from kilobase to whole-chromosome scale. Orca captures the sequence dependencies of structures including chromatin compartments and topologically associating domains, as
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Genomic analyses reveal domestication history and transgenic insertions in papaya Nat. Genet. (IF 38.33) Pub Date : 2022-05-12
The genome of the SunUp transgenic papaya cultivar includes a complex 1.64-Mb insertion that contains 3 transgenic fragments integrated with 61 nuclear genome fragments from the progenitor Sunset cultivar and 13 organelle genome fragments. Population genomic analyses yielded 147 selective sweeps during papaya domestication, which include essential genes that are involved in fruit flesh color formation
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Genome-wide analysis of cis-regulatory changes underlying metabolic adaptation of cavefish Nat. Genet. (IF 38.33) Pub Date : 2022-05-12 Jaya Krishnan, Chris W. Seidel, Ning Zhang, Narendra Pratap Singh, Jake VanCampen, Robert Peuß, Shaolei Xiong, Alexander Kenzior, Hua Li, Joan W. Conaway, Nicolas Rohner
Cis-regulatory changes are key drivers of adaptative evolution. However, their contribution to the metabolic adaptation of organisms is not well understood. Here, we used a unique vertebrate model, Astyanax mexicanus—different morphotypes of which survive in nutrient-rich surface and nutrient-deprived cave waters—to uncover gene regulatory networks underlying metabolic adaptation. We performed genome-wide
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SunUp and Sunset genomes revealed impact of particle bombardment mediated transformation and domestication history in papaya Nat. Genet. (IF 38.33) Pub Date : 2022-05-12 Jingjing Yue, Robert VanBuren, Juan Liu, Jingping Fang, Xingtan Zhang, Zhenyang Liao, Ching Man Wai, Xiuming Xu, Shuai Chen, Shengchen Zhang, Xiaokai Ma, Yaying Ma, Hongying Yu, Jing Lin, Ping Zhou, Yongji Huang, Ban Deng, Fang Deng, Xiaobing Zhao, Hansong Yan, Mahpara Fatima, Dessireé Zerpa-Catanho, Xiaodan Zhang, Zhicong Lin, Mei Yang, Nancy J. Chen, Eric Mora-Newcomer, Patricia Quesada-Rojas, Antonio
Transgenic papaya is widely publicized for controlling papaya ringspot virus. However, the impact of particle bombardment on the genome remains unknown. The transgenic SunUp and its progenitor Sunset genomes were assembled into 351.5 and 350.3 Mb in nine chromosomes, respectively. We identified a 1.64 Mb insertion containing three transgenic insertions in SunUp chromosome 5, consisting of 52 nuclear-plastid
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DeepSTARR predicts enhancer activity from DNA sequence and enables the de novo design of synthetic enhancers Nat. Genet. (IF 38.33) Pub Date : 2022-05-12 Bernardo P. de Almeida, Franziska Reiter, Michaela Pagani, Alexander Stark
Enhancer sequences control gene expression and comprise binding sites (motifs) for different transcription factors (TFs). Despite extensive genetic and computational studies, the relationship between DNA sequence and regulatory activity is poorly understood, and de novo enhancer design has been challenging. Here, we built a deep-learning model, DeepSTARR, to quantitatively predict the activities of
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Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation Nat. Genet. (IF 38.33) Pub Date : 2022-05-12 Anubha Mahajan, Cassandra N. Spracklen, Weihua Zhang, Maggie C. Y. Ng, Lauren E. Petty, Hidetoshi Kitajima, Grace Z. Yu, Sina Rüeger, Leo Speidel, Young Jin Kim, Momoko Horikoshi, Josep M. Mercader, Daniel Taliun, Sanghoon Moon, Soo-Heon Kwak, Neil R. Robertson, Nigel W. Rayner, Marie Loh, Bong-Jo Kim, Joshua Chiou, Irene Miguel-Escalada, Pietro della Briotta Parolo, Kuang Lin, Fiona Bragg, Michael
We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10−9)
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DNMT3A binds ubiquitinated histones to regulate bivalent genes Nat. Genet. (IF 38.33) Pub Date : 2022-05-09 Aled J. Parry, Wolf Reik
A new study demonstrates that the disordered N-terminal domain of DNMT3A1 binds PRC1-catalyzed H2AK119ub, targeting DNA methylation to bivalent promoters in mouse brain cortical cells. Methylation around bivalent genes is critical for mouse postnatal development, and could be equally important in other cell types and in disease.
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Promoting the genomic revolution in Africa through the Nigerian 100K Genome Project Nat. Genet. (IF 38.33) Pub Date : 2022-05-09 Segun Fatumo, Aminu Yakubu, Olubukunola Oyedele, Jumi Popoola, Delali Attiogbe Attipoe, Golibe Eze-Echesi, Fatima Z Modibbo, Nabila Ado-Wanka, Omolola Salako, Oyekanmi Nashiru, Babatunde L Salako, Colm O’Dushlaine, Abasi Ene-Obong
To leverage the genetic diversity in Nigeria, we established the Non-Communicable Diseases Genetic Heritage Study (NCD-GHS) consortium to help produce a comprehensive catalog of human genetic variation in Nigeria and assess the burden and etiological characteristics of non-communicable diseases in 100,000 adults in Nigeria.
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The disordered N-terminal domain of DNMT3A recognizes H2AK119ub and is required for postnatal development Nat. Genet. (IF 38.33) Pub Date : 2022-05-09 Tianpeng Gu, Dapeng Hao, Junsung Woo, Teng-Wei Huang, Lei Guo, Xueqiu Lin, Anna G. Guzman, Ayala Tovy, Carina Rosas, Mira Jeong, Yubin Zhou, Benjamin Deneen, Yun Huang, Wei Li, Margaret A. Goodell
DNA methyltransferase 3a (DNMT3A) plays a crucial role during mammalian development. Two isoforms of DNMT3A are differentially expressed from stem cells to somatic tissues, but their individual functions remain largely uncharacterized. Here we report that the long isoform DNMT3A1, but not the short DNMT3A2, is essential for mouse postnatal development. DNMT3A1 binds to and regulates bivalent neurodevelopmental
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Meningioma DNA methylation groups identify biological drivers and therapeutic vulnerabilities Nat. Genet. (IF 38.33) Pub Date : 2022-05-09 Abrar Choudhury, Stephen T. Magill, Charlotte D. Eaton, Briana C. Prager, William C. Chen, Martha A. Cady, Kyounghee Seo, Calixto-Hope G. Lucas, Tim J. Casey-Clyde, Harish N. Vasudevan, S. John Liu, Javier E. Villanueva-Meyer, Tai-Chung Lam, Jenny Kan-Suen Pu, Lai-Fung Li, Gilberto Ka-Kit Leung, Danielle L. Swaney, Michael Y. Zhang, Jason W. Chan, Zhixin Qiu, Michael V. Martin, Matthew S. Susko, Steve
Meningiomas are the most common primary intracranial tumors. There are no effective medical therapies for meningioma patients, and new treatments have been encumbered by limited understanding of meningioma biology. Here, we use DNA methylation profiling on 565 meningiomas integrated with genetic, transcriptomic, biochemical, proteomic and single-cell approaches to show meningiomas are composed of three
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Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects Nat. Genet. (IF 38.33) Pub Date : 2022-05-09 Laurence J. Howe, Michel G. Nivard, Tim T. Morris, Ailin F. Hansen, Humaira Rasheed, Yoonsu Cho, Geetha Chittoor, Rafael Ahlskog, Penelope A. Lind, Teemu Palviainen, Matthijs D. van der Zee, Rosa Cheesman, Massimo Mangino, Yunzhang Wang, Shuai Li, Lucija Klaric, Scott M. Ratliff, Lawrence F. Bielak, Marianne Nygaard, Alexandros Giannelis, Emily A. Willoughby, Chandra A. Reynolds, Jared V. Balbona,
Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086
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Polygenic risk scores for CARDINAL study Nat. Genet. (IF 38.33) Pub Date : 2022-05-05 Clement A. Adebamowo, Adebowale Adeyemo, Adeyinka Ashaye, Onoja M. Akpa, Tinashe Chikowore, Ananyo Choudhury, Yasmina J. Fakim, Segun Fatumo, Neil Hanchard, Michael Hauser, Braxton Mitchell, Nicola Mulder, Solomon F. Ofori-Acquah, Mayowa Owolabi, Michèle Ramsay, Bamidele Tayo, Archana Bhavani VasanthKumar, Yuji Zhang, Sally N. Adebamowo
The Cardiometabolic Disorders in African-Ancestry Populations (CARDINAL) study site is a well-powered, first-of-its-kind resource for developing, refining and validating methods for research into polygenic risk scores that accounts for local ancestry, to improve risk prediction in diverse populations.
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Systematic characterization of gene function in the photosynthetic alga Chlamydomonas reinhardtii Nat. Genet. (IF 38.33) Pub Date : 2022-05-05 Friedrich Fauser, Josep Vilarrasa-Blasi, Masayuki Onishi, Silvia Ramundo, Weronika Patena, Matthew Millican, Jacqueline Osaki, Charlotte Philp, Matthew Nemeth, Patrice A. Salomé, Xiaobo Li, Setsuko Wakao, Rick G. Kim, Yuval Kaye, Arthur R. Grossman, Krishna K. Niyogi, Sabeeha S. Merchant, Sean R. Cutler, Peter Walter, José R. Dinneny, Martin C. Jonikas, Robert E. Jinkerson
Most genes in photosynthetic organisms remain functionally uncharacterized. Here, using a barcoded mutant library of the model eukaryotic alga Chlamydomonas reinhardtii, we determined the phenotypes of more than 58,000 mutants under more than 121 different environmental growth conditions and chemical treatments. A total of 59% of genes are represented by at least one mutant that showed a phenotype
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Author Correction: Indirect paths from genetics to education. Nat. Genet. (IF 38.33) Pub Date : 2022-06-01 Andrew J Schork,Roseann E Peterson,Andrew Dahl,Na Cai,Kenneth S Kendler
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Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells Nat. Genet. (IF 38.33) Pub Date : 2022-05-05 Kousuke Mouri, Michael H. Guo, Carl G. de Boer, Michelle M. Lissner, Ingrid A. Harten, Gregory A. Newby, Hannah A. DeBerg, Winona F. Platt, Matteo Gentili, David R. Liu, Daniel J. Campbell, Nir Hacohen, Ryan Tewhey, John P. Ray
Genome-wide association studies (GWASs) have uncovered hundreds of autoimmune disease-associated loci; however, the causal genetic variants within each locus are mostly unknown. Here, we perform high-throughput allele-specific reporter assays to prioritize disease-associated variants for five autoimmune diseases. By examining variants that both promote allele-specific reporter expression and are located
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CCL22 mutations drive natural killer cell lymphoproliferative disease by deregulating microenvironmental crosstalk Nat. Genet. (IF 38.33) Pub Date : 2022-05-05 Constance Baer, Shunsuke Kimura, Mitra S. Rana, Andrew B. Kleist, Tim Flerlage, David J. Feith, Peter Chockley, Wencke Walter, Manja Meggendorfer, Thomas L. Olson, HeeJin Cheon, Kristine C. Olson, Aakrosh Ratan, Martha-Lena Mueller, James M. Foran, Laura J. Janke, Chunxu Qu, Shaina N. Porter, Shondra M. Pruett-Miller, Ravi C. Kalathur, Claudia Haferlach, Wolfgang Kern, Elisabeth Paietta, Paul G. Thomas
Chronic lymphoproliferative disorder of natural killer cells (CLPD-NK) is characterized by clonal expansion of natural killer (NK) cells where the underlying genetic mechanisms are incompletely understood. In the present study, we report somatic mutations in the chemokine gene CCL22 as the hallmark of a distinct subset of CLPD-NK. CCL22 mutations were enriched at highly conserved residues, mutually
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Improving polygenic prediction in ancestrally diverse populations Nat. Genet. (IF 38.33) Pub Date : 2022-05-05 Yunfeng Ruan, Yen-Feng Lin, Yen-Chen Anne Feng, Chia-Yen Chen, Max Lam, Zhenglin Guo, Lin He, Akira Sawa, Alicia R. Martin, Shengying Qin, Hailiang Huang, Tian Ge
Polygenic risk scores (PRS) have attenuated cross-population predictive performance. As existing genome-wide association studies (GWAS) have been conducted predominantly in individuals of European descent, the limited transferability of PRS reduces their clinical value in non-European populations, and may exacerbate healthcare disparities. Recent efforts to level ancestry imbalance in genomic research
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Genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis Nat. Genet. (IF 38.33) Pub Date : 2022-05-05 Andrew D. Grotzinger, Travis T. Mallard, Wonuola A. Akingbuwa, Hill F. Ip, Mark J. Adams, Cathryn M. Lewis, Andrew M. McIntosh, Jakob Grove, Søren Dalsgaard, Klaus-Peter Lesch, Nora Strom, Sandra M. Meier, Manuel Mattheisen, Anders D. Børglum, Ole Mors, Gerome Breen, Phil H. Lee, Kenneth S. Kendler, Jordan W. Smoller, Elliot M. Tucker-Drob, Michel G. Nivard
We interrogate the joint genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis. We identify four broad factors (neurodevelopmental, compulsive, psychotic and internalizing) that underlie genetic correlations among the disorders and test whether these factors adequately explain their genetic correlations with biobehavioral
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Plasma proteome analyses in individuals of European and African ancestry identify cis-pQTLs and models for proteome-wide association studies Nat. Genet. (IF 38.33) Pub Date : 2022-05-02 Jingning Zhang, Diptavo Dutta, Anna Köttgen, Adrienne Tin, Pascal Schlosser, Morgan E. Grams, Benjamin Harvey, Bing Yu, Eric Boerwinkle, Josef Coresh, Nilanjan Chatterjee
Improved understanding of genetic regulation of the proteome can facilitate identification of the causal mechanisms for complex traits. We analyzed data on 4,657 plasma proteins from 7,213 European American (EA) and 1,871 African American (AA) individuals from the Atherosclerosis Risk in Communities study, and further replicated findings on 467 AA individuals from the African American Study of Kidney
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Genomic selection and genetic architecture of agronomic traits during modern rapeseed breeding Nat. Genet. (IF 38.33) Pub Date : 2022-04-28 Jihong Hu, Biyun Chen, Jing Zhao, Fugui Zhang, Ting Xie, Kun Xu, Guizhen Gao, Guixin Yan, Hongge Li, Lixia Li, Gaoxiang Ji, Hong An, Hao Li, Qian Huang, Meili Zhang, Jinfeng Wu, Weilin Song, Xiaojun Zhang, Yujie Luo, J. Chris Pires, Jacqueline Batley, Shilin Tian, Xiaoming Wu
Rapeseed (Brassica napus L.) is an important oil-producing crop for the world. Its adaptation, yield and quality have been considerably improved in recent decades, but the genomic basis underlying successful breeding selection remains unclear. Hence, we conducted a comprehensive genomic assessment of rapeseed in the breeding process based on the whole-genome resequencing of 418 diverse rapeseed accessions
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HOXB13 suppresses de novo lipogenesis through HDAC3-mediated epigenetic reprogramming in prostate cancer Nat. Genet. (IF 38.33) Pub Date : 2022-04-25 Xiaodong Lu, Ka-wing Fong, Galina Gritsina, Fang Wang, Sylvan C. Baca, Lourdes T. Brea, Jacob E. Berchuck, Sandor Spisak, Jenny Ross, Colm Morrissey, Eva Corey, Navdeep S. Chandel, William J. Catalona, Ximing Yang, Matthew L. Freedman, Jonathan C. Zhao, Jindan Yu
HOXB13, a homeodomain transcription factor, critically regulates androgen receptor (AR) activities and androgen-dependent prostate cancer (PCa) growth. However, its functions in AR-independent contexts remain elusive. Here we report HOXB13 interaction with histone deacetylase HDAC3, which is disrupted by the HOXB13 G84E mutation that has been associated with early-onset PCa. Independently of AR, HOXB13
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Author Correction: Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility Nat. Genet. (IF 38.33) Pub Date : 2022-04-26 Julien Barc,Rafik Tadros,Charlotte Glinge,David Y. Chiang,Mariam Jouni,Floriane Simonet,Sean J. Jurgens,Manon Baudic,Michele Nicastro,Franck Potet,Joost A. Offerhaus,Roddy Walsh,Seung Hoan Choi,Arie O. Verkerk,Yuka Mizusawa,Soraya Anys,Damien Minois,Marine Arnaud,Josselin Duchateau,Yanushi D. Wijeyeratne,Alison Muir,Michael Papadakis,Silvia Castelletti,Margherita Torchio,Cristina Gil Ortuño,Javier
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Breast tumor microenvironment structures are associated with genomic features and clinical outcome Nat. Genet. (IF 38.33) Pub Date : 2022-04-18 Esther Danenberg, Helen Bardwell, Vito R. T. Zanotelli, Elena Provenzano, Suet-Feung Chin, Oscar M. Rueda, Andrew Green, Emad Rakha, Samuel Aparicio, Ian O. Ellis, Bernd Bodenmiller, Carlos Caldas, H. Raza Ali
The functions of the tumor microenvironment (TME) are orchestrated by precise spatial organization of specialized cells, yet little is known about the multicellular structures that form within the TME. Here we systematically mapped TME structures in situ using imaging mass cytometry and multitiered spatial analysis of 693 breast tumors linked to genomic and clinical data. We identified ten recurrent
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Understanding COVID-19 through genome-wide association studies Nat. Genet. (IF 38.33) Pub Date : 2022-04-11 Tom H. Karlsen
Defining the most appropriate phenotypes in genome-wide association studies of COVID-19 is challenging, and two new publications demonstrate how case-control definitions critically determine outcomes and downstream clinical utility of findings.
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BET proteins loop and compartmentalize the 3D genome Nat. Genet. (IF 38.33) Pub Date : 2022-04-11 Kyle P. Eagen
Chromosomes are shaped by an interplay between loop extrusion and compartmentalization. Two new studies demonstrate that bromodomain and extraterminal domain (BET) proteins contribute to both processes, with BRD4 facilitating one process and surprisingly inhibiting the other.
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BRD2 compartmentalizes the accessible genome Nat. Genet. (IF 38.33) Pub Date : 2022-04-11 Liangqi Xie, Peng Dong, Yifeng Qi, Tsung-Han S. Hsieh, Brian P. English, SeolKyoung Jung, Xingqi Chen, Margherita De Marzio, Rafael Casellas, Howard Y. Chang, Bin Zhang, Robert Tjian, Zhe Liu
Mammalian chromosomes are organized into megabase-sized compartments that are further subdivided into topologically associating domains (TADs). While the formation of TADs is dependent on cohesin, the mechanism behind compartmentalization remains enigmatic. Here, we show that the bromodomain and extraterminal (BET) family scaffold protein BRD2 promotes spatial mixing and compartmentalization of active
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Expanded COVID-19 phenotype definitions reveal distinct patterns of genetic association and protective effects Nat. Genet. (IF 38.33) Pub Date : 2022-04-11 Genevieve H. L. Roberts, Raghavendran Partha, Brooke Rhead, Spencer C. Knight, Danny S. Park, Marie V. Coignet, Miao Zhang, Nathan Berkowitz, David A. Turrisini, Michael Gaddis, Shannon R. McCurdy, Milos Pavlovic, Luong Ruiz, Chodon Sass, Asher K. Haug Baltzell, Harendra Guturu, Ahna R. Girshick, Catherine A. Ball, Eurie L. Hong, Kristin A. Rand
Multiple COVID-19 genome-wide association studies (GWASs) have identified reproducible genetic associations indicating that there is a genetic component to susceptibility and severity risk. To complement these studies, we collected deep coronavirus disease 2019 (COVID-19) phenotype data from a survey of 736,723 AncestryDNA research participants. With these data, we defined eight phenotypes related
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DNMT3A-dependent DNA methylation is required for spermatogonial stem cells to commit to spermatogenesis Nat. Genet. (IF 38.33) Pub Date : 2022-04-11 Mathilde Dura, Aurélie Teissandier, Mélanie Armand, Joan Barau, Clémentine Lapoujade, Pierre Fouchet, Lorraine Bonneville, Mathieu Schulz, Michael Weber, Laura G. Baudrin, Sonia Lameiras, Deborah Bourc’his
DNA methylation plays a critical role in spermatogenesis, as evidenced by the male sterility of DNA methyltransferase (DNMT) mutant mice. Here, we report a division of labor in the establishment of the methylation landscape of male germ cells and its functions in spermatogenesis. Although DNMT3C is essential for preventing retrotransposons from interfering with meiosis, DNMT3A broadly methylates the
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Pangenome-based genome inference allows efficient and accurate genotyping across a wide spectrum of variant classes Nat. Genet. (IF 38.33) Pub Date : 2022-04-11 Jana Ebler, Peter Ebert, Wayne E. Clarke, Tobias Rausch, Peter A. Audano, Torsten Houwaart, Yafei Mao, Jan O. Korbel, Evan E. Eichler, Michael C. Zody, Alexander T. Dilthey, Tobias Marschall
Typical genotyping workflows map reads to a reference genome before identifying genetic variants. Generating such alignments introduces reference biases and comes with substantial computational burden. Furthermore, short-read lengths limit the ability to characterize repetitive genomic regions, which are particularly challenging for fast k-mer-based genotypers. In the present study, we propose a new
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Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia Nat. Genet. (IF 38.33) Pub Date : 2022-04-11 Duncan S. Palmer, Daniel P. Howrigan, Sinéad B. Chapman, Rolf Adolfsson, Nick Bass, Douglas Blackwood, Marco P. M. Boks, Chia-Yen Chen, Claire Churchhouse, Aiden P. Corvin, Nicholas Craddock, David Curtis, Arianna Di Florio, Faith Dickerson, Nelson B. Freimer, Fernando S. Goes, Xiaoming Jia, Ian Jones, Lisa Jones, Lina Jonsson, Rene S. Kahn, Mikael Landén, Adam E. Locke, Andrew M. McIntosh, Andrew
We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enrichment of ultra-rare PTVs within genes implicated from
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Single-cell analysis of somatic mutations in human bronchial epithelial cells in relation to aging and smoking Nat. Genet. (IF 38.33) Pub Date : 2022-04-11 Zhenqiu Huang, Shixiang Sun, Moonsook Lee, Alexander Y. Maslov, Miao Shi, Spencer Waldman, Ava Marsh, Taha Siddiqui, Xiao Dong, Yakov Peter, Ali Sadoughi, Chirag Shah, Kenny Ye, Simon D. Spivack, Jan Vijg
Although lung cancer risk among smokers is dependent on smoking dose, it remains unknown if this increased risk reflects an increased rate of somatic mutation accumulation in normal lung cells. Here, we applied single-cell whole-genome sequencing of proximal bronchial basal cells from 33 participants aged between 11 and 86 years with smoking histories varying from never-smoking to 116 pack-years. We
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H3K27me3 conditions chemotolerance in triple-negative breast cancer Nat. Genet. (IF 38.33) Pub Date : 2022-04-11 Justine Marsolier, Pacôme Prompsy, Adeline Durand, Anne-Marie Lyne, Camille Landragin, Amandine Trouchet, Sabrina Tenreira Bento, Almut Eisele, Sophie Foulon, Léa Baudre, Kevin Grosselin, Mylène Bohec, Sylvain Baulande, Ahmed Dahmani, Laura Sourd, Eric Letouzé, Anne-Vincent Salomon, Elisabetta Marangoni, Leïla Perié, Céline Vallot
The persistence of cancer cells resistant to therapy remains a major clinical challenge. In triple-negative breast cancer, resistance to chemotherapy results in the highest recurrence risk among breast cancer subtypes. The drug-tolerant state seems largely defined by nongenetic features, but the underlying mechanisms are poorly understood. Here, by monitoring epigenomes, transcriptomes and lineages
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Common variants contribute to intrinsic human brain functional networks Nat. Genet. (IF 38.33) Pub Date : 2022-04-07 Bingxin Zhao, Tengfei Li, Stephen M. Smith, Di Xiong, Xifeng Wang, Yue Yang, Tianyou Luo, Ziliang Zhu, Yue Shan, Nana Matoba, Quan Sun, Yuchen Yang, Mads E. Hauberg, Jaroslav Bendl, John F. Fullard, Panagiotis Roussos, Weili Lin, Yun Li, Jason L. Stein, Hongtu Zhu
The human brain forms functional networks of correlated activity, which have been linked with both cognitive and clinical outcomes. However, the genetic variants affecting brain function are largely unknown. Here, we used resting-state functional magnetic resonance images from 47,276 individuals to discover and validate common genetic variants influencing intrinsic brain activity. We identified 45