An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer Nat. Genet. (IF 27.959) Pub Date : 2018-01-15 Ming Chen, Jiangwen Zhang, Katia Sampieri, John G. Clohessy, Lourdes Mendez, Enrique Gonzalez-Billalabeitia, Xue-Song Liu, Yu-Ru Lee, Jacqueline Fung, Jesse M. Katon, Archita Venugopal Menon, Kaitlyn A. Webster, Christopher Ng, Maria Dilia Palumbieri, Moussa S. Diolombi, Susanne B. Breitkopf, Julie Teruya-Feldstein, Sabina Signoretti, Roderick T. Bronson, John M. Asara, Mireia Castillo-Martin, Carlos Cordon-Cardo, Pier Paolo Pandolfi
Lipids, either endogenously synthesized or exogenous, have been linked to human cancer. Here we found that PML is frequently co-deleted with PTEN in metastatic human prostate cancer (CaP). We demonstrated that conditional inactivation of Pml in the mouse prostate morphs indolent Pten-null tumors into lethal metastatic disease. We identified MAPK reactivation, subsequent hyperactivation of an aberrant SREBP prometastatic lipogenic program, and a distinctive lipidomic profile as key characteristic features of metastatic Pml and Pten double-null CaP. Furthermore, targeting SREBP in vivo by fatostatin blocked both tumor growth and distant metastasis. Importantly, a high-fat diet (HFD) induced lipid accumulation in prostate tumors and was sufficient to drive metastasis in a nonmetastatic Pten-null mouse model of CaP, and an SREBP signature was highly enriched in metastatic human CaP. Thus, our findings uncover a prometastatic lipogenic program and lend direct genetic and experimental support to the notion that a Western HFD can promote metastasis.
Pan-genome analysis highlights the extent of genomic variation in cultivated and wild rice Nat. Genet. (IF 27.959) Pub Date : 2018-01-15 Qiang Zhao, Qi Feng, Hengyun Lu, Yan Li, Ahong Wang, Qilin Tian, Qilin Zhan, Yiqi Lu, Lei Zhang, Tao Huang, Yongchun Wang, Danlin Fan, Yan Zhao, Ziqun Wang, Congcong Zhou, Jiaying Chen, Chuanrang Zhu, Wenjun Li, Qijun Weng, Qun Xu, Zi-Xuan Wang, Xinghua Wei, Bin Han, Xuehui Huang
The rich genetic diversity in Oryza sativa and Oryza rufipogon serves as the main sources in rice breeding. Large-scale resequencing has been undertaken to discover allelic variants in rice, but much of the information for genetic variation is often lost by direct mapping of short sequence reads onto the O. sativa japonica Nipponbare reference genome. Here we constructed a pan-genome dataset of the O. sativa–O. rufipogon species complex through deep sequencing and de novo assembly of 66 divergent accessions. Intergenomic comparisons identified 23 million sequence variants in the rice genome. This catalog of sequence variations includes many known quantitative trait nucleotides and will be helpful in pinpointing new causal variants that underlie complex traits. In particular, we systemically investigated the whole set of coding genes using this pan-genome data, which revealed extensive presence and absence of variation among rice accessions. This pan-genome resource will further promote evolutionary and functional studies in rice.
Genetics of lipid metabolism in prostate cancer Nat. Genet. (IF 27.959) Pub Date : 2018-01-15 Ninu Poulose, Francesca Amoroso, Rebecca E. Steele, Reema Singh, Chee Wee Ong, Ian G. Mills
Genetics of lipid metabolism in prostate cancer Genetics of lipid metabolism in prostate cancer, Published online: 15 January 2018; doi:10.1038/s41588-017-0037-0 Dysregulated lipid metabolism is a prominent feature of prostate cancers. Two papers in this issue identify novel genomic drivers of lipid metabolism in prostate cancer and provide implications for the subtyping and treatment of the disease.
Transposon-derived small RNAs triggered by miR845 mediate genome dosage response in Arabidopsis Nat. Genet. (IF 27.959) Pub Date : 2018-01-15 Filipe Borges, Jean-Sébastien Parent, Frédéric van Ex, Philip Wolff, German Martínez, Claudia Köhler, Robert A. Martienssen
Chromosome dosage has substantial effects on reproductive isolation and speciation in both plants and animals, but the underlying mechanisms are largely obscure1. Transposable elements in animals can regulate hybridity through maternal small RNA2, whereas small RNAs in plants have been postulated to regulate dosage response via neighboring imprinted genes3,4. Here we show that a highly conserved microRNA in plants, miR845, targets the tRNAMet primer-binding site (PBS) of long terminal repeat (LTR) retrotransposons in Arabidopsis pollen, and triggers the accumulation of 21–22-nucleotide (nt) small RNAs in a dose-dependent fashion via RNA polymerase IV. We show that these epigenetically activated small interfering RNAs (easiRNAs) mediate hybridization barriers between diploid seed parents and tetraploid pollen parents (the ‘triploid block’), and that natural variation for miR845 may account for ‘endosperm balance’ allowing the formation of triploid seeds. Targeting of the PBS with small RNA is a common mechanism for transposon control in mammals and plants, and provides a uniquely sensitive means to monitor chromosome dosage and imprinting in the developing seed.
Transcription factors orchestrate dynamic interplay between genome topology and gene regulation during cell reprogramming Nat. Genet. (IF 27.959) Pub Date : 2018-01-15 Ralph Stadhouders, Enrique Vidal, François Serra, Bruno Di Stefano, François Le Dily, Javier Quilez, Antonio Gomez, Samuel Collombet, Clara Berenguer, Yasmina Cuartero, Jochen Hecht, Guillaume J. Filion, Miguel Beato, Marc A. Marti-Renom, Thomas Graf
Chromosomal architecture is known to influence gene expression, yet its role in controlling cell fate remains poorly understood. Reprogramming of somatic cells into pluripotent stem cells (PSCs) by the transcription factors (TFs) OCT4, SOX2, KLF4 and MYC offers an opportunity to address this question but is severely limited by the low proportion of responding cells. We have recently developed a highly efficient reprogramming protocol that synchronously converts somatic into pluripotent stem cells. Here, we used this system to integrate time-resolved changes in genome topology with gene expression, TF binding and chromatin-state dynamics. The results showed that TFs drive topological genome reorganization at multiple architectural levels, often before changes in gene expression. Removal of locus-specific topological barriers can explain why pluripotency genes are activated sequentially, instead of simultaneously, during reprogramming. Together, our results implicate genome topology as an instructive force for implementing transcriptional programs and cell fate in mammals.
Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer Nat. Genet. (IF 27.959) Pub Date : 2018-01-15 Jingjing Chen, Ilaria Guccini, Diletta Di Mitri, Daniela Brina, Ajinkya Revandkar, Manuela Sarti, Emiliano Pasquini, Abdullah Alajati, Sandra Pinton, Marco Losa, Gianluca Civenni, Carlo V. Catapano, Jacopo Sgrignani, Andrea Cavalli, Rocco D’Antuono, John M. Asara, Andrea Morandi, Paola Chiarugi, Sara Crotti, Marco Agostini, Monica Montopoli, Ionica Masgras, Andrea Rasola, Ramon Garcia-Escudero, Nicolas Delaleu, Andrea Rinaldi, Francesco Bertoni, Johann de Bono, Arkaitz Carracedo, Andrea Alimonti
The mechanisms by which mitochondrial metabolism supports cancer anabolism remain unclear. Here, we found that genetic and pharmacological inactivation of pyruvate dehydrogenase A1 (PDHA1), a subunit of the pyruvate dehydrogenase complex (PDC), inhibits prostate cancer development in mouse and human xenograft tumor models by affecting lipid biosynthesis. Mechanistically, we show that in prostate cancer, PDC localizes in both the mitochondria and the nucleus. Whereas nuclear PDC controls the expression of sterol regulatory element-binding transcription factor (SREBF)-target genes by mediating histone acetylation, mitochondrial PDC provides cytosolic citrate for lipid synthesis in a coordinated manner, thereby sustaining anabolism. Additionally, we found that PDHA1 and the PDC activator pyruvate dehydrogenase phosphatase 1 (PDP1) are frequently amplified and overexpressed at both the gene and protein levels in prostate tumors. Together, these findings demonstrate that both mitochondrial and nuclear PDC sustain prostate tumorigenesis by controlling lipid biosynthesis, thus suggesting this complex as a potential target for cancer therapy.
Paternal easiRNAs regulate parental genome dosage in Arabidopsis Nat. Genet. (IF 27.959) Pub Date : 2018-01-15 German Martinez, Philip Wolff, Zhenxing Wang, Jordi Moreno-Romero, Juan Santos-González, Lei Liu Conze, Christopher DeFraia, R. Keith Slotkin, Claudia Köhler
The regulation of parental genome dosage is of fundamental importance in animals and plants, as exemplified by X-chromosome inactivation and dosage compensation. The ‘triploid block’ is a classic example of dosage regulation in plants that establishes a reproductive barrier between species differing in chromosome number1,2. This barrier acts in the embryo-nourishing endosperm tissue and induces the abortion of hybrid seeds through a yet unknown mechanism3. Here we show that depletion of paternal epigenetically activated small interfering RNAs (easiRNAs) bypasses the triploid block in response to increased paternal ploidy in Arabidopsis thaliana. Paternal loss of the plant-specific RNA polymerase IV suppressed easiRNA formation and rescued triploid seeds by restoring small-RNA-directed DNA methylation at transposable elements (TEs), correlating with reduced expression of paternally expressed imprinted genes (PEGs). Our data suggest that easiRNAs form a quantitative signal for paternal chromosome number and that their balanced dosage is required for post-fertilization genome stability and seed viability.
Reconstructing an African haploid genome from the 18th century Nat. Genet. (IF 27.959) Pub Date : 2018-01-15 Anuradha Jagadeesan, Ellen D. Gunnarsdóttir, S. Sunna Ebenesersdóttir, Valdis B. Guðmundsdóttir, Elisabet Linda Thordardottir, Margrét S. Einarsdóttir, Hákon Jónsson, Jean-Michel Dugoujon, Cesar Fortes-Lima, Florence Migot-Nabias, Achille Massougbodji, Gil Bellis, Luisa Pereira, Gísli Másson, Augustine Kong, Kári Stefánsson, Agnar Helgason
A genome is a mosaic of chromosome fragments from ancestors who existed some arbitrary number of generations earlier. Here, we reconstruct the genome of Hans Jonatan (HJ), born in the Caribbean in 1784 to an enslaved African mother and European father. HJ migrated to Iceland in 1802, married and had two children. We genotyped 182 of his 788 descendants using single-nucleotide polymorphism (SNP) chips and whole-genome sequenced (WGS) 20 of them. Using these data, we reconstructed 38% of HJ’s maternal genome and inferred that his mother was from the region spanned by Benin, Nigeria and Cameroon.
Loss-of-function variants in ADCY3 increase risk of obesity and type 2 diabetes Nat. Genet. (IF 27.959) Pub Date : Niels Grarup, Ida Moltke, Mette K. Andersen, Maria Dalby, Kristoffer Vitting-Seerup, Timo Kern, Yuvaraj Mahendran, Emil Jørsboe, Christina V. L. Larsen, Inger K. Dahl-Petersen, Arthur Gilly, Daniel Suveges, George Dedoussis, Eleftheria Zeggini, Oluf Pedersen, Robin Andersson, Peter Bjerregaard, Marit E. Jørgensen, Anders Albrechtsen, Torben Hansen
We have identified a variant in ADCY3 (encoding adenylate cyclase 3) associated with markedly increased risk of obesity and type 2 diabetes in the Greenlandic population. The variant disrupts a splice acceptor site, and carriers have decreased ADCY3 RNA expression. Additionally, we observe an enrichment of rare ADCY3 loss-of-function variants among individuals with type 2 diabetes in trans-ancestry cohorts. These findings provide new information on disease etiology relevant for future treatment strategies.
Subcellular localization of MC4R with ADCY3 at neuronal primary cilia underlies a common pathway for genetic predisposition to obesity Nat. Genet. (IF 27.959) Pub Date : Jacqueline E. Siljee, Yi Wang, Adelaide A. Bernard, Baran A. Ersoy, Sumei Zhang, Aaron Marley, Mark Von Zastrow, Jeremy F. Reiter, Christian Vaisse
Subcellular localization of MC4R with ADCY3 at neuronal primary cilia underlies a common pathway for genetic predisposition to obesity Subcellular localization of MC4R with ADCY3 at neuronal primary cilia underlies a common pathway for genetic predisposition to obesity, Published online: 08 January 2018; doi:10.1038/s41588-017-0020-9 MC4R colocalizes with ADCY3 at primary cilia in hypothalamic neurons, and MC4R mutations associated with human obesity impair this localization. Inhibition of adenylyl cyclase signaling at primary cilia of neurons leads to increased body weight in mice.
Loss-of-function mutations in ADCY3 cause monogenic severe obesity Nat. Genet. (IF 27.959) Pub Date : Sadia Saeed, Amélie Bonnefond, Filippo Tamanini, Muhammad Usman Mirza, Jaida Manzoor, Qasim M. Janjua, Sadia M. Din, Julien Gaitan, Alexandra Milochau, Emmanuelle Durand, Emmanuel Vaillant, Attiya Haseeb, Franck De Graeve, Iandry Rabearivelo, Olivier Sand, Gurvan Queniat, Raphaël Boutry, Dina A. Schott, Hina Ayesha, Muhammad Ali, Waqas I. Khan, Taeed A. Butt, Tuula Rinne, Connie Stumpel, Amar Abderrahmani, Jochen Lang, Muhammad Arslan, Philippe Froguel
Loss-of-function mutations in ADCY3 cause monogenic severe obesity Loss-of-function mutations in ADCY3 cause monogenic severe obesity, Published online: 08 January 2018; doi:10.1038/s41588-017-0023-6 Genetic analysis of children with severe obesity identifies mutations in the ADCY3 gene (encoding adenylate cyclase 3). These variants are rare in public databases and affect the functional activity of the protein, indicating that ADCY3 is a potential pharmacological target for obesity treatment.
Multi-trait analysis of genome-wide association summary statistics using MTAG Nat. Genet. (IF 27.959) Pub Date : 2018-01-01 Patrick Turley, Raymond K. Walters, Omeed Maghzian, Aysu Okbay, James J. Lee, Mark Alan Fontana, Tuan Anh Nguyen-Viet, Robbee Wedow, Meghan Zacher, Nicholas A. Furlotte, Patrik Magnusson, Sven Oskarsson, Magnus Johannesson, Peter M. Visscher, David Laibson, David Cesarini, Benjamin M. Neale, Daniel J. Benjamin
We introduce multi-trait analysis of GWAS (MTAG), a method for joint analysis of summary statistics from genome-wide association studies (GWAS) of different traits, possibly from overlapping samples. We apply MTAG to summary statistics for depressive symptoms (Neff = 354,862), neuroticism (N = 168,105), and subjective well-being (N = 388,538). As compared to the 32, 9, and 13 genome-wide significant loci identified in the single-trait GWAS (most of which are themselves novel), MTAG increases the number of associated loci to 64, 37, and 49, respectively. Moreover, association statistics from MTAG yield more informative bioinformatics analyses and increase the variance explained by polygenic scores by approximately 25%, matching theoretical expectations.
Is H3K4me1 at enhancers correlative or causative? Nat. Genet. (IF 27.959) Pub Date : 2017-12-22 Alvaro Rada-Iglesias
Is H3K4me1 at enhancers correlative or causative? Is H3K4me1 at enhancers correlative or causative?, Published online: 22 December 2017; doi:10.1038/s41588-017-0018-3 H3K4me1 is enriched at active and primed enhancers. However, whether H3K4me1 controls or simply correlates with enhancer activity and function has remained unclear. Several recent reports, including two in Nature Genetics, provide major mechanistic and functional insights into the role of H3K4me1 at enhancers.
A landscape of commitment Nat. Genet. (IF 27.959) Pub Date : 2017-12-22
A landscape of commitment A landscape of commitment, Published online: 22 December 2017; doi:10.1038/s41588-017-0028-1 This issue features epigenetic analysis of cell commitment at many levels in mammalian genomes: during early embryonic development, in stem cells, and in cancer cells. The establishment, propagation and dynamic robustness of cell states is addressed by comprehensive interrogation of the coordination of DNA methylation with the marks and organization of chromatin and programs of gene expression. Understanding this landscape of commitment is essential to interpretation of the functional consequences of genome variation.
Bacterial genomics of plant adaptation Nat. Genet. (IF 27.959) Pub Date : 2017-12-22 Ryan A. Melnyk, Cara H. Haney
Bacterial genomics of plant adaptation Bacterial genomics of plant adaptation, Published online: 22 December 2017; doi:10.1038/s41588-017-0019-2 What allows bacteria, both pathogens and mutualists alike, to survive in close association with a eukaryotic host? A new study performed a large-scale comparative genomics analysis to identify novel genetic and genomic traits that are enriched in plant-associated bacterial taxa.
Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks Nat. Genet. (IF 27.959) Pub Date : 2017-12-22 Florence Demenais, Patricia Margaritte-Jeannin, Kathleen C. Barnes, William O. C. Cookson, Janine Altmüller, Wei Ang, R. Graham Barr, Terri H. Beaty, Allan B. Becker, John Beilby, Hans Bisgaard, Unnur Steina Bjornsdottir, Eugene Bleecker, Klaus Bønnelykke, Dorret I. Boomsma, Emmanuelle Bouzigon, Christopher E. Brightling, Myriam Brossard, Guy G. Brusselle, Esteban Burchard, Kristin M. Burkart, Andrew Bush, Moira Chan-Yeung, Kian Fan Chung, Alexessander Couto Alves, John A. Curtin, Adnan Custovic, Denise Daley, Johan C. de Jongste, Blanca E. Del-Rio-Navarro, Kathleen M. Donohue, Liesbeth Duijts, Celeste Eng, Johan G. Eriksson, Martin Farrall, Yuliya Fedorova, Bjarke Feenstra, Manuel A. Ferreira, Maxim B. Freidin, Zofia Gajdos, Jim Gauderman, Ulrike Gehring, Frank Geller, Jon Genuneit, Sina A. Gharib, Frank Gilliland, Raquel Granell, Penelope E. Graves, Daniel F. Gudbjartsson, Tari Haahtela, Susan R. Heckbert, Dick Heederik, Joachim Heinrich, Markku Heliövaara, John Henderson, ..
We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.
Mapping regulatory variants in hiPSC models Nat. Genet. (IF 27.959) Pub Date : 2017-12-22 Gabriel E. Hoffman, Kristen J. Brennand
Mapping regulatory variants in hiPSC models Mapping regulatory variants in hiPSC models, Published online: 22 December 2017; doi:10.1038/s41588-017-0017-4 A new study illustrates the power of the human induced pluripotent stem cell (hiPSC) platform by studying hiPSC-derived sensory neurons from 107 individuals. In addition to identifying thousands of quantitative trait loci influencing gene expression, chromatin accessibility and RNA splicing, the work highlights several underappreciated challenges in the hiPSC field.
Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity Nat. Genet. (IF 27.959) Pub Date : 2017-12-22 Valérie Turcot, Yingchang Lu, Heather M. Highland, Claudia Schurmann, Anne E. Justice, Rebecca S. Fine, Jonathan P. Bradfield, Tõnu Esko, Ayush Giri, Mariaelisa Graff, Xiuqing Guo, Audrey E. Hendricks, Tugce Karaderi, Adelheid Lempradl, Adam E. Locke, Anubha Mahajan, Eirini Marouli, Suthesh Sivapalaratnam, Kristin L. Young, Tamuno Alfred, Mary F. Feitosa, Nicholas G. D. Masca, Alisa K. Manning, Carolina Medina-Gomez, Poorva Mudgal, Maggie C. Y. Ng, Alex P. Reiner, Sailaja Vedantam, Sara M. Willems, Thomas W. Winkler, Gonçalo Abecasis, Katja K. Aben, Dewan S. Alam, Sameer E. Alharthi, Matthew Allison, Philippe Amouyel, Folkert W. Asselbergs, Paul L. Auer, Beverley Balkau, Lia E. Bang, Inês Barroso, Lisa Bastarache, Marianne Benn, Sven Bergmann, Lawrence F. Bielak, Matthias Blüher, Michael Boehnke, Heiner Boeing, Eric Boerwinkle, Carsten A. Böger, Jette Bork-Jensen, Michiel L. Bots, Erwin P. Bottinger, Donald W. Bowden, Ivan Brandslund, Gerome Breen, Murray H. Brilliant, Linda ..
Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
Identification of H3K4me1-associated proteins at mammalian enhancers Nat. Genet. (IF 27.959) Pub Date : 2017-12-18 Andrea Local, Hui Huang, Claudio P. Albuquerque, Namit Singh, Ah Young Lee, Wei Wang, Chaochen Wang, Judy E. Hsia, Andrew K. Shiau, Kai Ge, Kevin D. Corbett, Dong Wang, Huilin Zhou, Bing Ren
Enhancers act to regulate cell-type-specific gene expression by facilitating the transcription of target genes. In mammalian cells, active or primed enhancers are commonly marked by monomethylation of histone H3 at lysine 4 (H3K4me1) in a cell-type-specific manner. Whether and how this histone modification regulates enhancer-dependent transcription programs in mammals is unclear. In this study, we conducted SILAC mass spectrometry experiments with mononucleosomes and identified multiple H3K4me1-associated proteins, including many involved in chromatin remodeling. We demonstrate that H3K4me1 augments association of the chromatin-remodeling complex BAF to enhancers in vivo and that, in vitro, H3K4me1-marked nucleosomes are more efficiently remodeled by the BAF complex. Crystal structures of the BAF component BAF45C indicate that monomethylation, but not trimethylation, is accommodated by BAF45C’s H3K4-binding site. Our results suggest that H3K4me1 has an active role at enhancers by facilitating binding of the BAF complex and possibly other chromatin regulators.
Mutations in SELENBP1, encoding a novel human methanethiol oxidase, cause extraoral halitosis Nat. Genet. (IF 27.959) Pub Date : 2017-12-18 Arjan Pol, G. Herma Renkema, Albert Tangerman, Edwin G. Winkel, Udo F. Engelke, Arjan P. M. de Brouwer, Kent C. Lloyd, Renee S. Araiza, Lambert van den Heuvel, Heymut Omran, Heike Olbrich, Marijn Oude Elberink, Christian Gilissen, Richard J. Rodenburg, Jörn Oliver Sass, K. Otfried Schwab, Hendrik Schäfer, Hanka Venselaar, J. Silvia Sequeira, Huub J. M. Op den Camp, Ron A. Wevers
Selenium-binding protein 1 (SELENBP1) has been associated with several cancers, although its exact role is unknown. We show that SELENBP1 is a methanethiol oxidase (MTO), related to the MTO in methylotrophic bacteria, that converts methanethiol to H2O2, formaldehyde, and H2S, an activity not previously known to exist in humans. We identified mutations in SELENBP1 in five patients with cabbage-like breath odor. The malodor was attributable to high levels of methanethiol and dimethylsulfide, the main odorous compounds in their breath. Elevated urinary excretion of dimethylsulfoxide was associated with MTO deficiency. Patient fibroblasts had low SELENBP1 protein levels and were deficient in MTO enzymatic activity; these effects were reversed by lentivirus-mediated expression of wild-type SELENBP1. Selenbp1-knockout mice showed biochemical characteristics similar to those in humans. Our data reveal a potentially frequent inborn error of metabolism that results from MTO deficiency and leads to a malodor syndrome.
Author Correction: TET proteins safeguard bivalent promoters from de novo methylation in human embryonic stem cells Nat. Genet. (IF 27.959) Pub Date : 2017-12-18 Nipun Verma, Heng Pan, Louis C. Doré, Abhijit Shukla, Qing V. Li, Bobbie Pelham-Webb, Virginia Teijeiro, Federico González, Andrei Krivtsov, Chan-Jung Chang, Eirini P. Papapetrou, Chuan He, Olivier Elemento, Danwei Huangfu
Author Correction: TET proteins safeguard bivalent promoters from de novo methylation in human embryonic stem cells Author Correction: TET proteins safeguard bivalent promoters from de novo methylation in human embryonic stem cells, Published online: 18 December 2017; doi:10.1038/s41588-017-0025-4 Author Correction: TET proteins safeguard bivalent promoters from de novo methylation in human embryonic stem cells
Association analysis in over 329,000 individuals identifies 116 independent variants influencing neuroticism Nat. Genet. (IF 27.959) Pub Date : 2017-12-18 Michelle Luciano, Saskia P. Hagenaars, Gail Davies, W. David Hill, Toni-Kim Clarke, Masoud Shirali, Sarah E. Harris, Riccardo E. Marioni, David C. Liewald, Chloe Fawns-Ritchie, Mark J. Adams, David M. Howard, Cathryn M. Lewis, Catharine R. Gale, Andrew M. McIntosh, Ian J. Deary
Neuroticism is a relatively stable personality trait characterized by negative emotionality (for example, worry and guilt)1; heritability estimated from twin studies ranges from 30 to 50%2, and SNP-based heritability ranges from 6 to 15%3,4,5,6. Increased neuroticism is associated with poorer mental and physical health7,8, translating to high economic burden9. Genome-wide association studies (GWAS) of neuroticism have identified up to 11 associated genetic loci3,4. Here we report 116 significant independent loci from a GWAS of neuroticism in 329,821 UK Biobank participants; 15 of these loci replicated at P < 0.00045 in an unrelated cohort (N = 122,867). Genetic signals were enriched in neuronal genesis and differentiation pathways, and substantial genetic correlations were found between neuroticism and depressive symptoms (rg = 0.82, standard error (s.e.) = 0.03), major depressive disorder (MDD; rg = 0.69, s.e. = 0.07) and subjective well-being (rg = –0.68, s.e. = 0.03) alongside other mental health traits. These discoveries significantly advance understanding of neuroticism and its association with MDD.
A molecular roadmap for the emergence of early-embryonic-like cells in culture Nat. Genet. (IF 27.959) Pub Date : 2017-12-18 Diego Rodriguez-Terrones, Xavier Gaume, Takashi Ishiuchi, Amélie Weiss, Arnaud Kopp, Kai Kruse, Audrey Penning, Juan M. Vaquerizas, Laurent Brino, Maria-Elena Torres-Padilla
Unlike pluripotent cells, which generate only embryonic tissues, totipotent cells can generate a full organism, including extra-embryonic tissues. A rare population of cells resembling 2-cell-stage embryos arises in pluripotent embryonic stem (ES) cell cultures. These 2-cell-like cells display molecular features of totipotency and broader developmental plasticity. However, their specific nature and the process through which they arise remain outstanding questions. Here we identified intermediate cellular states and molecular determinants during the emergence of 2-cell-like cells. By deploying a quantitative single-cell expression approach, we identified an intermediate population characterized by expression of the transcription factor ZSCAN4 as a precursor of 2-cell-like cells. By using a small interfering RNA (siRNA) screen, we identified epigenetic regulators of 2-cell-like cell emergence, including the non-canonical PRC1 complex PRC1.6 and the EP400–TIP60 complex. Our data shed light on the mechanisms that underlie exit from the ES cell state toward the formation of early-embryonic-like cells in culture and identify key epigenetic pathways that promote this transition.
Hidden genetic variation shapes the structure of functional elements in Drosophila Nat. Genet. (IF 27.959) Pub Date : 2017-12-18 Mahul Chakraborty, Nicholas W. VanKuren, Roy Zhao, Xinwen Zhang, Shannon Kalsow, J. J. Emerson
Mutations that add, subtract, rearrange, or otherwise refashion genome structure often affect phenotypes, although the fragmented nature of most contemporary assemblies obscures them. To discover such mutations, we assembled the first new reference-quality genome of Drosophila melanogaster since its initial sequencing. By comparing this new genome to the existing D. melanogaster assembly, we created a structural variant map of unprecedented resolution and identified extensive genetic variation that has remained hidden until now. Many of these variants constitute candidates underlying phenotypic variation, including tandem duplications and a transposable element insertion that amplifies the expression of detoxification-related genes associated with nicotine resistance. The abundance of important genetic variation that still evades discovery highlights how crucial high-quality reference genomes are to deciphering phenotypes.
Single-cell DNA methylome sequencing of human preimplantation embryos Nat. Genet. (IF 27.959) Pub Date : 2017-12-18 Ping Zhu, Hongshan Guo, Yixin Ren, Yu Hou, Ji Dong, Rong Li, Ying Lian, Xiaoying Fan, Boqiang Hu, Yun Gao, Xiaoye Wang, Yuan Wei, Ping Liu, Jie Yan, Xiulian Ren, Peng Yuan, Yifeng Yuan, Zhiqiang Yan, Lu Wen, Liying Yan, Jie Qiao, Fuchou Tang
DNA methylation is a crucial layer of epigenetic regulation during mammalian embryonic development1,2,3. Although the DNA methylome of early human embryos has been analyzed4,5,6, some of the key features have not been addressed thus far. Here we performed single-cell DNA methylome sequencing for human preimplantation embryos and found that tens of thousands of genomic loci exhibited de novo DNA methylation. This finding indicates that genome-wide DNA methylation reprogramming during preimplantation development is a dynamic balance between strong global demethylation and drastic focused remethylation. Furthermore, demethylation of the paternal genome is much faster and thorough than that of the maternal genome. From the two-cell to the postimplantation stage, methylation of the paternal genome is consistently lower than that of the maternal genome. We also show that the genetic lineage of early blastomeres can be traced by DNA methylation analysis. Our work paves the way for deciphering the secrets of DNA methylation reprogramming in early human embryos.
Publisher Correction: TET proteins safeguard bivalent promoters from de novo methylation in human embryonic stem cells Nat. Genet. (IF 27.959) Pub Date : 2017-12-18 Nipun Verma, Heng Pan, Louis C. Doré, Abhijit Shukla, Qing V. Li, Bobbie Pelham-Webb, Virginia Teijeiro, Federico González, Andrei Krivtsov, Chan-Jung Chang, Eirini P. Papapetrou, Chuan He, Olivier Elemento, Danwei Huangfu
Publisher Correction: TET proteins safeguard bivalent promoters from de novo methylation in human embryonic stem cells Publisher Correction: TET proteins safeguard bivalent promoters from de novo methylation in human embryonic stem cells, Published online: 18 December 2017; doi:10.1038/s41588-017-0024-5 Publisher Correction: TET proteins safeguard bivalent promoters from de novo methylation in human embryonic stem cells
Annotation-free quantification of RNA splicing using LeafCutter Nat. Genet. (IF 27.959) Pub Date : 2017-12-11 Yang I. Li, David A. Knowles, Jack Humphrey, Alvaro N. Barbeira, Scott P. Dickinson, Hae Kyung Im, Jonathan K. Pritchard
The excision of introns from pre-mRNA is an essential step in mRNA processing. We developed LeafCutter to study sample and population variation in intron splicing. LeafCutter identifies variable splicing events from short-read RNA-seq data and finds events of high complexity. Our approach obviates the need for transcript annotations and circumvents the challenges in estimating relative isoform or exon usage in complex splicing events. LeafCutter can be used both to detect differential splicing between sample groups and to map splicing quantitative trait loci (sQTLs). Compared with contemporary methods, our approach identified 1.4–2.1 times more sQTLs, many of which helped us ascribe molecular effects to disease-associated variants. Transcriptome-wide associations between LeafCutter intron quantifications and 40 complex traits increased the number of associated disease genes at a 5% false discovery rate by an average of 2.1-fold compared with that detected through the use of gene expression levels alone. LeafCutter is fast, scalable, easy to use, and available online.
Molecular and functional variation in iPSC-derived sensory neurons Nat. Genet. (IF 27.959) Pub Date : 2017-12-11 Jeremy Schwartzentruber, Stefanie Foskolou, Helena Kilpinen, Julia Rodrigues, Kaur Alasoo, Andrew J. Knights, Minal Patel, Angela Goncalves, Rita Ferreira, Caroline Louise Benn, Anna Wilbrey, Magda Bictash, Emma Impey, Lishuang Cao, Sergio Lainez, Alexandre Julien Loucif, Paul John Whiting, Alex Gutteridge, Daniel J. Gaffney
Induced pluripotent stem cells (iPSCs), and cells derived from them, have become key tools for modeling biological processes, particularly in cell types that are difficult to obtain from living donors. Here we present a map of regulatory variants in iPSC-derived neurons, based on 123 differentiations of iPSCs to a sensory neuronal fate. Gene expression was more variable across cultures than in primary dorsal root ganglion, particularly for genes related to nervous system development. Using single-cell RNA-sequencing, we found that the number of neuronal versus contaminating cells was influenced by iPSC culture conditions before differentiation. Despite high differentiation-induced variability, our allele-specific method detected thousands of quantitative trait loci (QTLs) that influenced gene expression, chromatin accessibility, and RNA splicing. On the basis of these detected QTLs, we estimate that recall-by-genotype studies that use iPSC-derived cells will require cells from at least 20–80 individuals to detect the effects of regulatory variants with moderately large effect sizes.
TET proteins safeguard bivalent promoters from de novo methylation in human embryonic stem cells Nat. Genet. (IF 27.959) Pub Date : 2017-12-04 Nipun Verma, Heng Pan, Louis C. Doré, Abhijit Shukla, Qing V. Li, Bobbie Pelham-Webb, Virginia Teijeiro, Federico González, Andrei Krivtsov, Chan-Jung Chang, Eirini P. Papapetrou, Chuan He, Olivier Elemento, Danwei Huangfu
TET enzymes oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which can lead to DNA demethylation. However, direct connections between TET-mediated DNA demethylation and transcriptional output are difficult to establish owing to challenges in distinguishing global versus locus-specific effects. Here we show that TET1, TET2 and TET3 triple-knockout (TKO) human embryonic stem cells (hESCs) exhibit prominent bivalent promoter hypermethylation without an overall corresponding decrease in gene expression in the undifferentiated state. Focusing on the bivalent PAX6 locus, we find that increased DNMT3B binding is associated with promoter hypermethylation, which precipitates a neural differentiation defect and failure of PAX6 induction during differentiation. dCas9-mediated locus-specific demethylation and global inactivation of DNMT3B in TKO hESCs partially reverses the hypermethylation at the PAX6 promoter and improves differentiation to neuroectoderm. Taking these findings together with further genome-wide methylation and TET1 and DNMT3B ChIP–seq analyses, we conclude that TET proteins safeguard bivalent promoters from de novo methylation to ensure robust lineage-specific transcription upon differentiation.
Dynamic epigenomic landscapes during early lineage specification in mouse embryos Nat. Genet. (IF 27.959) Pub Date : 2017-12-04 Yu Zhang, Yunlong Xiang, Qiangzong Yin, Zhenhai Du, Xu Peng, Qiujun Wang, Miguel Fidalgo, Weikun Xia, Yuanyuan Li, Zhen-ao Zhao, Wenhao Zhang, Jing Ma, Feng Xu, Jianlong Wang, Lei Li, Wei Xie
In mammals, all somatic development originates from lineage segregation in early embryos. However, the dynamics of transcriptomes and epigenomes acting in concert with initial cell fate commitment remains poorly characterized. Here we report a comprehensive investigation of transcriptomes and base-resolution methylomes for early lineages in peri- and postimplantation mouse embryos. We found allele-specific and lineage-specific de novo methylation at CG and CH sites that led to differential methylation between embryonic and extraembryonic lineages at promoters of lineage regulators, gene bodies, and DNA-methylation valleys. By using Hi-C experiments to define chromatin architecture across the same developmental period, we demonstrated that both global demethylation and remethylation in early development correlate with chromatin compartments. Dynamic local methylation was evident during gastrulation, which enabled the identification of putative regulatory elements. Finally, we found that de novo methylation patterning does not strictly require implantation. These data reveal dynamic transcriptomes, DNA methylomes, and 3D chromatin landscapes during the earliest stages of mammalian lineage specification.
Evolutionary insights from wild vervet genomes Nat. Genet. (IF 27.959) Pub Date : 2017-11-29 Ellen M Leffler
Evolutionary insights from wild vervet genomes Evolutionary insights from wild vervet genomes, Published online: 29 November 2017; doi:10.1038/ng.3992 A new study reports genome-wide variation in 163 vervet monkeys from across their taxonomic and geographic ranges. The analysis suggests a complex history of admixture and identifies signals of repeated evolutionary selection, some of which may be linked to response to simian immunodeficiency virus.
Correcting CRISPR for copy number Nat. Genet. (IF 27.959) Pub Date : 2017-11-29 John Paul Shen, Trey Ideker
Correcting CRISPR for copy number Correcting CRISPR for copy number, Published online: 29 November 2017; doi:10.1038/ng.3994 The CRISPR–Cas9 system enables global screens of gene function with high sensitivity and specificity, but off-target effects have been reported for CRISPR guide RNAs targeting genes that are amplified at high copy number. A new study describes a computational approach to correct for this copy number effect, increasing the specificity of CRIPSR screens to identify essential genes.
The hammer of reason Nat. Genet. (IF 27.959) Pub Date : 2017-11-29
The hammer of reason The hammer of reason, Published online: 29 November 2017; doi:10.1038/ng.3996 In the motivation, conduct and reporting of science, there is no substitute for reason, and it must prevail whenever scientific methods are used. Similarly, scientific recommendations can only be useful if they meet with rational decision-making. Because people come to decisions from diverse viewpoints and values, listening to the values and views of scientists and non-scientists—while explicitly refraining from debate and persuasion—may point the way to determining when and where scientific ideas are of interest and likely to be adopted.
Mismatch repair prefers exons Nat. Genet. (IF 27.959) Pub Date : 2017-11-29 Dashiell J Massey, Amnon Koren
Mismatch repair prefers exons Mismatch repair prefers exons, Published online: 29 November 2017; doi:10.1038/ng.3993 A new analysis of cancer genomes identifies a decrease in the mutation burden of exons, but not introns, as compared to expectation. This difference can be explained by preferential recruitment of the DNA mismatch repair machinery to a protein modification that marks exons.
Mutant-IDH1-dependent chromatin state reprogramming, reversibility, and persistence Nat. Genet. (IF 27.959) Pub Date : 2017-11-27 Sevin Turcan, Vladimir Makarov, Julian Taranda, Yuxiang Wang, Armida W. M. Fabius, Wei Wu, Yupeng Zheng, Nour El-Amine, Sara Haddock, Gouri Nanjangud, H. Carl LeKaye, Cameron Brennan, Justin Cross, Jason T. Huse, Neil L. Kelleher, Pavel Osten, Craig B. Thompson, Timothy A. Chan
Mutations in IDH1 and IDH2 (encoding isocitrate dehydrogenase 1 and 2) drive the development of gliomas and other human malignancies. Mutant IDH1 induces epigenetic changes that promote tumorigenesis, but the scale and reversibility of these changes are unknown. Here, using human astrocyte and glioma tumorsphere systems, we generate a large-scale atlas of mutant-IDH1-induced epigenomic reprogramming. We characterize the reversibility of the alterations in DNA methylation, the histone landscape, and transcriptional reprogramming that occur following IDH1 mutation. We discover genome-wide coordinate changes in the localization and intensity of multiple histone marks and chromatin states. Mutant IDH1 establishes a CD24+ population with a proliferative advantage and stem-like transcriptional features. Strikingly, prolonged exposure to mutant IDH1 results in irreversible genomic and epigenetic alterations. Together, these observations provide unprecedented high-resolution molecular portraits of mutant-IDH1-dependent epigenomic reprogramming. These findings have substantial implications for understanding of mutant IDH function and for optimizing therapeutic approaches to targeting IDH-mutant tumors.
Bayesian inference of negative and positive selection in human cancers Nat. Genet. (IF 27.959) Pub Date : 2017-11-06 Donate Weghorn, Shamil Sunyaev
Bayesian inference of negative and positive selection in human cancers Bayesian inference of negative and positive selection in human cancers, Published online: 06 November 2017; doi:10.1038/ng.3987 NatureArticleSnippet(type=short-summary, markup= This study presents a probabilistic framework for inferring negative and positive selection in human cancers that addresses the problem of mutation rate variation. Applying the model to sequencing data from 17 cancer types identifies new significantly mutated genes and detects significant signals of negative selection in many cancer types. , isJats=true)
Reduced mutation rate in exons due to differential mismatch repair Nat. Genet. (IF 27.959) Pub Date : 2017-11-06 Joan Frigola, Radhakrishnan Sabarinathan, Loris Mularoni, Ferran Muiños, Abel Gonzalez-Perez, Núria López-Bigas
Reduced mutation rate in exons due to differential mismatch repair Reduced mutation rate in exons due to differential mismatch repair, Published online: 06 November 2017; doi:10.1038/ng.3991 NatureArticleSnippet(type=short-summary, markup= This analysis of cancer sequencing data identifies a reduced somatic mutation rate in exons and shows that this phenomenon is due to higher mismatch-repair activity in exons as compared to introns. These findings have implications for the understanding of mutational and DNA repair processes and for studying the evolution of both tumors and species. , isJats=true)
Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers Nat. Genet. (IF 27.959) Pub Date : 2017-11-06 Collin M Blakely, Thomas B K Watkins, Wei Wu, Beatrice Gini, Jacob J Chabon, Caroline E McCoach, Nicholas McGranahan, Gareth A Wilson, Nicolai J Birkbak, Victor R Olivas, Julia Rotow, Ashley Maynard, Victoria Wang, Matthew A Gubens, Kimberly C Banks, Richard B Lanman, Aleah F Caulin, John St John, Anibal R Cordero, Petros Giannikopoulos, Andrew D Simmons, Philip C Mack, David R Gandara, Hatim Husain, Robert C Doebele, Jonathan W Riess, Maximilian Diehn, Charles Swanton, Trever G Bivona
Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers, Published online: 06 November 2017; doi:10.1038/ng.3990 NatureArticleSnippet(type=short-summary, markup= Analysis of a large cohort of EGFR -mutant lung cancer cell-free DNA samples along with longitudinal samples from a patient with EGFR -mutant lung cancer identifies pathways that inhibit EGFR-inhibitor response. Co-occurring genetic alterations influence clinical outcomes and underscore the need for combination therapies. , isJats=true)
High-throughput annotation of full-length long noncoding RNAs with capture long-read sequencing Nat. Genet. (IF 27.959) Pub Date : 2017-11-06 Julien Lagarde, Barbara Uszczynska-Ratajczak, Silvia Carbonell, Sílvia Pérez-Lluch, Amaya Abad, Carrie Davis, Thomas R Gingeras, Adam Frankish, Jennifer Harrow, Roderic Guigo, Rory Johnson
High-throughput annotation of full-length long noncoding RNAs with capture long-read sequencing High-throughput annotation of full-length long noncoding RNAs with capture long-read sequencing, Published online: 06 November 2017; doi:10.1038/ng.3988 NatureArticleSnippet(type=short-summary, markup= RNA Capture Long Seq (CLS) is a new method for transcript annotation that combines targeted RNA capture with long-read sequencing. CLS reannotates GENCODE lncRNAs and increases the number of validated splice junctions and transcript models for targeted loci. , isJats=true)
Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology Nat. Genet. (IF 27.959) Pub Date : 2017-10-30 Manuel A Ferreira, Judith M Vonk, Hansjörg Baurecht, Ingo Marenholz, Chao Tian, Joshua D Hoffman, Quinta Helmer, Annika Tillander, Vilhelmina Ullemar, Jenny van Dongen, Yi Lu, Franz Rüschendorf, Jorge Esparza-Gordillo, Chris W Medway, Edward Mountjoy, Kimberley Burrows, Oliver Hummel, Sarah Grosche, Ben M Brumpton, John S Witte, Jouke-Jan Hottenga, Gonneke Willemsen, Jie Zheng, Elke Rodríguez, Melanie Hotze, Andre Franke, Joana A Revez, Jonathan Beesley, Melanie C Matheson, Shyamali C Dharmage, Lisa M Bain, Lars G Fritsche, Maiken E Gabrielsen, Brunilda Balliu, 23andMe Research Team, AAGC collaborators, BIOS consortium, LifeLines Cohort Study, Jonas B Nielsen, Wei Zhou, Kristian Hveem, Arnulf Langhammer, Oddgeir L Holmen, Mari Løset, Gonçalo R Abecasis, Cristen J Willer, Andreas Arnold, Georg Homuth, Carsten O Schmidt, Philip J Thompson, Nicholas G Martin, David L Duffy, Natalija Novak, Holger Schulz, Stefan Karrasch, Christian Gieger, Konstantin Strauch, Ronald B Melles, Dav..
Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology, Published online: 30 October 2017; doi:10.1038/ng.3985 NatureArticleSnippet(type=short-summary, markup= This large-scale genome-wide association analysis of subjects with asthma, hay fever or eczema provides insights into the shared genetic basis of these allergic diseases. The findings suggest that these diseases partly co-occur because they share many genetic risk variants that dysregulate the expression of immune-related genes. , isJats=true)
Ancient hybridization and strong adaptation to viruses across African vervet monkey populations Nat. Genet. (IF 27.959) Pub Date : 2017-10-30 Hannes Svardal, Anna J Jasinska, Cristian Apetrei, Giovanni Coppola, Yu Huang, Christopher A Schmitt, Beatrice Jacquelin, Vasily Ramensky, Michaela Müller-Trutwin, Martin Antonio, George Weinstock, J Paul Grobler, Ken Dewar, Richard K Wilson, Trudy R Turner, Wesley C Warren, Nelson B Freimer, Magnus Nordborg
Ancient hybridization and strong adaptation to viruses across African vervet monkey populations Ancient hybridization and strong adaptation to viruses across African vervet monkey populations, Published online: 30 October 2017; doi:10.1038/ng.3980 NatureArticleSnippet(type=short-summary, markup= Analysis of whole-genome sequencing data from 163 vervet monkeys from Africa and the Caribbean shows high diversity among taxa and identifies signatures of selection. Selection signals affect viral processes, and genes that show response to SIV in vervets but not macaques have elevated selection scores. , isJats=true)
Exome chip meta-analysis identifies novel loci and East Asian–specific coding variants that contribute to lipid levels and coronary artery disease Nat. Genet. (IF 27.959) Pub Date : 2017-10-30 Xiangfeng Lu, Gina M Peloso, Dajiang J Liu, Ying Wu, He Zhang, Wei Zhou, Jun Li, Clara Sze-man Tang, Rajkumar Dorajoo, Huaixing Li, Jirong Long, Xiuqing Guo, Ming Xu, Cassandra N Spracklen, Yang Chen, Xuezhen Liu, Yan Zhang, Chiea Chuen Khor, Jianjun Liu, Liang Sun, Laiyuan Wang, Yu-Tang Gao, Yao Hu, Kuai Yu, Yiqin Wang, Chloe Yu Yan Cheung, Feijie Wang, Jianfeng Huang, Qiao Fan, Qiuyin Cai, Shufeng Chen, Jinxiu Shi, Xueli Yang, Wanting Zhao, Wayne H-H Sheu, Stacey Shawn Cherny, Meian He, Alan B Feranil, Linda S Adair, Penny Gordon-Larsen, Shufa Du, Rohit Varma, Yii-Der Ida Chen, Xiao-Ou Shu, Karen Siu Ling Lam, Tien Yin Wong, Santhi K Ganesh, Zengnan Mo, Kristian Hveem, Lars G Fritsche, Jonas Bille Nielsen, Hung-fat Tse, Yong Huo, Ching-Yu Cheng, Y Eugene Chen, Wei Zheng, E Shyong Tai, Wei Gao, Xu Lin, Wei Huang, Goncalo Abecasis, GLGC Consortium, Sekar Kathiresan, Karen L Mohlke, Tangchun Wu, Pak Chung Sham, Dongfeng Gu, Cristen J Willer
Exome chip meta-analysis identifies novel loci and East Asian–specific coding variants that contribute to lipid levels and coronary artery disease Exome chip meta-analysis identifies novel loci and East Asian–specific coding variants that contribute to lipid levels and coronary artery disease, Published online: 30 October 2017; doi:10.1038/ng.3978 NatureArticleSnippet(type=short-summary, markup= A meta-analysis of exome-wide association studies for blood lipid levels in East Asian populations identifies a novel coding variant. Exome array data from the Global Lipids Genetics Consortium were integrated and led to the discovery of novel and population-specific variants associated with cholesterol and triglycerides. , isJats=true)
Computational correction of copy number effect improves specificity of CRISPR–Cas9 essentiality screens in cancer cells Nat. Genet. (IF 27.959) Pub Date : 2017-10-30 Robin M Meyers, Jordan G Bryan, James M McFarland, Barbara A Weir, Ann E Sizemore, Han Xu, Neekesh V Dharia, Phillip G Montgomery, Glenn S Cowley, Sasha Pantel, Amy Goodale, Yenarae Lee, Levi D Ali, Guozhi Jiang, Rakela Lubonja, William F Harrington, Matthew Strickland, Ting Wu, Derek C Hawes, Victor A Zhivich, Meghan R Wyatt, Zohra Kalani, Jaime J Chang, Michael Okamoto, Kimberly Stegmaier, Todd R Golub, Jesse S Boehm, Francisca Vazquez, David E Root, William C Hahn, Aviad Tsherniak
Computational correction of copy number effect improves specificity of CRISPR–Cas9 essentiality screens in cancer cells Computational correction of copy number effect improves specificity of CRISPR–Cas9 essentiality screens in cancer cells, Published online: 30 October 2017; doi:10.1038/ng.3984 NatureArticleSnippet(type=short-summary, markup= CERES is a new computational method to estimate gene-dependency levels from CRISPR–Cas9 essentiality screens while accounting for copy number effects and variable sgRNA activity. Applying CERES to new genome-scale CRISPR–Cas9 essentiality screen data from 342 cancer cell lines and other published data sets shows that CERES decreases false-positive results and provides consistent estimates of sgRNA activity. , isJats=true)
Ancestry-inspired genomic health Nat. Genet. (IF 27.959) Pub Date : 2017-08-30
A solution to screening for recessive heritable disorders and identifying genetic influences on common diseases is to be found in the history of one of the world's most populous regions. Large South Asian populations are a mosaic of smaller populations, many of which have founder effects as extreme as those in the European isolates that first inspired genetic medicine.
Expanding the effects of ERG on chromatin landscapes and dysregulated transcription in prostate cancer Nat. Genet. (IF 27.959) Pub Date : 2017-08-30 Deepak Babu, Melissa J Fullwood
ERG overexpression in prostate cancers promotes the development of widespread changes in gene expression and chromatin landscapes, leading to redistribution of key transcription factors in prostate cancers positive for the TMPRSS2-ERG fusion gene. The overexpression of ERG is further assisted by the development of a super-enhancer in the ERG locus.
Genetic insights into mammalian heart regeneration Nat. Genet. (IF 27.959) Pub Date : 2017-08-30 Ana Vujic, Vinícius Bassaneze, Richard T Lee
Genetic and functional analyses of 120 mouse strains have identified a heart regeneration candidate gene that modulates the contractile sarcomeric apparatus. This gene, Tnni3k, controls the frequency of the mononuclear, diploid cardiomyocyte population, which affects cardiomyocyte proliferative potential after injury.
Concepts, estimation and interpretation of SNP-based heritability Nat. Genet. (IF 27.959) Pub Date : 2017-08-30 Jian Yang, Jian Zeng, Michael E Goddard, Naomi R Wray, Peter M Visscher
Jian Yang and colleagues explore the uses and abuses of heritability estimates derived from pedigrees and from GWAS SNPs and make recommendations for best practice in future applications of SNP-based heritability.
Genomic prediction unifies animal and plant breeding programs to form platforms for biological discovery Nat. Genet. (IF 27.959) Pub Date : 2017-08-30 John M Hickey, Tinashe Chiurugwi, Ian Mackay, Wayne Powell
Wayne Powell and colleagues compare the different tools and approaches used by the plant breeding community versus the animal breeding community for crop and livestock improvement. They argue that the two disciplines can be united via adoption of genomic selection along with the exchange of resources and techniques between the two areas.
Reaching for the next branch on the biobank tree of knowledge Nat. Genet. (IF 27.959) Pub Date : 2017-08-30 Nancy J Cox
An innovative study analyzing genetic association across tree-structured routine healthcare data in the UK Biobank represents a new branch on a tree that is poised to grow rapidly and offer new kinds of insights on how genome variation relates to human health and disease. Indeed, this tree is likely to offer new kinds of insights into the very nature of human disease.
Classification of common human diseases derived from shared genetic and environmental determinants Nat. Genet. (IF 27.959) Pub Date : 2017-08-07 Kanix Wang, Hallie Gaitsch, Hoifung Poon, Nancy J Cox, Andrey Rzhetsky
Andrey Rzhetsky and colleagues analyze electronic medical records from over one-third of the US population to estimate disease heritability and to determine the genetic and environmental contributions to disease variance. They obtain 84 new heritability estimates and find that the genetic correlation values for disease pairs differ from their environmental correlation values.
Bayesian analysis of genetic association across tree-structured routine healthcare data in the UK Biobank Nat. Genet. (IF 27.959) Pub Date : 2017-07-31 Adrian Cortes, Calliope A Dendrou, Allan Motyer, Luke Jostins, Damjan Vukcevic, Alexander Dilthey, Peter Donnelly, Stephen Leslie, Lars Fugger, Gil McVean
Gil McVean and colleagues present a new Bayesian analysis framework that exploits the hierarchical structure of diagnosis classifications to analyze genetic variants against UK Biobank disease phenotypes derived from self-reporting and hospital episode statistics. Their method displays increased power to detect genetic effects over other approaches and identifies novel associations between classical HLA alleles and common immune-mediated diseases.
A common intronic variant of PARP1 confers melanoma risk and mediates melanocyte growth via regulation of MITF Nat. Genet. (IF 27.959) Pub Date : 2017-07-31 Jiyeon Choi, Mai Xu, Matthew M Makowski, Tongwu Zhang, Matthew H Law, Michael A Kovacs, Anton Granzhan, Wendy J Kim, Hemang Parikh, Michael Gartside, Jeffrey M Trent, Marie-Paule Teulade-Fichou, Mark M Iles, Julia A Newton-Bishop, D Timothy Bishop, Stuart MacGregor, Nicholas K Hayward, Michiel Vermeulen, Kevin M Brown
Previous genome-wide association studies have identified a melanoma-associated locus at 1q42.1 that encompasses a ~100-kb region spanning the PARP1 gene. Expression quantitative trait locus (eQTL) analysis in multiple cell types of the melanocytic lineage consistently demonstrated that the 1q42.1 melanoma risk allele (rs3219090[G]) is correlated with higher PARP1 levels. In silico fine-mapping and functional validation identified a common intronic indel, rs144361550 (−/GGGCCC; r2 = 0.947 with rs3219090), as displaying allele-specific transcriptional activity. A proteomic screen identified RECQL as binding to rs144361550 in an allele-preferential manner. In human primary melanocytes, PARP1 promoted cell proliferation and rescued BRAFV600E-induced senescence phenotypes in a PARylation-independent manner. PARP1 also transformed TERT-immortalized melanocytes expressing BRAFV600E. PARP1-mediated senescence rescue was accompanied by transcriptional activation of the melanocyte-lineage survival oncogene MITF, highlighting a new role for PARP1 in melanomagenesis.
TMPRSS2–ERG fusion co-opts master transcription factors and activates NOTCH signaling in primary prostate cancer Nat. Genet. (IF 27.959) Pub Date : 2017-08-07 Ken J Kron, Alexander Murison, Stanley Zhou, Vincent Huang, Takafumi N Yamaguchi, Yu-Jia Shiah, Michael Fraser, Theodorus van der Kwast, Paul C Boutros, Robert G Bristow, Mathieu Lupien
TMPRSS2–ERG (T2E) structural rearrangements typify ~50% of prostate tumors and result in overexpression of the ERG transcription factor. Using chromatin, genomic and expression data, we show distinct cis-regulatory landscapes between T2E-positive and non-T2E primary prostate tumors, which include clusters of regulatory elements (COREs). This difference is mediated by ERG co-option of HOXB13 and FOXA1, implementing a T2E-specific transcriptional profile. We also report a T2E-specific CORE on the structurally rearranged ERG locus arising from spreading of the TMPRSS2 locus pre-existing CORE, assisting in its overexpression. Finally, we show that the T2E-specific cis-regulatory landscape underlies a vulnerability against the NOTCH pathway. Indeed, NOTCH pathway inhibition antagonizes the growth and invasion of T2E-positive prostate cancer cells. Taken together, our work shows that overexpressed ERG co-opts master transcription factors to deploy a unique cis-regulatory landscape, inducing a druggable dependency on NOTCH signaling in T2E-positive prostate tumors.
Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration Nat. Genet. (IF 27.959) Pub Date : 2017-08-07 Michaela Patterson, Lindsey Barske, Ben Van Handel, Christoph D Rau, Peiheng Gan, Avneesh Sharma, Shan Parikh, Matt Denholtz, Ying Huang, Yukiko Yamaguchi, Hua Shen, Hooman Allayee, J Gage Crump, Thomas I Force, Ching-Ling Lien, Takako Makita, Aldons J Lusis, S Ram Kumar, Henry M Sucov
Adult mammalian cardiomyocyte regeneration after injury is thought to be minimal. Mononuclear diploid cardiomyocytes (MNDCMs), a relatively small subpopulation in the adult heart, may account for the observed degree of regeneration, but this has not been tested. We surveyed 120 inbred mouse strains and found that the frequency of adult mononuclear cardiomyocytes was surprisingly variable (>7-fold). Cardiomyocyte proliferation and heart functional recovery after coronary artery ligation both correlated with pre-injury MNDCM content. Using genome-wide association, we identified Tnni3k as one gene that influences variation in this composition and demonstrated that Tnni3k knockout resulted in elevated MNDCM content and increased cardiomyocyte proliferation after injury. Reciprocally, overexpression of Tnni3k in zebrafish promoted cardiomyocyte polyploidization and compromised heart regeneration. Our results corroborate the relevance of MNDCMs in heart regeneration. Moreover, they imply that intrinsic heart regeneration is not limited nor uniform in all individuals, but rather is a variable trait influenced by multiple genes.
PRDM15 safeguards naive pluripotency by transcriptionally regulating WNT and MAPK–ERK signaling Nat. Genet. (IF 27.959) Pub Date : 2017-07-24 Slim Mzoughi, Jingxian Zhang, Delphine Hequet, Shun Xie Teo, Haitong Fang, Qiao Rui Xing, Marco Bezzi, Michelle Kay Yi Seah, Sheena L M Ong, Eun Myoung Shin, Heike Wollmann, Esther S M Wong, Muthafar Al-Haddawi, Colin L Stewart, Vinay Tergaonkar, Yuin-Han Loh, N Ray Dunn, Daniel M Messerschmidt, Ernesto Guccione
The transcriptional network acting downstream of LIF, WNT and MAPK–ERK to stabilize mouse embryonic stem cells (ESCs) in their naive state has been extensively characterized. However, the upstream factors regulating these three signaling pathways remain largely uncharted. PR-domain-containing proteins (PRDMs) are zinc-finger sequence-specific chromatin factors that have essential roles in embryonic development and cell fate decisions. Here we characterize the transcriptional regulator PRDM15, which acts independently of PRDM14 to regulate the naive state of mouse ESCs. Mechanistically, PRDM15 modulates WNT and MAPK–ERK signaling by directly promoting the expression of Rspo1 (R-spondin1) and Spry1 (Sprouty1). Consistent with these findings, CRISPR–Cas9-mediated disruption of PRDM15-binding sites in the Rspo1 and Spry1 promoters recapitulates PRDM15 depletion, both in terms of local chromatin organization and the transcriptional modulation of these genes. Collectively, our findings uncover an essential role for PRDM15 as a chromatin factor that modulates the transcription of upstream regulators of WNT and MAPK–ERK signaling to safeguard naive pluripotency.
A gene encoding maize caffeoyl-CoA O-methyltransferase confers quantitative resistance to multiple pathogens Nat. Genet. (IF 27.959) Pub Date : 2017-07-24 Qin Yang, Yijian He, Mercy Kabahuma, Timothy Chaya, Amy Kelly, Eli Borrego, Yang Bian, Farid El Kasmi, Li Yang, Paulo Teixeira, Judith Kolkman, Rebecca Nelson, Michael Kolomiets, Jeffery L Dangl, Randall Wisser, Jeffrey Caplan, Xu Li, Nick Lauter, Peter Balint-Kurti
Alleles that confer multiple disease resistance (MDR) are valuable in crop improvement, although the molecular mechanisms underlying their functions remain largely unknown. A quantitative trait locus, qMdr9.02, associated with resistance to three important foliar maize diseases—southern leaf blight, gray leaf spot and northern leaf blight—has been identified on maize chromosome 9. Through fine-mapping, association analysis, expression analysis, insertional mutagenesis and transgenic validation, we demonstrate that ZmCCoAOMT2, which encodes a caffeoyl-CoA O-methyltransferase associated with the phenylpropanoid pathway and lignin production, is the gene within qMdr9.02 conferring quantitative resistance to both southern leaf blight and gray leaf spot. We suggest that resistance might be caused by allelic variation at the level of both gene expression and amino acid sequence, thus resulting in differences in levels of lignin and other metabolites of the phenylpropanoid pathway and regulation of programmed cell death.
Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease Nat. Genet. (IF 27.959) Pub Date : 2017-07-17 Rebecca Sims, Sven J van der Lee, Adam C Naj, Céline Bellenguez, Nandini Badarinarayan, Johanna Jakobsdottir, Brian W Kunkle, Anne Boland, Rachel Raybould, Joshua C Bis, Eden R Martin, Benjamin Grenier-Boley, Stefanie Heilmann-Heimbach, Vincent Chouraki, Amanda B Kuzma, Kristel Sleegers, Maria Vronskaya, Agustin Ruiz, Robert R Graham, Robert Olaso, Per Hoffmann, Megan L Grove, Badri N Vardarajan, Mikko Hiltunen, Markus M Nöthen, Charles C White, Kara L Hamilton-Nelson, Jacques Epelbaum, Wolfgang Maier, Seung-Hoan Choi, Gary W Beecham, Cécile Dulary, Stefan Herms, Albert V Smith, Cory C Funk, Céline Derbois, Andreas J Forstner, Shahzad Ahmad, Hongdong Li, Delphine Bacq, Denise Harold, Claudia L Satizabal, Otto Valladares, Alessio Squassina, Rhodri Thomas, Jennifer A Brody, Liming Qu, Pascual Sánchez-Juan, Taniesha Morgan, Frank J Wolters, Yi Zhao, Florentino Sanchez Garcia, Nicola Denning, Myriam Fornage, John Malamon, Maria Candida Deniz Naranjo, Elisa Majounie, Thomas H Mosl..
Sven van der Lee, Julie Williams, Gerard Schellenberg and colleagues identify rare coding variants in PLCG2, ABI3 and TREM2 associated with Alzheimer's disease. These genes are highly expressed in microglia and provide additional evidence that the microglia-mediated immune response contributes to the development of Alzheimer's disease.
Association analyses based on false discovery rate implicate new loci for coronary artery disease Nat. Genet. (IF 27.959) Pub Date : 2017-07-17 Christopher P Nelson, Anuj Goel, Adam S Butterworth, Stavroula Kanoni, Tom R Webb, Eirini Marouli, Lingyao Zeng, Ioanna Ntalla, Florence Y Lai, Jemma C Hopewell, Olga Giannakopoulou, Tao Jiang, Stephen E Hamby, Emanuele Di Angelantonio, Themistocles L Assimes, Erwin P Bottinger, John C Chambers, Robert Clarke, Colin N A Palmer, Richard M Cubbon, Patrick Ellinor, Raili Ermel, Evangelos Evangelou, Paul W Franks, Christopher Grace, Dongfeng Gu, Aroon D Hingorani, Joanna M M Howson, Erik Ingelsson, Adnan Kastrati, Thorsten Kessler, Theodosios Kyriakou, Terho Lehtimäki, Xiangfeng Lu, Yingchang Lu, Winfried März, Ruth McPherson, Andres Metspalu, Mar Pujades-Rodriguez, Arno Ruusalepp, Eric E Schadt, Amand F Schmidt, Michael J Sweeting, Pierre A Zalloua, Kamal AlGhalayini, Bernard D Keavney, Jaspal S Kooner, Ruth J F Loos, Riyaz S Patel, Martin K Rutter, Maciej Tomaszewski, Ioanna Tzoulaki, Eleftheria Zeggini, Jeanette Erdmann, George Dedoussis, Johan L M Björkegren, Heribert Schunke..
Hugh Watkins and colleagues meta-analyze data from the UK Biobank along with recent genome-wide association studies for coronary artery disease. They identify 13 new loci that were genome-wide significant and 243 loci at a 5% false discovery rate.
Genetic analysis in UK Biobank links insulin resistance and transendothelial migration pathways to coronary artery disease Nat. Genet. (IF 27.959) Pub Date : 2017-07-17 Derek Klarin, Qiuyu Martin Zhu, Connor A Emdin, Mark Chaffin, Steven Horner, Brian J McMillan, Alison Leed, Michael E Weale, Chris C A Spencer, François Aguet, Ayellet V Segrè, Kristin G Ardlie, Amit V Khera, Virendar K Kaushik, Pradeep Natarajan, Sekar Kathiresan
Sekar Kathiresan and colleagues perform a genome-wide association test for coronary artery disease (CAD) using data from the UK Biobank. They identify 15 new loci and perform phenome-wide association scanning, implicating insulin resistance pathways and transendothelial migration of leukocytes in CAD.
Effect of sequence variants on variance in glucose levels predicts type 2 diabetes risk and accounts for heritability Nat. Genet. (IF 27.959) Pub Date : 2017-08-07 Erna V Ivarsdottir, Valgerdur Steinthorsdottir, Maryam S Daneshpour, Gudmar Thorleifsson, Patrick Sulem, Hilma Holm, Snaevar Sigurdsson, Astradur B Hreidarsson, Gunnar Sigurdsson, Ragnar Bjarnason, Arni V Thorsson, Rafn Benediktsson, Gudmundur Eyjolfsson, Olof Sigurdardottir, Isleifur Olafsson, Sirous Zeinali, Fereidoun Azizi, Unnur Thorsteinsdottir, Daniel F Gudbjartsson, Kari Stefansson
Daniel Gudbjartsson, Kari Stefansson and colleagues assess the effect of variants associated with mean fasting glucose levels on the variance in fasting glucose levels. They find that variants that increase both the levels and variance of fasting glucose increase type 2 diabetes risk, whereas those that increase the levels but reduce the variance do not.
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