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Nature Genetics

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
Study of monogenic forms of obesity has demonstrated the pivotal role of the central leptin-melanocortin pathway in controlling energy balance, appetite and body weight 1 . The majority of loss-of-function mutations (mostly recessive or co-dominant) have been identified in genes that are directly involved in leptin-melanocortin signaling. These genes, however, only explain obesity in <5% of cases, predominantly from outbred populations 2 . We previously showed that, in a consanguineous population in Pakistan, recessive mutations in known obesity-related genes explain ~30% of cases with severe obesity3-5...
January 8, 2018: Nature Genetics
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.
January 8, 2018: Nature Genetics
Jacqueline E Siljee, Yi Wang, Adelaide A Bernard, Baran A Ersoy, Sumei Zhang, Aaron Marley, Mark Von Zastrow, Jeremy F Reiter, Christian Vaisse
Most monogenic cases of obesity in humans have been linked to mutations in genes encoding members of the leptin-melanocortin pathway. Specifically, mutations in MC4R, the melanocortin-4 receptor gene, account for 3-5% of all severe obesity cases in humans 1-3 . Recently, ADCY3 (adenylyl cyclase 3) gene mutations have been implicated in obesity 4,5 . ADCY3 localizes to the primary cilia of neurons 6 , organelles that function as hubs for select signaling pathways. Mutations that disrupt the functions of primary cilia cause ciliopathies, rare recessive pleiotropic diseases in which obesity is a cardinal manifestation 7 ...
January 8, 2018: Nature Genetics
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 (N eff = 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...
January 1, 2018: Nature Genetics
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No abstract text is available yet for this article.
December 22, 2017: Nature Genetics
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
The version of the Supplementary Text and Figures file initially posted was missing Supplementary Tables 1-6 and the Supplementary Note and used incorrect versions of the supplementary figures.
December 18, 2017: Nature Genetics
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
In the version of this article initially published, in the Methods, the Gene Expression Omnibus accession code for H3K36me3 ChIP-seq data was incorrectly given as GSM1003585 instead of GSM733725. The error has been corrected in the HTML, PDF and print versions of the article.
December 18, 2017: Nature Genetics
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...
December 18, 2017: Nature Genetics
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...
December 18, 2017: Nature Genetics
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...
December 18, 2017: Nature Genetics
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% 3-6 . Increased neuroticism is associated with poorer mental and physical health 7,8 , translating to high economic burden 9 . Genome-wide association studies (GWAS) of neuroticism have identified up to 11 associated genetic loci 3,4 . 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...
December 18, 2017: Nature Genetics
Asaf Levy, Isai Salas Gonzalez, Maximilian Mittelviefhaus, Scott Clingenpeel, Sur Herrera Paredes, Jiamin Miao, Kunru Wang, Giulia Devescovi, Kyra Stillman, Freddy Monteiro, Bryan Rangel Alvarez, Derek S Lundberg, Tse-Yuan Lu, Sarah Lebeis, Zhao Jin, Meredith McDonald, Andrew P Klein, Meghan E Feltcher, Tijana Glavina Rio, Sarah R Grant, Sharon L Doty, Ruth E Ley, Bingyu Zhao, Vittorio Venturi, Dale A Pelletier, Julia A Vorholt, Susannah G Tringe, Tanja Woyke, Jeffery L Dangl
Plants intimately associate with diverse bacteria. Plant-associated bacteria have ostensibly evolved genes that enable them to adapt to plant environments. However, the identities of such genes are mostly unknown, and their functions are poorly characterized. We sequenced 484 genomes of bacterial isolates from roots of Brassicaceae, poplar, and maize. We then compared 3,837 bacterial genomes to identify thousands of plant-associated gene clusters. Genomes of plant-associated bacteria encode more carbohydrate metabolism functions and fewer mobile elements than related non-plant-associated genomes do...
December 18, 2017: Nature Genetics
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...
December 18, 2017: Nature Genetics
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 development 1-3 . Although the DNA methylome of early human embryos has been analyzed 4-6 , 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...
December 18, 2017: Nature Genetics
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...
December 11, 2017: Nature Genetics
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)...
December 11, 2017: Nature Genetics
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...
December 4, 2017: Nature Genetics
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...
November 27, 2017: Nature Genetics
Joan Frigola, Radhakrishnan Sabarinathan, Loris Mularoni, Ferran Muiños, Abel Gonzalez-Perez, Núria López-Bigas
While recent studies have identified higher than anticipated heterogeneity of mutation rate across genomic regions, mutations in exons and introns are assumed to be generated at the same rate. Here we find fewer somatic mutations in exons than expected from their sequence content and demonstrate that this is not due to purifying selection. Instead, we show that it is caused by higher mismatch-repair activity in exonic than in intronic regions. Our findings have important implications for understanding of mutational and DNA repair processes and knowledge of the evolution of eukaryotic genes, and they have practical ramifications for the study of evolution of both tumors and species...
November 6, 2017: Nature Genetics
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
Accurate annotation of genes and their transcripts is a foundation of genomics, but currently no annotation technique combines throughput and accuracy. As a result, reference gene collections remain incomplete-many gene models are fragmentary, and thousands more remain uncataloged, particularly for long noncoding RNAs (lncRNAs). To accelerate lncRNA annotation, the GENCODE consortium has developed RNA Capture Long Seq (CLS), which combines targeted RNA capture with third-generation long-read sequencing. Here we present an experimental reannotation of the GENCODE intergenic lncRNA populations in matched human and mouse tissues that resulted in novel transcript models for 3,574 and 561 gene loci, respectively...
November 6, 2017: Nature Genetics
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