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A golden goat genome pp485 - 486 Kim C Worley doi:10.1038/ng.3824 The newly described de novo goat genome sequence is the most contiguous diploid vertebrate assembly generated thus far using whole-genome assembly and scaffolding methods. The contiguity of this assembly is approaching that of the finished human and mouse genomes and suggests an affordable roadmap to high-quality references for thousands of species.
Genetic interactions improve models of quantitative traits pp486 - 488 Anna L Tyler & Gregory W Carter doi:10.1038/ng.3829 A study of genetic variation in yeast has identified key quantitative trait loci (QTLs) that suppress the effects of variation at multiple other loci. These loci prove essential to accurately modeling yeast growth in response to different environments.
Resequencing at scale in neurodevelopmental disorders pp488 - 489 David R FitzPatrick doi:10.1038/ng.3827 An international collaboration has assembled DNA samples and detailed phenotypic information from >13,000 individuals with a clinical diagnosis of either autism spectrum disorder (ASD) or intellectual disability/developmental delay (ID/DD). The application of molecular inversion probe technologies to sequence 208 candidate genes at scale in this impressive resource has identified a large set of plausibly causative mutations for these disorders.
Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples pp504 - 510 Jack A Kosmicki, Kaitlin E Samocha, Daniel P Howrigan, Stephan J Sanders, Kamil Slowikowski, Monkol Lek, Konrad J Karczewski, David J Cutler, Bernie Devlin, Kathryn Roeder, Joseph D Buxbaum, Benjamin M Neale, Daniel G MacArthur, Dennis P Wall, Elise B Robinson & Mark J Daly doi:10.1038/ng.3789 Mark Daly and colleagues use population reference samples to refine the role of de novo protein-truncating variants in neurodevelopmental disorders. They show that variants independently observed in population reference samples do not contribute substantively to neurodevelopmental risk, and they use a loss-of-function intolerance metric to identify a small subset of genes that contain the entire observed signal of associated de novo protein-truncating variants in these disorders.
Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance pp511 - 514 Ashley P L Marsh, Delphine Heron, Timothy J Edwards, Angélique Quartier, Charles Galea, Caroline Nava, Agnès Rastetter, Marie-Laure Moutard, Vicki Anderson, Pierre Bitoun, Jens Bunt, Anne Faudet, Catherine Garel, Greta Gillies, Ilan Gobius, Justine Guegan, Solveig Heide, Boris Keren, Fabien Lesne, Vesna Lukic, Simone A Mandelstam, George McGillivray, Alissandra McIlroy, Aurélie Méneret, Cyril Mignot, Laura R Morcom, Sylvie Odent, Annalisa Paolino, Kate Pope, Florence Riant, Gail A Robinson, Megan Spencer-Smith, Myriam Srour, Sarah E M Stephenson, Rick Tankard, Oriane Trouillard, Quentin Welniarz, Amanda Wood, Alexis Brice, Guy Rouleau, Tania Attié-Bitach, Martin B Delatycki, Jean-Louis Mandel, David J Amor, Emmanuel Roze, Amélie Piton, Melanie Bahlo, Thierry Billette de Villemeur, Elliott H Sherr, Richard J Leventer, Linda J Richards, Paul J Lockhart & Christel Depienne doi:10.1038/ng.3794 Linda Richards, Paul Lockhart, Christel Depienne and colleagues identify heterozygous DCC mutations in four families and five sporadic individuals with agenesis of the corpus callosum (ACC). They report that DCC mutations result in variable dominant phenotypes with incomplete penetrance, including mirror movements and ACC associated with a favorable developmental prognosis.
Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases pp515 - 526 Holly A F Stessman, Bo Xiong, Bradley P Coe, Tianyun Wang, Kendra Hoekzema, Michaela Fenckova, Malin Kvarnung, Jennifer Gerdts, Sandy Trinh, Nele Cosemans, Laura Vives, Janice Lin, Tychele N Turner, Gijs Santen, Claudia Ruivenkamp, Marjolein Kriek, Arie van Haeringen, Emmelien Aten, Kathryn Friend, Jan Liebelt, Christopher Barnett, Eric Haan, Marie Shaw, Jozef Gecz, Britt-Marie Anderlid, Ann Nordgren, Anna Lindstrand, Charles Schwartz, R Frank Kooy, Geert Vandeweyer, Celine Helsmoortel, Corrado Romano, Antonino Alberti, Mirella Vinci, Emanuela Avola, Stefania Giusto, Eric Courchesne, Tiziano Pramparo, Karen Pierce, Srinivasa Nalabolu, David G Amaral, Ingrid E Scheffer, Martin B Delatycki, Paul J Lockhart, Fereydoun Hormozdiari, Benjamin Harich, Anna Castells-Nobau, Kun Xia, Hilde Peeters, Magnus Nordenskjöld, Annette Schenck, Raphael A Bernier & Evan E Eichler doi:10.1038/ng.3792 Evan Eichler and colleagues use single-molecule molecular-inversion probes to sequence the coding and splicing regions of 208 candidate genes in more than 11,730 individuals with neurodevelopmental disorders. They report 91 genes with an excess of de novo or private disruptive mutations, identify 25 genes showing a bias for autism versus intellectual disability, and highlight a network associated with high-functioning autism.
Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans pp527 - 536 Hsiang-Chih Lu, Qiumin Tan, Maxime W C Rousseaux, Wei Wang, Ji-Yoen Kim, Ronald Richman, Ying-Wooi Wan, Szu-Ying Yeh, Jay M Patel, Xiuyun Liu, Tao Lin, Yoontae Lee, John D Fryer, Jing Han, Maria Chahrour, Richard H Finnell, Yunping Lei, Maria E Zurita-Jimenez, Priyanka Ahimaz, Kwame Anyane-Yeboa, Lionel Van Maldergem, Daphne Lehalle, Nolwenn Jean-Marcais, Anne-Laure Mosca-Boidron, Julien Thevenon, Margot A Cousin, Della E Bro, Brendan C Lanpher, Eric W Klee, Nora Alexander, Matthew N Bainbridge, Harry T Orr, Roy V Sillitoe, M Cecilia Ljungberg, Zhandong Liu, Christian P Schaaf & Huda Y Zoghbi doi:10.1038/ng.3808 Huda Zoghbi and colleagues report that loss of the ATXN1-CIC protein complex in the developing mouse forebrain results in hyperactivity and defects in learning and memory. Loss of Cic in specific brain regions causes social interaction defects, and patients with de novo CIC mutations present signs of hyperactivity, autism spectrum disorder and intellectual disability.
Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism pp537 - 549 John J Reynolds, Louise S Bicknell, Paula Carroll, Martin R Higgs, Ranad Shaheen, Jennie E Murray, Dimitrios K Papadopoulos, Andrea Leitch, Olga Murina, Žygimantė Tarnauskaitė, Sarah R Wessel, Anastasia Zlatanou, Audrey Vernet, Alex von Kriegsheim, Rachel M A Mottram, Clare V Logan, Hannah Bye, Yun Li, Alexander Brean, Sateesh Maddirevula, Rachel C Challis, Kassiani Skouloudaki, Agaadir Almoisheer, Hessa S Alsaif, Ariella Amar, Natalie J Prescott, Michael B Bober, Angela Duker, Eissa Faqeih, Mohammed Zain Seidahmed, Saeed Al Tala, Abdulrahman Alswaid, Saleem Ahmed, Jumana Yousuf Al-Aama, Janine Altmüller, Mohammed Al Balwi, Angela F Brady, Luciana Chessa, Helen Cox, Rita Fischetto, Raoul Heller, Bertram D Henderson, Emma Hobson, Peter Nürnberg, E Ferda Percin, Angela Peron, Luigina Spaccini, Alan J Quigley, Seema Thakur, Carol A Wise, Grace Yoon, Maha Alnemer, Pavel Tomancak, Gökhan Yigit, A Malcolm R Taylor, Martin A M Reijns, Michael A Simpson, David Cortez, Fowzan S Alkuraya, Christopher G Mathew, Andrew P Jackson & Grant S Stewart doi:10.1038/ng.3790 Grant Stewart, Andrew Jackson, Christopher Mathew, Fowzan Alkuraya and colleagues identify a novel replication fork protein, DONSON, which is important for maintaining genome stability. Mutations in DONSON cause microcephalic dwarfism and lead to stalled replication forks and DNA damage.
Promoter shape varies across populations and affects promoter evolution and expression noise pp550 - 558 Ignacio E Schor, Jacob F Degner, Dermot Harnett, Enrico Cannavò, Francesco P Casale, Heejung Shim, David A Garfield, Ewan Birney, Matthew Stephens, Oliver Stegle & Eileen E M Furlong doi:10.1038/ng.3791 Eileen Furlong, Oliver Stegle and colleagues quantify transcriptional start site (TSS) usage across 81 Drosophila lines, identifying genetic variants that affect transcript levels or the distribution of the TSS within a promoter. Using single-cell measurements, they show that variants modulating promoter shape often increase expression noise.
Genome-wide analyses identify common variants associated with macular telangiectasia type 2 pp559 - 567 Thomas S Scerri, Anna Quaglieri, Carolyn Cai, Jana Zernant, Nori Matsunami, Lisa Baird, Lea Scheppke, Roberto Bonelli, Lawrence A Yannuzzi, Martin Friedlander, MacTel Project Consortium, Catherine A Egan, Marcus Fruttiger, Mark Leppert, Rando Allikmets & Melanie Bahlo doi:10.1038/ng.3799 Melanie Bahlo and colleagues perform the first genome-wide association analysis for macular telangiectasia type 2. They identify three significant loci and report on a potential connection to the glycine/serine metabolism pathway.
Whole-genome sequencing identifies common-to-rare variants associated with human blood metabolites pp568 - 578 Tao Long, Michael Hicks, Hung-Chun Yu, William H Biggs, Ewen F Kirkness, Cristina Menni, Jonas Zierer, Kerrin S Small, Massimo Mangino, Helen Messier, Suzanne Brewerton, Yaron Turpaz, Brad A Perkins, Anne M Evans, Luke A D Miller, Lining Guo, C Thomas Caskey, Nicholas J Schork, Chad Garner, Tim D Spector, J Craig Venter & Amalio Telenti doi:10.1038/ng.3809 Amalio Telenti, Craig Venter and colleagues report common, low-frequency and rare variants associated with blood metabolite levels using whole-genome sequencing and comprehensive metabolite profiling in 1,960 individuals. They identify 246 metabolites whose levels are associated with genetic variation at 101 loci.
Asymmetric subgenome selection and cis-regulatory divergence during cotton domestication pp579 - 587 Maojun Wang, Lili Tu, Min Lin, Zhongxu Lin, Pengcheng Wang, Qingyong Yang, Zhengxiu Ye, Chao Shen, Jianying Li, Lin Zhang, Xiaolin Zhou, Xinhui Nie, Zhonghua Li, Kai Guo, Yizan Ma, Cong Huang, Shuangxia Jin, Longfu Zhu, Xiyan Yang, Ling Min, Daojun Yuan, Qinghua Zhang, Keith Lindsey & Xianlong Zhang doi:10.1038/ng.3807 Xianlong Zhang, Keith Lindsey and colleagues report a population genomic analysis of Upland cotton (Gossypium hirsutum) that identifies 93 potential domestication-sweep regions and 19 candidate loci for fiber-quality-related traits. Their analysis provides evidence for asymmetric subgenome selection for long white fibers in cultivated cotton.
Diversity in non-repetitive human sequences not found in the reference genome pp588 - 593 Birte Kehr, Anna Helgadottir, Pall Melsted, Hakon Jonsson, Hannes Helgason, Adalbjörg Jonasdottir, Aslaug Jonasdottir, Asgeir Sigurdsson, Arnaldur Gylfason, Gisli H Halldorsson, Snaedis Kristmundsdottir, Gudmundur Thorgeirsson, Isleifur Olafsson, Hilma Holm, Unnur Thorsteinsdottir, Patrick Sulem, Agnar Helgason, Daniel F Gudbjartsson, Bjarni V Halldorsson & Kari Stefansson doi:10.1038/ng.3801 Bjarni Halldorsson, Kari Stefansson and colleagues analyze genomic data from 15,219 Icelanders to identify non-repetitive sequences that are missing from the reference genome. They describe 3,791 breakpoint-resolved sequence variants and find overlap with GWAS markers as well as the presence of a proportion of these variants in the chimpanzee genome.
Spatiotemporal genomic architecture informs precision oncology in glioblastoma pp594 - 599 Jin-Ku Lee, Jiguang Wang, Jason K Sa, Erik Ladewig, Hae-Ock Lee, In-Hee Lee, Hyun Ju Kang, Daniel S Rosenbloom, Pablo G Camara, Zhaoqi Liu, Patrick van Nieuwenhuizen, Sang Won Jung, Seung Won Choi, Junhyung Kim, Andrew Chen, Kyu-Tae Kim, Sang Shin, Yun Jee Seo, Jin-Mi Oh, Yong Jae Shin, Chul-Kee Park, Doo-Sik Kong, Ho Jun Seol, Andrew Blumberg, Jung-Il Lee, Antonio Iavarone, Woong-Yang Park, Raul Rabadan & Do-Hyun Nam doi:10.1038/ng.3806 Raul Rabadan, Woong-Yang Park, Do-Hyun Nam and colleagues examine the genomic and transcriptomic profiles of tumors from 52 patients with glioblastoma using both bulk and single-cell analyses. They find that tumors that are isolated from distinct locations or at different times are seeded from different clones, suggesting the need for multisector biopsies.
Biallelic mutations in human DCC cause developmental split-brain syndrome pp606 - 612 Saumya S Jamuar, Klaus Schmitz-Abe, Alissa M D'Gama, Marie Drottar, Wai-Man Chan, Maya Peeva, Sarah Servattalab, Anh-Thu N Lam, Mauricio R Delgado, Nancy J Clegg, Zayed Al Zayed, Mohammad Asif Dogar, Ibrahim A Alorainy, Abdullah Abu Jamea, Khaled Abu-Amero, May Griebel, Wendy Ward, Ed S Lein, Kyriacos Markianos, A James Barkovich, Caroline D Robson, P Ellen Grant, Thomas M Bosley, Elizabeth C Engle, Christopher A Walsh & Timothy W Yu doi:10.1038/ng.3804 Timothy Yu and colleagues report that biallelic mutations in DCC cause a developmental syndrome characterized by widespread disruption of midline-bridging neuronal commissures, including agenesis of the corpus callosum, absence of hippocampal and anterior commissures, and ventral midline brainstem malformations. Clinical manifestations include horizontal gaze palsy, mirror movements, scoliosis and intellectual disability.
Germline mutations in ABL1 cause an autosomal dominant syndrome characterized by congenital heart defects and skeletal malformations pp613 - 617 Xia Wang, Wu-Lin Charng, Chun-An Chen, Jill A Rosenfeld, Aisha Al Shamsi, Lihadh Al-Gazali, Marianne McGuire, Nicholas Ah Mew, Georgianne L Arnold, Chunjing Qu, Yan Ding, Donna M Muzny, Richard A Gibbs, Christine M Eng, Magdalena Walkiewicz, Fan Xia, Sharon E Plon, James R Lupski, Christian P Schaaf & Yaping Yang doi:10.1038/ng.3815 Christian Schaaf, Yaping Yang and colleagues report that germline mutations in ABL1, which is best known as part of the fusion gene BCR-ABL1 on the Philadelphia chromosome, cause an autosomal dominant disorder characterized by heart disease, skeletal abnormalities and failure to thrive. They find that these mutations increase the kinase activity of ABL1, establishing another example of mutations in a proto-oncogene leading to developmental defects.
Variant-aware saturating mutagenesis using multiple Cas9 nucleases identifies regulatory elements at trait-associated loci pp625 - 634 Matthew C Canver, Samuel Lessard, Luca Pinello, Yuxuan Wu, Yann Ilboudo, Emily N Stern, Austen J Needleman, Frédéric Galactéros, Carlo Brugnara, Abdullah Kutlar, Colin McKenzie, Marvin Reid, Diane D Chen, Partha Pratim Das, Mitchel A Cole, Jing Zeng, Ryo Kurita, Yukio Nakamura, Guo-Cheng Yuan, Guillaume Lettre, Daniel E Bauer & Stuart H Orkin doi:10.1038/ng.3793 Stuart Orkin, Daniel Bauer and colleagues present DNA Striker, a computational tool to design variant-aware saturating-mutagenesis screens with multiple CRISPR-associated nucleases. They apply their methodology to the HBS1L-MYB intergenic region, which is associated with red-blood-cell traits, and identify putative regulatory elements that control MYB expression.
Single-molecule sequencing and chromatin conformation capture enable de novo reference assembly of the domestic goat genome OPENpp643 - 650 Derek M Bickhart, Benjamin D Rosen, Sergey Koren, Brian L Sayre, Alex R Hastie, Saki Chan, Joyce Lee, Ernest T Lam, Ivan Liachko, Shawn T Sullivan, Joshua N Burton, Heather J Huson, John C Nystrom, Christy M Kelley, Jana L Hutchison, Yang Zhou, Jiajie Sun, Alessandra Crisà, F Abel Ponce de León, John C Schwartz, John A Hammond, Geoffrey C Waldbieser, Steven G Schroeder, George E Liu, Maitreya J Dunham, Jay Shendure, Tad S Sonstegard, Adam M Phillippy, Curtis P Van Tassell & Timothy P L Smith doi:10.1038/ng.3802 Adam Phillippy, Curtis Van Tassell, Timothy Smith and colleagues present a new reference genome assembly for the domestic goat using a pipeline that improves contiguity of the assembly by more than 250-fold. The pipeline uses a combination of short- and long-read sequencing, optical mapping, and chromatin interaction mapping.
Erratum: Distinct Salmonella Enteritidis lineages associated with enterocolitis in high-income settings and invasive disease in low-income settings p651 Nicholas A Feasey, James Hadfield, Karen H Keddy, Timothy J Dallman, Jan Jacobs, Xiangyu Deng, Paul Wigley, Lars Barquist, Gemma C Langridge, Theresa Feltwell, Simon R Harris, Alison E Mather, Maria Fookes, Martin Aslett, Chisomo Msefula, Samuel Kariuki, Calman A Maclennan, Robert S Onsare, François-Xavier Weill, Simon Le Hello, Anthony M Smith, Michael McClelland, Prerak Desai, Christopher M Parry, John Cheesbrough, Neil French, Josefina Campos, Jose A Chabalgoity, Laura Betancor, Katie L Hopkins, Satheesh Nair, Tom J Humphrey, Octavie Lunguya, Tristan A Cogan, Milagritos D Tapia, Samba O Sow, Sharon M Tennant, Kristin Bornstein, Myron M Levine, Lizeth Lacharme-Lora, Dean B Everett, Robert A Kingsley, Julian Parkhill, Robert S Heyderman, Gordon Dougan, Melita A Gordon & Nicholas R Thomson doi:10.1038/ng0417-651c
Corrigendum: Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer p651 Yufei Wang, James D McKay, Thorunn Rafnar, Zhaoming Wang, Maria N Timofeeva, Peter Broderick, Xuchen Zong, Marina Laplana, Yongyue Wei, Younghun Han, Amy Lloyd, Manon Delahaye-Sourdeix, Daniel Chubb, Valerie Gaborieau, William Wheeler, Nilanjan Chatterjee, Gudmar Thorleifsson, Patrick Sulem, Geoffrey Liu, Rudolf Kaaks, Marc Henrion, Ben Kinnersley, Maxime Vallée, Florence Le Calvez-Kelm, Victoria L Stevens, Susan M Gapstur, Wei V Chen, David Zaridze, Neonilia Szeszenia-Dabrowska, Jolanta Lissowska, Peter Rudnai, Eleonora Fabianova, Dana Mates, Vladimir Bencko, Lenka Foretova, Vladimir Janout, Hans E Krokan, Maiken Elvestad Gabrielsen, Frank Skorpen, Lars Vatten, Inger Njølstad, Chu Chen, Gary Goodman, Simone Benhamou, Tonu Vooder, Kristjan Välk, Mari Nelis, Andres Metspalu, Marcin Lener, Jan Lubiński, Mattias Johansson, Paolo Vineis, Antonio Agudo, Francoise Clavel-Chapelon, H Bas Bueno-de-Mesquita, Dimitrios Trichopoulos, Kay-Tee Khaw, Mikael Johansson, Elisabete Weiderpass, Anne Tjønneland, Elio Riboli, Mark Lathrop, Ghislaine Scelo, Demetrius Albanes, Neil E Caporaso, Yuanqing Ye, Jian Gu, Xifeng Wu, Margaret R Spitz, Hendrik Dienemann, Albert Rosenberger, Li Su, Athena Matakidou, Timothy Eisen, Kari Stefansson, Angela Risch, Stephen J Chanock, David C Christiani, Rayjean J Hung, Paul Brennan, Maria Teresa Landi, Richard S Houlston & Christopher I Amos doi:10.1038/ng0417-651a
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