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Nature Genetics

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https://www.readbyqxmd.com/read/28530678/the-complex-genetics-of-hypoplastic-left-heart-syndrome
#1
Xiaoqin Liu, Hisato Yagi, Shazina Saeed, Abha S Bais, George C Gabriel, Zhaohan Chen, Kevin A Peterson, You Li, Molly C Schwartz, William T Reynolds, Manush Saydmohammed, Brian Gibbs, Yijen Wu, William Devine, Bishwanath Chatterjee, Nikolai T Klena, Dennis Kostka, Karen L de Mesy Bentley, Madhavi K Ganapathiraju, Phillip Dexheimer, Linda Leatherbury, Omar Khalifa, Anchit Bhagat, Maliha Zahid, William Pu, Simon Watkins, Paul Grossfeld, Stephen A Murray, George A Porter, Michael Tsang, Lisa J Martin, D Woodrow Benson, Bruce J Aronow, Cecilia W Lo
Congenital heart disease (CHD) affects up to 1% of live births. Although a genetic etiology is indicated by an increased recurrence risk, sporadic occurrence suggests that CHD genetics is complex. Here, we show that hypoplastic left heart syndrome (HLHS), a severe CHD, is multigenic and genetically heterogeneous. Using mouse forward genetics, we report what is, to our knowledge, the first isolation of HLHS mutant mice and identification of genes causing HLHS. Mutations from seven HLHS mouse lines showed multigenic enrichment in ten human chromosome regions linked to HLHS...
May 22, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28530677/whole-genome-resequencing-of-292-pigeonpea-accessions-identifies-genomic-regions-associated-with-domestication-and-agronomic-traits
#2
Rajeev K Varshney, Rachit K Saxena, Hari D Upadhyaya, Aamir W Khan, Yue Yu, Changhoon Kim, Abhishek Rathore, Dongseon Kim, Jihun Kim, Shaun An, Vinay Kumar, Ghanta Anuradha, Kalinati Narasimhan Yamini, Wei Zhang, Sonnappa Muniswamy, Jong-So Kim, R Varma Penmetsa, Eric von Wettberg, Swapan K Datta
Pigeonpea (Cajanus cajan), a tropical grain legume with low input requirements, is expected to continue to have an important role in supplying food and nutritional security in developing countries in Asia, Africa and the tropical Americas. From whole-genome resequencing of 292 Cajanus accessions encompassing breeding lines, landraces and wild species, we characterize genome-wide variation. On the basis of a scan for selective sweeps, we find several genomic regions that were likely targets of domestication and breeding...
May 22, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28530676/mutations-in-dzip1l-which-encodes-a-ciliary-transition-zone-protein-cause-autosomal-recessive-polycystic-kidney-disease
#3
Hao Lu, Maria C Rondón Galeano, Elisabeth Ott, Geraldine Kaeslin, P Jaya Kausalya, Carina Kramer, Nadina Ortiz-Brüchle, Nadescha Hilger, Vicki Metzis, Milan Hiersche, Shang Yew Tay, Robert Tunningley, Shubha Vij, Andrew D Courtney, Belinda Whittle, Elke Wühl, Udo Vester, Björn Hartleben, Steffen Neuber, Valeska Frank, Melissa H Little, Daniel Epting, Peter Papathanasiou, Andrew C Perkins, Graham D Wright, Walter Hunziker, Heon Yung Gee, Edgar A Otto, Klaus Zerres, Friedhelm Hildebrandt, Sudipto Roy, Carol Wicking, Carsten Bergmann
Autosomal recessive polycystic kidney disease (ARPKD), usually considered to be a genetically homogeneous disease caused by mutations in PKHD1, has been associated with ciliary dysfunction. Here, we describe mutations in DZIP1L, which encodes DAZ interacting protein 1-like, in patients with ARPKD. We further validated these findings through loss-of-function studies in mice and zebrafish. DZIP1L localizes to centrioles and to the distal ends of basal bodies, and interacts with septin2, a protein implicated in maintenance of the periciliary diffusion barrier at the ciliary transition zone...
May 22, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28530675/reevaluation-of-snp-heritability-in-complex-human-traits
#4
Doug Speed, Na Cai, Michael R Johnson, Sergey Nejentsev, David J Balding
SNP heritability, the proportion of phenotypic variance explained by SNPs, has been reported for many hundreds of traits. Its estimation requires strong prior assumptions about the distribution of heritability across the genome, but current assumptions have not been thoroughly tested. By analyzing imputed data for a large number of human traits, we empirically derive a model that more accurately describes how heritability varies with minor allele frequency (MAF), linkage disequilibrium (LD) and genotype certainty...
May 22, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28530674/fifteen-new-risk-loci-for-coronary-artery-disease-highlight-arterial-wall-specific-mechanisms
#5
Joanna M M Howson, Wei Zhao, Daniel R Barnes, Weang-Kee Ho, Robin Young, Dirk S Paul, Lindsay L Waite, Daniel F Freitag, Eric B Fauman, Elias L Salfati, Benjamin B Sun, John D Eicher, Andrew D Johnson, Wayne H H Sheu, Sune F Nielsen, Wei-Yu Lin, Praveen Surendran, Anders Malarstig, Jemma B Wilk, Anne Tybjærg-Hansen, Katrine L Rasmussen, Pia R Kamstrup, Panos Deloukas, Jeanette Erdmann, Sekar Kathiresan, Nilesh J Samani, Heribert Schunkert, Hugh Watkins, Ron Do, Daniel J Rader, Julie A Johnson, Stanley L Hazen, Arshed A Quyyumi, John A Spertus, Carl J Pepine, Nora Franceschini, Anne Justice, Alex P Reiner, Steven Buyske, Lucia A Hindorff, Cara L Carty, Kari E North, Charles Kooperberg, Eric Boerwinkle, Kristin Young, Mariaelisa Graff, Ulrike Peters, Devin Absher, Chao A Hsiung, Wen-Jane Lee, Kent D Taylor, Ying-Hsiang Chen, I-Te Lee, Xiuqing Guo, Ren-Hua Chung, Yi-Jen Hung, Jerome I Rotter, Jyh-Ming J Juang, Thomas Quertermous, Tzung-Dau Wang, Asif Rasheed, Philippe Frossard, Dewan S Alam, Abdulla Al Shafi Majumder, Emanuele Di Angelantonio, Rajiv Chowdhury, Yii-Der Ida Chen, Børge G Nordestgaard, Themistocles L Assimes, John Danesh, Adam S Butterworth, Danish Saleheen
Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls...
May 22, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28530673/genome-wide-association-meta-analysis-of-78-308-individuals-identifies-new-loci-and-genes-influencing-human-intelligence
#6
Suzanne Sniekers, Sven Stringer, Kyoko Watanabe, Philip R Jansen, Jonathan R I Coleman, Eva Krapohl, Erdogan Taskesen, Anke R Hammerschlag, Aysu Okbay, Delilah Zabaneh, Najaf Amin, Gerome Breen, David Cesarini, Christopher F Chabris, William G Iacono, M Arfan Ikram, Magnus Johannesson, Philipp Koellinger, James J Lee, Patrik K E Magnusson, Matt McGue, Mike B Miller, William E R Ollier, Antony Payton, Neil Pendleton, Robert Plomin, Cornelius A Rietveld, Henning Tiemeier, Cornelia M van Duijn, Danielle Posthuma
Intelligence is associated with important economic and health-related life outcomes. Despite intelligence having substantial heritability (0.54) and a confirmed polygenic nature, initial genetic studies were mostly underpowered. Here we report a meta-analysis for intelligence of 78,308 individuals. We identify 336 associated SNPs (METAL P < 5 × 10(-8)) in 18 genomic loci, of which 15 are new. Around half of the SNPs are located inside a gene, implicating 22 genes, of which 11 are new findings. Gene-based analyses identified an additional 30 genes (MAGMA P < 2...
May 22, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28504703/polygenic-transmission-disequilibrium-confirms-that-common-and-rare-variation-act-additively-to-create-risk-for-autism-spectrum-disorders
#7
Daniel J Weiner, Emilie M Wigdor, Stephan Ripke, Raymond K Walters, Jack A Kosmicki, Jakob Grove, Kaitlin E Samocha, Jacqueline I Goldstein, Aysu Okbay, Jonas Bybjerg-Grauholm, Thomas Werge, David M Hougaard, Jacob Taylor, David Skuse, Bernie Devlin, Richard Anney, Stephan J Sanders, Somer Bishop, Preben Bo Mortensen, Anders D Børglum, George Davey Smith, Mark J Daly, Elise B Robinson
Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD...
May 15, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28504702/pgbd5-promotes-site-specific-oncogenic-mutations-in-human-tumors
#8
Anton G Henssen, Richard Koche, Jiali Zhuang, Eileen Jiang, Casie Reed, Amy Eisenberg, Eric Still, Ian C MacArthur, Elias Rodríguez-Fos, Santiago Gonzalez, Montserrat Puiggròs, Andrew N Blackford, Christopher E Mason, Elisa de Stanchina, Mithat Gönen, Anne-Katrin Emde, Minita Shah, Kanika Arora, Catherine Reeves, Nicholas D Socci, Elizabeth Perlman, Cristina R Antonescu, Charles W M Roberts, Hanno Steen, Elizabeth Mullen, Stephen P Jackson, David Torrents, Zhiping Weng, Scott A Armstrong, Alex Kentsis
Genomic rearrangements are a hallmark of human cancers. Here, we identify the piggyBac transposable element derived 5 (PGBD5) gene as encoding an active DNA transposase expressed in the majority of childhood solid tumors, including lethal rhabdoid tumors. Using assembly-based whole-genome DNA sequencing, we found previously undefined genomic rearrangements in human rhabdoid tumors. These rearrangements involved PGBD5-specific signal (PSS) sequences at their breakpoints and recurrently inactivated tumor-suppressor genes...
May 15, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28504701/paused-rna-polymerase-ii-inhibits-new-transcriptional-initiation
#9
Wanqing Shao, Julia Zeitlinger
RNA polymerase II (Pol II) pauses downstream of the transcription initiation site before beginning productive elongation. This pause is a key component of metazoan gene expression regulation. Some promoters have a strong disposition for Pol II pausing and often mediate faster, more synchronous changes in expression. This requires multiple rounds of transcription and thus cannot rely solely on pause release. However, it is unclear how pausing affects the initiation of new transcripts during consecutive rounds of transcription...
May 15, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28504700/lineage-specific-functions-of-tet1-in-the-postimplantation-mouse-embryo
#10
Rita Khoueiry, Abhishek Sohni, Bernard Thienpont, Xinlong Luo, Joris Vande Velde, Michela Bartoccetti, Bram Boeckx, An Zwijsen, Anjana Rao, Diether Lambrechts, Kian Peng Koh
The mammalian TET enzymes catalyze DNA demethylation. While they have been intensely studied as major epigenetic regulators, little is known about their physiological roles and the extent of functional redundancy following embryo implantation. Here we define non-redundant roles for TET1 at an early postimplantation stage of the mouse embryo, when its paralogs Tet2 and Tet3 are not detectably expressed. TET1 regulates numerous genes defining differentiation programs in the epiblast and extraembryonic ectoderm...
May 15, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28481342/recurrent-noncoding-regulatory-mutations-in-pancreatic-ductal-adenocarcinoma
#11
Michael E Feigin, Tyler Garvin, Peter Bailey, Nicola Waddell, David K Chang, David R Kelley, Shimin Shuai, Steven Gallinger, John D McPherson, Sean M Grimmond, Ekta Khurana, Lincoln D Stein, Andrew V Biankin, Michael C Schatz, David A Tuveson
The contributions of coding mutations to tumorigenesis are relatively well known; however, little is known about somatic alterations in noncoding DNA. Here we describe GECCO (Genomic Enrichment Computational Clustering Operation) to analyze somatic noncoding alterations in 308 pancreatic ductal adenocarcinomas (PDAs) and identify commonly mutated regulatory regions. We find recurrent noncoding mutations to be enriched in PDA pathways, including axon guidance and cell adhesion, and newly identified processes, including transcription and homeobox genes...
June 2017: Nature Genetics
https://www.readbyqxmd.com/read/28481341/genome-sequencing-and-population-genomic-analyses-provide-insights-into-the-adaptive-landscape-of-silver-birch
#12
Jarkko Salojärvi, Olli-Pekka Smolander, Kaisa Nieminen, Sitaram Rajaraman, Omid Safronov, Pezhman Safdari, Airi Lamminmäki, Juha Immanen, Tianying Lan, Jaakko Tanskanen, Pasi Rastas, Ali Amiryousefi, Balamuralikrishna Jayaprakash, Juhana I Kammonen, Risto Hagqvist, Gugan Eswaran, Viivi Helena Ahonen, Juan Alonso Serra, Fred O Asiegbu, Juan de Dios Barajas-Lopez, Daniel Blande, Olga Blokhina, Tiina Blomster, Suvi Broholm, Mikael Brosché, Fuqiang Cui, Chris Dardick, Sanna E Ehonen, Paula Elomaa, Sacha Escamez, Kurt V Fagerstedt, Hiroaki Fujii, Adrien Gauthier, Peter J Gollan, Pauliina Halimaa, Pekka I Heino, Kristiina Himanen, Courtney Hollender, Saijaliisa Kangasjärvi, Leila Kauppinen, Colin T Kelleher, Sari Kontunen-Soppela, J Patrik Koskinen, Andriy Kovalchuk, Sirpa O Kärenlampi, Anna K Kärkönen, Kean-Jin Lim, Johanna Leppälä, Lee Macpherson, Juha Mikola, Katriina Mouhu, Ari Pekka Mähönen, Ülo Niinemets, Elina Oksanen, Kirk Overmyer, E Tapio Palva, Leila Pazouki, Ville Pennanen, Tuula Puhakainen, Péter Poczai, Boy J H M Possen, Matleena Punkkinen, Moona M Rahikainen, Matti Rousi, Raili Ruonala, Christiaan van der Schoot, Alexey Shapiguzov, Maija Sierla, Timo P Sipilä, Suvi Sutela, Teemu H Teeri, Arja I Tervahauta, Aleksia Vaattovaara, Jorma Vahala, Lidia Vetchinnikova, Annikki Welling, Michael Wrzaczek, Enjun Xu, Lars G Paulin, Alan H Schulman, Martin Lascoux, Victor A Albert, Petri Auvinen, Ykä Helariutta, Jaakko Kangasjärvi
Silver birch (Betula pendula) is a pioneer boreal tree that can be induced to flower within 1 year. Its rapid life cycle, small (440-Mb) genome, and advanced germplasm resources make birch an attractive model for forest biotechnology. We assembled and chromosomally anchored the nuclear genome of an inbred B. pendula individual. Gene duplicates from the paleohexaploid event were enriched for transcriptional regulation, whereas tandem duplicates were overrepresented by environmental responses. Population resequencing of 80 individuals showed effective population size crashes at major points of climatic upheaval...
June 2017: Nature Genetics
https://www.readbyqxmd.com/read/28481340/widespread-adenine-n6-methylation-of-active-genes-in-fungi
#13
Stephen J Mondo, Richard O Dannebaum, Rita C Kuo, Katherine B Louie, Adam J Bewick, Kurt LaButti, Sajeet Haridas, Alan Kuo, Asaf Salamov, Steven R Ahrendt, Rebecca Lau, Benjamin P Bowen, Anna Lipzen, William Sullivan, Bill B Andreopoulos, Alicia Clum, Erika Lindquist, Christopher Daum, Trent R Northen, Govindarajan Kunde-Ramamoorthy, Robert J Schmitz, Andrii Gryganskyi, David Culley, Jon Magnuson, Timothy Y James, Michelle A O'Malley, Jason E Stajich, Joseph W Spatafora, Axel Visel, Igor V Grigoriev
N6-methyldeoxyadenine (6mA) is a noncanonical DNA base modification present at low levels in plant and animal genomes, but its prevalence and association with genome function in other eukaryotic lineages remains poorly understood. Here we report that abundant 6mA is associated with transcriptionally active genes in early-diverging fungal lineages. Using single-molecule long-read sequencing of 16 diverse fungal genomes, we observed that up to 2.8% of all adenines were methylated in early-diverging fungi, far exceeding levels observed in other eukaryotes and more derived fungi...
June 2017: Nature Genetics
https://www.readbyqxmd.com/read/28459457/conserved-roles-of-mouse-dux-and-human-dux4-in-activating-cleavage-stage-genes-and-mervl-hervl-retrotransposons
#14
Peter G Hendrickson, Jessie A Doráis, Edward J Grow, Jennifer L Whiddon, Jong-Won Lim, Candice L Wike, Bradley D Weaver, Christian Pflueger, Benjamin R Emery, Aaron L Wilcox, David A Nix, C Matthew Peterson, Stephen J Tapscott, Douglas T Carrell, Bradley R Cairns
To better understand transcriptional regulation during human oogenesis and preimplantation development, we defined stage-specific transcription, which highlighted the cleavage stage as being highly distinctive. Here, we present multiple lines of evidence that a eutherian-specific multicopy retrogene, DUX4, encodes a transcription factor that activates hundreds of endogenous genes (for example, ZSCAN4, KDM4E and PRAMEF-family genes) and retroviral elements (MERVL/HERVL family) that define the cleavage-specific transcriptional programs in humans and mice...
June 2017: Nature Genetics
https://www.readbyqxmd.com/read/28459456/dux-family-transcription-factors-regulate-zygotic-genome-activation-in-placental-mammals
#15
Alberto De Iaco, Evarist Planet, Andrea Coluccio, Sonia Verp, Julien Duc, Didier Trono
In animal embryos, transcription is mostly silent for several cell divisions, until the release of the first major wave of embryonic transcripts through so-called zygotic genome activation (ZGA). Maternally provided ZGA-triggering factors have been identified in Drosophila melanogaster and Danio rerio, but their mammalian homologs are still undefined. Here, we provide evidence that the DUX family of transcription factors is essential to this process in mice and potentially in humans. First, human DUX4 and mouse Dux are both expressed before ZGA in their respective species...
June 2017: Nature Genetics
https://www.readbyqxmd.com/read/28459455/dna-sequence-homology-induces-cytosine-to-thymine-mutation-by-a-heterochromatin-related-pathway-in-neurospora
#16
Eugene Gladyshev, Nancy Kleckner
Most eukaryotic genomes contain substantial amounts of repetitive DNA organized in the form of constitutive heterochromatin and associated with repressive epigenetic modifications, such as H3K9me3 and C5 cytosine methylation (5mC). In the fungus Neurospora crassa, H3K9me3 and 5mC are catalyzed, respectively, by a conserved SUV39 histone methyltransferase, DIM-5, and a DNMT1-like cytosine methyltransferase, DIM-2. Here we show that DIM-2 can also mediate repeat-induced point mutation (RIP) of repetitive DNA in N...
June 2017: Nature Genetics
https://www.readbyqxmd.com/read/28459454/conservation-and-innovation-in-the-dux4-family-gene-network
#17
Jennifer L Whiddon, Ashlee T Langford, Chao-Jen Wong, Jun Wen Zhong, Stephen J Tapscott
Facioscapulohumeral dystrophy (FSHD; MIM158900, MIM158901) is caused by misexpression of the DUX4 transcription factor in skeletal muscle. Animal models of FSHD are hindered by incomplete knowledge regarding the conservation of the DUX4 transcriptional program in other species. Despite the divergence of their binding motifs, both mouse DUX and human DUX4 in mouse and human muscle cells, respectively, activate genes associated with cleavage-stage embryos, including MERVL and ERVL-MaLR retrotransposons. We found that human DUX4 expressed in mouse cells maintained modest activation of cleavage-stage genes driven by conventional promoters but did not activate MERVL-promoted genes...
June 2017: Nature Genetics
https://www.readbyqxmd.com/read/28459453/the-nephila-clavipes-genome-highlights-the-diversity-of-spider-silk-genes-and-their-complex-expression
#18
Paul L Babb, Nicholas F Lahens, Sandra M Correa-Garhwal, David N Nicholson, Eun Ji Kim, John B Hogenesch, Matjaž Kuntner, Linden Higgins, Cheryl Y Hayashi, Ingi Agnarsson, Benjamin F Voight
Spider silks are the toughest known biological materials, yet are lightweight and virtually invisible to the human immune system, and they thus have revolutionary potential for medicine and industry. Spider silks are largely composed of spidroins, a unique family of structural proteins. To investigate spidroin genes systematically, we constructed the first genome of an orb-weaving spider: the golden orb-weaver (Nephila clavipes), which builds large webs using an extensive repertoire of silks with diverse physical properties...
June 2017: Nature Genetics
https://www.readbyqxmd.com/read/28436987/genomic-consequences-of-aberrant-dna-repair-mechanisms-stratify-ovarian-cancer-histotypes
#19
Yi Kan Wang, Ali Bashashati, Michael S Anglesio, Dawn R Cochrane, Diljot S Grewal, Gavin Ha, Andrew McPherson, Hugo M Horlings, Janine Senz, Leah M Prentice, Anthony N Karnezis, Daniel Lai, Mohamed R Aniba, Allen W Zhang, Karey Shumansky, Celia Siu, Adrian Wan, Melissa K McConechy, Hector Li-Chang, Alicia Tone, Diane Provencher, Manon de Ladurantaye, Hubert Fleury, Aikou Okamoto, Satoshi Yanagida, Nozomu Yanaihara, Misato Saito, Andrew J Mungall, Richard Moore, Marco A Marra, C Blake Gilks, Anne-Marie Mes-Masson, Jessica N McAlpine, Samuel Aparicio, David G Huntsman, Sohrab P Shah
We studied the whole-genome point mutation and structural variation patterns of 133 tumors (59 high-grade serous (HGSC), 35 clear cell (CCOC), 29 endometrioid (ENOC), and 10 adult granulosa cell (GCT)) as a substrate for class discovery in ovarian cancer. Ab initio clustering of integrated point mutation and structural variation signatures identified seven subgroups both between and within histotypes. Prevalence of foldback inversions identified a prognostically significant HGSC group associated with inferior survival...
June 2017: Nature Genetics
https://www.readbyqxmd.com/read/28436986/adiposity-amplifies-the-genetic-risk-of-fatty-liver-disease-conferred-by-multiple-loci
#20
Stefan Stender, Julia Kozlitina, Børge G Nordestgaard, Anne Tybjærg-Hansen, Helen H Hobbs, Jonathan C Cohen
Complex traits arise from the interplay between genetic and environmental factors. The actions of these factors usually appear to be additive, and few compelling examples of gene-environment synergy have been documented. Here we show that adiposity significantly amplifies the effect of three sequence variants (encoding PNPLA3 p.I148M, TM6SF2 p.E167K, and GCKR p.P446L) associated with nonalcoholic fatty liver disease (NAFLD). Synergy between adiposity and genotype promoted the full spectrum of NAFLD, from steatosis to hepatic inflammation to cirrhosis...
June 2017: Nature Genetics
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