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Nature Genetics

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https://www.readbyqxmd.com/read/28319091/whole-genome-sequencing-identifies-rare-genotypes-in-comp-and-chadl-associated-with-high-risk-of-hip-osteoarthritis
#1
Unnur Styrkarsdottir, Hannes Helgason, Asgeir Sigurdsson, Gudmundur L Norddahl, Arna B Agustsdottir, Louise N Reynard, Amanda Villalvilla, Gisli H Halldorsson, Aslaug Jonasdottir, Audur Magnusdottir, Asmundur Oddson, Gerald Sulem, Florian Zink, Gardar Sveinbjornsson, Agnar Helgason, Hrefna S Johannsdottir, Anna Helgadottir, Hreinn Stefansson, Solveig Gretarsdottir, Thorunn Rafnar, Ina S Almdahl, Anne Brækhus, Tormod Fladby, Geir Selbæk, Farhad Hosseinpanah, Fereidoun Azizi, Jung Min Koh, Nelson L S Tang, Maryams Danesphour, Jose I Mayordomo, Corrine Welt, Peter S Braund, Nilesh J Samani, Lambertus A Kiemeney, L Stefan Lohmander, Claus Christiansen, Ole A Andreassen, Olafur Magnusson, Gisli Masson, Augustine Kong, Ingileif Jonsdottir, Daniel Gudbjartsson, Patrick Sulem, Helgi Jonsson, John Loughlin, Thorvaldur Ingvarsson, Unnur Thorsteinsdottir, Kari Stefansson
We performed a genome-wide association study of total hip replacements, based on variants identified through whole-genome sequencing, which included 4,657 Icelandic patients and 207,514 population controls. We discovered two rare signals that strongly associate with osteoarthritis total hip replacement: a missense variant, c.1141G>C (p.Asp369His), in the COMP gene (allelic frequency = 0.026%, P = 4.0 × 10(-12), odds ratio (OR) = 16.7) and a frameshift mutation, rs532464664 (p.Val330Glyfs*106), in the CHADL gene that associates through a recessive mode of inheritance (homozygote frequency = 0...
March 20, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28319090/a-single-copy-sleeping-beauty-transposon-mutagenesis-screen-identifies-new-pten-cooperating-tumor-suppressor-genes
#2
Jorge de la Rosa, Julia Weber, Mathias Josef Friedrich, Yilong Li, Lena Rad, Hannes Ponstingl, Qi Liang, Sandra Bernaldo de Quirós, Imran Noorani, Emmanouil Metzakopian, Alexander Strong, Meng Amy Li, Aurora Astudillo, María Teresa Fernández-García, María Soledad Fernández-García, Gary J Hoffman, Rocío Fuente, George S Vassiliou, Roland Rad, Carlos López-Otín, Allan Bradley, Juan Cadiñanos
The overwhelming number of genetic alterations identified through cancer genome sequencing requires complementary approaches to interpret their significance and interactions. Here we developed a novel whole-body insertional mutagenesis screen in mice, which was designed for the discovery of Pten-cooperating tumor suppressors. Toward this aim, we coupled mobilization of a single-copy inactivating Sleeping Beauty transposon to Pten disruption within the same genome. The analysis of 278 transposition-induced prostate, breast and skin tumors detected tissue-specific and shared data sets of known and candidate genes involved in cancer...
March 20, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28319089/natural-variation-at-the-soybean-j-locus-improves-adaptation-to-the-tropics-and-enhances-yield
#3
Sijia Lu, Xiaohui Zhao, Yilong Hu, Shulin Liu, Haiyang Nan, Xiaoming Li, Chao Fang, Dong Cao, Xinyi Shi, Lingping Kong, Tong Su, Fengge Zhang, Shichen Li, Zheng Wang, Xiaohui Yuan, Elroy R Cober, James L Weller, Baohui Liu, Xingliang Hou, Zhixi Tian, Fanjiang Kong
Soybean is a major legume crop originating in temperate regions, and photoperiod responsiveness is a key factor in its latitudinal adaptation. Varieties from temperate regions introduced to lower latitudes mature early and have extremely low grain yields. Introduction of the long-juvenile (LJ) trait extends the vegetative phase and improves yield under short-day conditions, thereby enabling expansion of cultivation in tropical regions. Here we report the cloning and characterization of J, the major classical locus conferring the LJ trait, and identify J as the ortholog of Arabidopsis thaliana EARLY FLOWERING 3 (ELF3)...
March 20, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28319088/reference-component-analysis-of-single-cell-transcriptomes-elucidates-cellular-heterogeneity-in-human-colorectal-tumors
#4
Huipeng Li, Elise T Courtois, Debarka Sengupta, Yuliana Tan, Kok Hao Chen, Jolene Jie Lin Goh, Say Li Kong, Clarinda Chua, Lim Kiat Hon, Wah Siew Tan, Mark Wong, Paul Jongjoon Choi, Lawrence J K Wee, Axel M Hillmer, Iain Beehuat Tan, Paul Robson, Shyam Prabhakar
Intratumoral heterogeneity is a major obstacle to cancer treatment and a significant confounding factor in bulk-tumor profiling. We performed an unbiased analysis of transcriptional heterogeneity in colorectal tumors and their microenvironments using single-cell RNA-seq from 11 primary colorectal tumors and matched normal mucosa. To robustly cluster single-cell transcriptomes, we developed reference component analysis (RCA), an algorithm that substantially improves clustering accuracy. Using RCA, we identified two distinct subtypes of cancer-associated fibroblasts (CAFs)...
March 20, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28288115/fast-scalable-prediction-of-deleterious-noncoding-variants-from-functional-and-population-genomic-data
#5
Yi-Fei Huang, Brad Gulko, Adam Siepel
Many genetic variants that influence phenotypes of interest are located outside of protein-coding genes, yet existing methods for identifying such variants have poor predictive power. Here we introduce a new computational method, called LINSIGHT, that substantially improves the prediction of noncoding nucleotide sites at which mutations are likely to have deleterious fitness consequences, and which, therefore, are likely to be phenotypically important. LINSIGHT combines a generalized linear model for functional genomic data with a probabilistic model of molecular evolution...
March 13, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28288114/disruption-of-the-atxn1-cic-complex-causes-a-spectrum-of-neurobehavioral-phenotypes-in-mice-and-humans
#6
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
Gain-of-function mutations in some genes underlie neurodegenerative conditions, whereas loss-of-function mutations in the same genes have distinct phenotypes. This appears to be the case with the protein ataxin 1 (ATXN1), which forms a transcriptional repressor complex with capicua (CIC). Gain of function of the complex leads to neurodegeneration, but ATXN1-CIC is also essential for survival. We set out to understand the functions of the ATXN1-CIC complex in the developing forebrain and found that losing this complex results in hyperactivity, impaired learning and memory, and abnormal maturation and maintenance of upper-layer cortical neurons...
March 13, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28288113/germline-mutations-in-abl1-cause-an-autosomal-dominant-syndrome-characterized-by-congenital-heart-defects-and-skeletal-malformations
#7
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
ABL1 is a proto-oncogene well known as part of the fusion gene BCR-ABL1 in the Philadelphia chromosome of leukemia cancer cells. Inherited germline ABL1 changes have not been associated with genetic disorders. Here we report ABL1 germline variants cosegregating with an autosomal dominant disorder characterized by congenital heart disease, skeletal abnormalities, and failure to thrive. The variant c.734A>G (p.Tyr245Cys) was found to occur de novo or cosegregate with disease in five individuals (families 1-3)...
March 13, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28288112/reconstructing-the-genome-of-the-most-recent-common-ancestor-of-flowering-plants
#8
Florent Murat, Alix Armero, Caroline Pont, Christophe Klopp, Jérôme Salse
We describe here the reconstruction of the genome of the most recent common ancestor (MRCA) of modern monocots and eudicots, accounting for 95% of extant angiosperms, with its potential repertoire of 22,899 ancestral genes conserved in present-day crops. The MRCA provides a starting point for deciphering the reticulated evolutionary plasticity between species (rapidly versus slowly evolving lineages), subgenomes (pre- versus post-duplication blocks), genomic compartments (stable versus labile loci), genes (ancestral versus species-specific genes) and functions (gained versus lost ontologies), the key mutational forces driving the success of polyploidy in crops...
March 13, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28263319/asymmetric-subgenome-selection-and-cis-regulatory-divergence-during-cotton-domestication
#9
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
Comparative population genomics offers an excellent opportunity for unraveling the genetic history of crop domestication. Upland cotton (Gossypium hirsutum) has long been an important economic crop, but a genome-wide and evolutionary understanding of the effects of human selection is lacking. Here, we describe a variation map for 352 wild and domesticated cotton accessions. We scanned 93 domestication sweeps occupying 74 Mb of the A subgenome and 104 Mb of the D subgenome, and identified 19 candidate loci for fiber-quality-related traits through a genome-wide association study...
March 6, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28263318/spatiotemporal-genomic-architecture-informs-precision-oncology-in-glioblastoma
#10
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
Precision medicine in cancer proposes that genomic characterization of tumors can inform personalized targeted therapies. However, this proposition is complicated by spatial and temporal heterogeneity. Here we study genomic and expression profiles across 127 multisector or longitudinal specimens from 52 individuals with glioblastoma (GBM). Using bulk and single-cell data, we find that samples from the same tumor mass share genomic and expression signatures, whereas geographically separated, multifocal tumors and/or long-term recurrent tumors are seeded from different clones...
March 6, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28263317/identification-of-methylation-haplotype-blocks-aids-in-deconvolution-of-heterogeneous-tissue-samples-and-tumor-tissue-of-origin-mapping-from-plasma-dna
#11
Shicheng Guo, Dinh Diep, Nongluk Plongthongkum, Ho-Lim Fung, Kang Zhang, Kun Zhang
Adjacent CpG sites in mammalian genomes can be co-methylated owing to the processivity of methyltransferases or demethylases, yet discordant methylation patterns have also been observed, which are related to stochastic or uncoordinated molecular processes. We focused on a systematic search and investigation of regions in the full human genome that show highly coordinated methylation. We defined 147,888 blocks of tightly coupled CpG sites, called methylation haplotype blocks, after analysis of 61 whole-genome bisulfite sequencing data sets and validation with 101 reduced-representation bisulfite sequencing data sets and 637 methylation array data sets...
March 6, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28263316/single-molecule-sequencing-and-chromatin-conformation-capture-enable-de-novo-reference-assembly-of-the-domestic-goat-genome
#12
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
The decrease in sequencing cost and increased sophistication of assembly algorithms for short-read platforms has resulted in a sharp increase in the number of species with genome assemblies. However, these assemblies are highly fragmented, with many gaps, ambiguities, and errors, impeding downstream applications. We demonstrate current state of the art for de novo assembly using the domestic goat (Capra hircus) based on long reads for contig formation, short reads for consensus validation, and scaffolding by optical and chromatin interaction mapping...
March 6, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28263315/whole-genome-sequencing-identifies-common-to-rare-variants-associated-with-human-blood-metabolites
#13
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
Genetic factors modifying the blood metabolome have been investigated through genome-wide association studies (GWAS) of common genetic variants and through exome sequencing. We conducted a whole-genome sequencing study of common, low-frequency and rare variants to associate genetic variations with blood metabolite levels using comprehensive metabolite profiling in 1,960 adults. We focused the analysis on 644 metabolites with consistent levels across three longitudinal data collections. Genetic sequence variations at 101 loci were associated with the levels of 246 (38%) metabolites (P ≤ 1...
March 6, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28250458/accounting-for-genetic-interactions-improves-modeling-of-individual-quantitative-trait-phenotypes-in-yeast
#14
Simon K G Forsberg, Joshua S Bloom, Meru J Sadhu, Leonid Kruglyak, Örjan Carlborg
Experiments in model organisms report abundant genetic interactions underlying biologically important traits, whereas quantitative genetics theory predicts, and data support, the notion that most genetic variance in populations is additive. Here we describe networks of capacitating genetic interactions that contribute to quantitative trait variation in a large yeast intercross population. The additive variance explained by individual loci in a network is highly dependent on the allele frequencies of the interacting loci...
February 27, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28250457/genome-wide-analyses-identify-common-variants-associated-with-macular-telangiectasia-type-2
#15
Thomas S Scerri, Anna Quaglieri, Carolyn Cai, Jana Zernant, Nori Matsunami, Lisa Baird, Lea Scheppke, Roberto Bonelli, Lawrence A Yannuzzi, Martin Friedlander, Catherine A Egan, Marcus Fruttiger, Mark Leppert, Rando Allikmets, Melanie Bahlo
Idiopathic juxtafoveal retinal telangiectasis type 2 (macular telangiectasia type 2; MacTel) is a rare neurovascular degenerative retinal disease. To identify genetic susceptibility loci for MacTel, we performed a genome-wide association study (GWAS) with 476 cases and 1,733 controls of European ancestry. Genome-wide significant associations (P < 5 × 10(-8)) were identified at three independent loci (rs73171800 at 5q14.3, P = 7.74 × 10(-17); rs715 at 2q34, P = 9.97 × 10(-14); rs477992 at 1p12, P = 2.60 × 10(-12)) and then replicated (P < 0...
February 27, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28250456/biallelic-mutations-in-human-dcc-cause-developmental-split-brain-syndrome
#16
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
Motor, sensory, and integrative activities of the brain are coordinated by a series of midline-bridging neuronal commissures whose development is tightly regulated. Here we report a new human syndrome in which these commissures are widely disrupted, thus causing clinical manifestations of horizontal gaze palsy, scoliosis, and intellectual disability. Affected individuals were found to possess biallelic loss-of-function mutations in the gene encoding the axon-guidance receptor 'deleted in colorectal carcinoma' (DCC), which has been implicated in congenital mirror movements when it is mutated in the heterozygous state but whose biallelic loss-of-function human phenotype has not been reported...
February 27, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28250455/diversity-in-non-repetitive-human-sequences-not-found-in-the-reference-genome
#17
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
Genomes usually contain some non-repetitive sequences that are missing from the reference genome and occur only in a population subset. Such non-repetitive, non-reference (NRNR) sequences have remained largely unexplored in terms of their characterization and downstream analyses. Here we describe 3,791 breakpoint-resolved NRNR sequence variants called using PopIns from whole-genome sequence data of 15,219 Icelanders. We found that over 95% of the 244 NRNR sequences that are 200 bp or longer are present in chimpanzees, indicating that they are ancestral...
February 27, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28250454/mutations-in-dcc-cause-isolated-agenesis-of-the-corpus-callosum-with-incomplete-penetrance
#18
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
Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual...
February 27, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28218759/limited-statistical-evidence-for-shared-genetic-effects-of-eqtls-and-autoimmune-disease-associated-loci-in-three-major-immune-cell-types
#19
Sung Chun, Alexandra Casparino, Nikolaos A Patsopoulos, Damien C Croteau-Chonka, Benjamin A Raby, Philip L De Jager, Shamil R Sunyaev, Chris Cotsapas
Most autoimmune-disease-risk effects identified by genome-wide association studies (GWAS) localize to open chromatin with gene-regulatory activity. GWAS loci are also enriched in expression quantitative trait loci (eQTLs), thus suggesting that most risk variants alter gene expression. However, because causal variants are difficult to identify, and cis-eQTLs occur frequently, it remains challenging to identify specific instances of disease-relevant changes to gene regulation. Here, we used a novel joint likelihood framework with higher resolution than that of previous methods to identify loci where autoimmune-disease risk and an eQTL are driven by a single shared genetic effect...
February 20, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28218758/variant-aware-saturating-mutagenesis-using-multiple-cas9-nucleases-identifies-regulatory-elements-at-trait-associated-loci
#20
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
Cas9-mediated, high-throughput, saturating in situ mutagenesis permits fine-mapping of function across genomic segments. Disease- and trait-associated variants identified in genome-wide association studies largely cluster at regulatory loci. Here we demonstrate the use of multiple designer nucleases and variant-aware library design to interrogate trait-associated regulatory DNA at high resolution. We developed a computational tool for the creation of saturating-mutagenesis libraries with single or multiple nucleases with incorporation of variants...
February 20, 2017: Nature Genetics
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