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  • 1
    Publication Date: 2010-03-26
    Description: Although pioneered by human geneticists as a potential solution to the challenging problem of finding the genetic basis of common human diseases, genome-wide association (GWA) studies have, owing to advances in genotyping and sequencing technology, become an obvious general approach for studying the genetics of natural variation and traits of agricultural importance. They are particularly useful when inbred lines are available, because once these lines have been genotyped they can be phenotyped multiple times, making it possible (as well as extremely cost effective) to study many different traits in many different environments, while replicating the phenotypic measurements to reduce environmental noise. Here we demonstrate the power of this approach by carrying out a GWA study of 107 phenotypes in Arabidopsis thaliana, a widely distributed, predominantly self-fertilizing model plant known to harbour considerable genetic variation for many adaptively important traits. Our results are dramatically different from those of human GWA studies, in that we identify many common alleles of major effect, but they are also, in many cases, harder to interpret because confounding by complex genetics and population structure make it difficult to distinguish true associations from false. However, a-priori candidates are significantly over-represented among these associations as well, making many of them excellent candidates for follow-up experiments. Our study demonstrates the feasibility of GWA studies in A. thaliana and suggests that the approach will be appropriate for many other organisms.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3023908/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3023908/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Atwell, Susanna -- Huang, Yu S -- Vilhjalmsson, Bjarni J -- Willems, Glenda -- Horton, Matthew -- Li, Yan -- Meng, Dazhe -- Platt, Alexander -- Tarone, Aaron M -- Hu, Tina T -- Jiang, Rong -- Muliyati, N Wayan -- Zhang, Xu -- Amer, Muhammad Ali -- Baxter, Ivan -- Brachi, Benjamin -- Chory, Joanne -- Dean, Caroline -- Debieu, Marilyne -- de Meaux, Juliette -- Ecker, Joseph R -- Faure, Nathalie -- Kniskern, Joel M -- Jones, Jonathan D G -- Michael, Todd -- Nemri, Adnane -- Roux, Fabrice -- Salt, David E -- Tang, Chunlao -- Todesco, Marco -- Traw, M Brian -- Weigel, Detlef -- Marjoram, Paul -- Borevitz, Justin O -- Bergelson, Joy -- Nordborg, Magnus -- GM057994/GM/NIGMS NIH HHS/ -- GM073822/GM/NIGMS NIH HHS/ -- GM078536/GM/NIGMS NIH HHS/ -- GM62932/GM/NIGMS NIH HHS/ -- P42ES007373/ES/NIEHS NIH HHS/ -- R01 GM057994/GM/NIGMS NIH HHS/ -- R01 GM057994-05A1/GM/NIGMS NIH HHS/ -- R01 GM062932/GM/NIGMS NIH HHS/ -- R01 GM062932-05/GM/NIGMS NIH HHS/ -- R01 GM073822/GM/NIGMS NIH HHS/ -- R01 GM073822-01A1/GM/NIGMS NIH HHS/ -- R01 GM078536-01A1/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Jun 3;465(7298):627-31. doi: 10.1038/nature08800. Epub 2010 Mar 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular and Computational Biology, University of Southern California, Los Angeles, California 90089, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20336072" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Arabidopsis/*classification/*genetics ; Arabidopsis Proteins/genetics ; Flowers/genetics ; Genes, Plant/genetics ; Genetic Loci/genetics ; Genome, Plant/*genetics ; *Genome-Wide Association Study ; Genotype ; Immunity, Innate/genetics ; Inbreeding ; *Phenotype ; Polymorphism, Single Nucleotide/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2014-07-11
    Description: Human pluripotent stem cells hold potential for regenerative medicine, but available cell types have significant limitations. Although embryonic stem cells (ES cells) from in vitro fertilized embryos (IVF ES cells) represent the 'gold standard', they are allogeneic to patients. Autologous induced pluripotent stem cells (iPS cells) are prone to epigenetic and transcriptional aberrations. To determine whether such abnormalities are intrinsic to somatic cell reprogramming or secondary to the reprogramming method, genetically matched sets of human IVF ES cells, iPS cells and nuclear transfer ES cells (NT ES cells) derived by somatic cell nuclear transfer (SCNT) were subjected to genome-wide analyses. Both NT ES cells and iPS cells derived from the same somatic cells contained comparable numbers of de novo copy number variations. In contrast, DNA methylation and transcriptome profiles of NT ES cells corresponded closely to those of IVF ES cells, whereas iPS cells differed and retained residual DNA methylation patterns typical of parental somatic cells. Thus, human somatic cells can be faithfully reprogrammed to pluripotency by SCNT and are therefore ideal for cell replacement therapies.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ma, Hong -- Morey, Robert -- O'Neil, Ryan C -- He, Yupeng -- Daughtry, Brittany -- Schultz, Matthew D -- Hariharan, Manoj -- Nery, Joseph R -- Castanon, Rosa -- Sabatini, Karen -- Thiagarajan, Rathi D -- Tachibana, Masahito -- Kang, Eunju -- Tippner-Hedges, Rebecca -- Ahmed, Riffat -- Gutierrez, Nuria Marti -- Van Dyken, Crystal -- Polat, Alim -- Sugawara, Atsushi -- Sparman, Michelle -- Gokhale, Sumita -- Amato, Paula -- Wolf, Don P -- Ecker, Joseph R -- Laurent, Louise C -- Mitalipov, Shoukhrat -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jul 10;511(7508):177-83. doi: 10.1038/nature13551. Epub 2014 Jul 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 Southwest Bond Avenue, Portland, Oregon 97239, USA [2] Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, 505 Northwest 185th Avenue, Beaverton, Oregon 97006, USA [3]. ; 1] Department of Reproductive Medicine, University of California, San Diego, Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, La Jolla, California 92037, USA [2]. ; 1] Genomic Analysis Laboratory, the Salk Institute for Biological Studies, La Jolla, California 92037, USA [2] Bioinformatics Program, University of California at San Diego, La Jolla, California 92093, USA. ; 1] Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 Southwest Bond Avenue, Portland, Oregon 97239, USA [2] Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, 505 Northwest 185th Avenue, Beaverton, Oregon 97006, USA. ; Genomic Analysis Laboratory, the Salk Institute for Biological Studies, La Jolla, California 92037, USA. ; Department of Reproductive Medicine, University of California, San Diego, Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, La Jolla, California 92037, USA. ; 1] Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, 505 Northwest 185th Avenue, Beaverton, Oregon 97006, USA [2] Department of Obstetrics and Gynecology, South Miyagi Medical Center, Shibata-gun, Miyagi 989-1253, Japan (M.T.); Department of Cell and Molecular Biology, Karolinska Institutet, SE-17177 Stockholm, Sweden (A.P.). ; Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, 505 Northwest 185th Avenue, Beaverton, Oregon 97006, USA. ; University Pathologists LLC, Boston University School of Medicine, Roger Williams Medical Center, Providence, Rhode Island 02118, USA. ; Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97239, USA. ; 1] Genomic Analysis Laboratory, the Salk Institute for Biological Studies, La Jolla, California 92037, USA [2] Howard Hughes Medical Institute, the Salk Institute for Biological Studies, La Jolla, California 92037, USA. ; 1] Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 Southwest Bond Avenue, Portland, Oregon 97239, USA [2] Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, 505 Northwest 185th Avenue, Beaverton, Oregon 97006, USA [3] Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97239, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25008523" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; *Cellular Reprogramming ; Chromosome Aberrations ; Chromosomes, Human, X/genetics/metabolism ; DNA Copy Number Variations ; DNA Methylation ; Genome-Wide Association Study ; Genomic Imprinting ; Humans ; Nuclear Transfer Techniques/standards ; Pluripotent Stem Cells/cytology/*metabolism ; Transcriptome
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2011-05-10
    Description: 5-hydroxymethylcytosine (5hmC) is a modified base present at low levels in diverse cell types in mammals. 5hmC is generated by the TET family of Fe(II) and 2-oxoglutarate-dependent enzymes through oxidation of 5-methylcytosine (5mC). 5hmC and TET proteins have been implicated in stem cell biology and cancer, but information on the genome-wide distribution of 5hmC is limited. Here we describe two novel and specific approaches to profile the genomic localization of 5hmC. The first approach, termed GLIB (glucosylation, periodate oxidation, biotinylation) uses a combination of enzymatic and chemical steps to isolate DNA fragments containing as few as a single 5hmC. The second approach involves conversion of 5hmC to cytosine 5-methylenesulphonate (CMS) by treatment of genomic DNA with sodium bisulphite, followed by immunoprecipitation of CMS-containing DNA with a specific antiserum to CMS. High-throughput sequencing of 5hmC-containing DNA from mouse embryonic stem (ES) cells showed strong enrichment within exons and near transcriptional start sites. 5hmC was especially enriched at the start sites of genes whose promoters bear dual histone 3 lysine 27 trimethylation (H3K27me3) and histone 3 lysine 4 trimethylation (H3K4me3) marks. Our results indicate that 5hmC has a probable role in transcriptional regulation, and suggest a model in which 5hmC contributes to the 'poised' chromatin signature found at developmentally-regulated genes in ES cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3124347/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3124347/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pastor, William A -- Pape, Utz J -- Huang, Yun -- Henderson, Hope R -- Lister, Ryan -- Ko, Myunggon -- McLoughlin, Erin M -- Brudno, Yevgeny -- Mahapatra, Sahasransu -- Kapranov, Philipp -- Tahiliani, Mamta -- Daley, George Q -- Liu, X Shirley -- Ecker, Joseph R -- Milos, Patrice M -- Agarwal, Suneet -- Rao, Anjana -- 1 R01 HD065812-01A1/HD/NICHD NIH HHS/ -- 1 UL1 RR 025758-02/RR/NCRR NIH HHS/ -- K08 HL089150/HL/NHLBI NIH HHS/ -- K08 HL089150-01A1/HL/NHLBI NIH HHS/ -- R01 AI044432/AI/NIAID NIH HHS/ -- R01 AI044432-10/AI/NIAID NIH HHS/ -- R01 AI44432/AI/NIAID NIH HHS/ -- R01 HD065812/HD/NICHD NIH HHS/ -- R01 HD065812-01A1/HD/NICHD NIH HHS/ -- RC1 DA028422/DA/NIDA NIH HHS/ -- RC1 DA028422-02/DA/NIDA NIH HHS/ -- UL1 RR025758/RR/NCRR NIH HHS/ -- England -- Nature. 2011 May 19;473(7347):394-7. doi: 10.1038/nature10102. Epub 2011 May 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Harvard Medical School, Immune Disease Institute and Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21552279" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biotinylation ; Cell Line ; Cytosine/*analogs & derivatives/analysis/isolation & purification/metabolism ; DNA Methylation ; Embryonic Stem Cells/*metabolism ; Exons/genetics ; Gene Expression Regulation, Developmental/genetics ; Genome/*genetics ; Glucose/metabolism ; Mice ; Periodic Acid/metabolism ; Promoter Regions, Genetic/genetics ; Sequence Analysis, DNA/*methods ; Transcription Initiation Site ; Transcription, Genetic/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2012-09-08
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ecker, Joseph R -- Bickmore, Wendy A -- Barroso, Ines -- Pritchard, Jonathan K -- Gilad, Yoav -- Segal, Eran -- England -- Nature. 2012 Sep 6;489(7414):52-5. doi: 10.1038/489052a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and the Salk Institute for Biological Studies, La Jolla, California 92037, USA. ecker@salk.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22955614" target="_blank"〉PubMed〈/a〉
    Keywords: Chromatin/genetics/metabolism ; DNA/*genetics ; DNA Methylation ; Deoxyribonuclease I/metabolism ; *Encyclopedias as Topic ; Evolution, Molecular ; Gene Expression Regulation/genetics ; Gene Regulatory Networks ; Genome, Human/*genetics ; *Genomics/trends ; Humans ; Interdisciplinary Communication ; *Molecular Sequence Annotation ; RNA, Untranslated/genetics ; Regulatory Sequences, Nucleic Acid/*genetics ; Sequence Analysis ; Transcription Factors/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2011-02-04
    Description: Induced pluripotent stem cells (iPSCs) offer immense potential for regenerative medicine and studies of disease and development. Somatic cell reprogramming involves epigenomic reconfiguration, conferring iPSCs with characteristics similar to embryonic stem (ES) cells. However, it remains unknown how complete the reestablishment of ES-cell-like DNA methylation patterns is throughout the genome. Here we report the first whole-genome profiles of DNA methylation at single-base resolution in five human iPSC lines, along with methylomes of ES cells, somatic cells, and differentiated iPSCs and ES cells. iPSCs show significant reprogramming variability, including somatic memory and aberrant reprogramming of DNA methylation. iPSCs share megabase-scale differentially methylated regions proximal to centromeres and telomeres that display incomplete reprogramming of non-CG methylation, and differences in CG methylation and histone modifications. Lastly, differentiation of iPSCs into trophoblast cells revealed that errors in reprogramming CG methylation are transmitted at a high frequency, providing an iPSC reprogramming signature that is maintained after differentiation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3100360/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3100360/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lister, Ryan -- Pelizzola, Mattia -- Kida, Yasuyuki S -- Hawkins, R David -- Nery, Joseph R -- Hon, Gary -- Antosiewicz-Bourget, Jessica -- O'Malley, Ronan -- Castanon, Rosa -- Klugman, Sarit -- Downes, Michael -- Yu, Ruth -- Stewart, Ron -- Ren, Bing -- Thomson, James A -- Evans, Ronald M -- Ecker, Joseph R -- 1U01ES017166-01/ES/NIEHS NIH HHS/ -- DK062434/DK/NIDDK NIH HHS/ -- P30 CA014195/CA/NCI NIH HHS/ -- U01 ES017166/ES/NIEHS NIH HHS/ -- U01 ES017166-01/ES/NIEHS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Mar 3;471(7336):68-73. doi: 10.1038/nature09798. Epub 2011 Feb 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21289626" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Differentiation/genetics ; Cell Line ; Cellular Reprogramming/*genetics ; CpG Islands/genetics ; DNA Methylation/*genetics ; Embryonic Stem Cells/cytology/metabolism ; Epigenomics ; Epistasis, Genetic/*genetics ; Fibroblasts/cytology/metabolism ; Genome, Human/*genetics ; Histones/metabolism ; Humans ; Induced Pluripotent Stem Cells/cytology/*metabolism ; Trophoblasts/cytology/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2013-03-08
    Description: Natural epigenetic variation provides a source for the generation of phenotypic diversity, but to understand its contribution to such diversity, its interaction with genetic variation requires further investigation. Here we report population-wide DNA sequencing of genomes, transcriptomes and methylomes of wild Arabidopsis thaliana accessions. Single cytosine methylation polymorphisms are not linked to genotype. However, the rate of linkage disequilibrium decay amongst differentially methylated regions targeted by RNA-directed DNA methylation is similar to the rate for single nucleotide polymorphisms. Association analyses of these RNA-directed DNA methylation regions with genetic variants identified thousands of methylation quantitative trait loci, which revealed the population estimate of genetically dependent methylation variation. Analysis of invariably methylated transposons and genes across this population indicates that loci targeted by RNA-directed DNA methylation are epigenetically activated in pollen and seeds, which facilitates proper development of these structures.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3798000/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3798000/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schmitz, Robert J -- Schultz, Matthew D -- Urich, Mark A -- Nery, Joseph R -- Pelizzola, Mattia -- Libiger, Ondrej -- Alix, Andrew -- McCosh, Richard B -- Chen, Huaming -- Schork, Nicholas J -- Ecker, Joseph R -- F32 HG004830/HG/NHGRI NIH HHS/ -- F32HG004830/HG/NHGRI NIH HHS/ -- K99 GM100000/GM/NIGMS NIH HHS/ -- K99GM100000/GM/NIGMS NIH HHS/ -- UL1 RR025774/RR/NCRR NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Mar 14;495(7440):193-8. doi: 10.1038/nature11968. Epub 2013 Mar 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Plant Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23467092" target="_blank"〉PubMed〈/a〉
    Keywords: Arabidopsis/*genetics ; DNA Methylation/genetics ; DNA Transposable Elements/genetics ; Epigenesis, Genetic/*genetics ; Epigenomics ; Genetic Variation/*genetics ; Genome, Plant/*genetics ; Linkage Disequilibrium/genetics ; Pollen/genetics ; Polymorphism, Genetic/genetics ; Quantitative Trait Loci ; RNA, Messenger/analysis/genetics ; RNA, Plant/genetics ; Seeds/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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