Screening for Intergenic Haplotype Stuctures Within Given Functional
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Analyses of Allele-Specific Gene Expression in Highly Divergent
ARTICLES Analyses of allele-specific gene expression in highly divergent mouse crosses identifies pervasive allelic imbalance James J Crowley1,10, Vasyl Zhabotynsky1,10, Wei Sun1,2,10, Shunping Huang3, Isa Kemal Pakatci3, Yunjung Kim1, Jeremy R Wang3, Andrew P Morgan1,4,5, John D Calaway1,4,5, David L Aylor1,9, Zaining Yun1, Timothy A Bell1,4,5, Ryan J Buus1,4,5, Mark E Calaway1,4,5, John P Didion1,4,5, Terry J Gooch1,4,5, Stephanie D Hansen1,4,5, Nashiya N Robinson1,4,5, Ginger D Shaw1,4,5, Jason S Spence1, Corey R Quackenbush1, Cordelia J Barrick1, Randal J Nonneman1, Kyungsu Kim2, James Xenakis2, Yuying Xie1, William Valdar1,4, Alan B Lenarcic1, Wei Wang3,9, Catherine E Welsh3, Chen-Ping Fu3, Zhaojun Zhang3, James Holt3, Zhishan Guo3, David W Threadgill6, Lisa M Tarantino7, Darla R Miller1,4,5, Fei Zou2,11, Leonard McMillan3,11, Patrick F Sullivan1,5,7,8,11 & Fernando Pardo-Manuel de Villena1,4,5,11 Complex human traits are influenced by variation in regulatory DNA through mechanisms that are not fully understood. Because regulatory elements are conserved between humans and mice, a thorough annotation of cis regulatory variants in mice could aid in further characterizing these mechanisms. Here we provide a detailed portrait of mouse gene expression across multiple tissues in a three-way diallel. Greater than 80% of mouse genes have cis regulatory variation. Effects from these variants influence complex traits and usually extend to the human ortholog. Further, we estimate that at least one in every thousand SNPs creates a cis regulatory effect. -
The Genetic Bases of Uterine Fibroids; a Review
Review Article The Genetic Bases of Uterine Fibroids; A Review Veronica Medikare 1, Lakshmi Rao Kandukuri 2, Venkateshwari Ananthapur 3, Mamata Deenadayal 4, Pratibha Nallari 1* 1- Department of Genetics, Osmania University, Hyderabad, India 2- Center for Cellular and Molecular Biology, Habsiguda, Hyderabad, India 3- Institute of Genetics and Hospital for Genetic Diseases, Begumpet, Hyderabad, India 4- Infertility Institute and research Center, Secunderabad, India Abstract Uterine leiomyomas/fibroids are the most common pelvic tumors of the female genital tract. The initiators remaining unknown, estrogens and progesterone are considered as promoters of fibroid growth. Fibroids are monoclonal tumors showing 40-50% karyo- typically detectable chromosomal abnormalities. Cytogenetic aberrations involving chromosomes 6, 7, 12 and 14 constitute the major chromosome abnormalities seen in leiomyomata. This has led to the discovery that disruptions or dysregulations of HMGIC and HMGIY genes contribute to the development of these tumors. Genes such as RAD51L1 act as translocation partners to HMGIC and lead to disruption of gene structure leading to the pathogenesis of uterine fibroids. The mechanism underlying * Corresponding Author: this disease is yet to be identified. The occurrence of PCOLCE amid a cluster of at Downloaded from http://www.jri.ir Pratibha Nallari, Department of Genetics, least eight Alu sequences is potentially relevant to the possible involvement of Osmania University, PCOLCE in the 7q22 rearrangements that occur in many leiomyomata. PCOLCE is Hyderabad, 500 007, implicated in cell growth processes. Involvement of Alu sequences in rearrangements India can lead to the disruption of this gene and, hence, loss of control for gene expression E-mail: leading to uncontrolled cell growth. -
Comparative Analysis of Human Chromosome 7Q21 and Mouse
Downloaded from genome.cshlp.org on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Letter Comparative analysis of human chromosome 7q21 and mouse proximal chromosome 6 reveals a placental-specific imprinted gene, TFPI2/Tfpi2, which requires EHMT2 and EED for allelic-silencing David Monk,1,6 Alexandre Wagschal,2 Philippe Arnaud,2 Pari-Sima Mu¨ller,3 Layla Parker-Katiraee,4 Déborah Bourc’his,5 Stephen W. Scherer,4 Robert Feil,2 Philip Stanier,1 and Gudrun E. Moore1 1Institute of Child Health, London WC1N 1EH, United Kingdom; 2Institute of Molecular Genetics, CNRS UMR-5535 and University of Montpellier-II, 34293 Montpellier, France; 3Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom; 4Center for Applied Genomics, The Hospital for Sick Children, Toronto M5G 1L7, Canada; 5Inserm U741, F-75251 Paris Cedex 05, France Genomic imprinting is a developmentally important mechanism that involves both differential DNA methylation and allelic histone modifications. Through detailed comparative characterization, a large imprinted domain mapping to chromosome 7q21 in humans and proximal chromosome 6 in mice was redefined. This domain is organized around a maternally methylated CpG island comprising the promoters of the adjacent PEG10 and SGCE imprinted genes. Examination of Dnmt3l−/+ conceptuses shows that imprinted expression for all genes of the cluster depends upon the germline methylation at this putative “imprinting control region” (ICR). Similarly as for other ICRs, we find its DNA-methylated allele to be associated with trimethylation of lysine 9 on histone H3 (H3K9me3) and trimethylation of lysine 20 on histone H4 (H4K20me3), whereas the transcriptionally active paternal allele is enriched in H3K4me2 and H3K9 acetylation. -
Homologous Recombination As a Potential Target for Ca€Eine
Oncogene (2000) 19, 5788 ± 5800 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc Homologous recombination as a potential target for caeine radiosensitization in mammalian cells: reduced caeine radiosensitization in XRCC2 and XRCC3 mutants Nesrin A Asaad1, Zhao-Chong Zeng1, Jun Guan1, John Thacker2 and George Iliakis*,1 1Department of Radiation Oncology of Kimmel Cancer Center, Jeerson Medical College, Philadelphia, Pennsylvania, PA 19107, USA; 2Medical Research Council, Radiation and Genome Stability Unit, Harwell, Oxfordshire, OX11 ORD, UK The radiosensitizing eect of caeine has been associated Introduction with the disruption of multiple DNA damage-responsive cell cycle checkpoints, but several lines of evidence also Caeine (1,3,7-trimethylxanthine) at submillimolar implicate inhibition of DNA repair. The role of DNA concentrations exerts a wide variety of physiological repair inhibition in caeine radiosensitization remains eects on dierent organisms from bacteria to man uncharacterized, and it is unknown which repair process, (Garattini, 1993; Timson, 1977). At higher concentra- or lesion, is aected. We show that a radiosensitive cell tions (0.5 ± 10 mM), it strongly enhances the cytotoxic line, mutant for the RAD51 homolog XRCC2 and eect of ionizing radiation and other physical or defective in homologous recombination repair (HRR), chemical agents that act by inducing damage in DNA displays signi®cantly diminished caeine radiosensitiza- (Kihlman, 1977; Murnane, 1995; Timson, 1977; tion that can be restored by expression of XRCC2. Waldren and Rasko, 1978). Radiosensitization is Despite the reduced radiosensitization, caeine eec- manifest at non-cytotoxic concentrations and therefore tively abrogates checkpoints in S and G2 phases in caeine is considered a model radiosensitizer. -
Mouse Ppp1r9a Conditional Knockout Project (CRISPR/Cas9)
https://www.alphaknockout.com Mouse Ppp1r9a Conditional Knockout Project (CRISPR/Cas9) Objective: To create a Ppp1r9a conditional knockout Mouse model (C57BL/6J) by CRISPR/Cas-mediated genome engineering. Strategy summary: The Ppp1r9a gene (NCBI Reference Sequence: NM_181595 ; Ensembl: ENSMUSG00000032827 ) is located on Mouse chromosome 6. 16 exons are identified, with the ATG start codon in exon 2 and the TGA stop codon in exon 16 (Transcript: ENSMUST00000035813). Exon 3 will be selected as conditional knockout region (cKO region). Deletion of this region should result in the loss of function of the Mouse Ppp1r9a gene. To engineer the targeting vector, homologous arms and cKO region will be generated by PCR using BAC clone RP23-2F8 as template. Cas9, gRNA and targeting vector will be co-injected into fertilized eggs for cKO Mouse production. The pups will be genotyped by PCR followed by sequencing analysis. Note: Mice homozygous for a knock-out allele exhibit defects in dopamine-mediated neuromodulation, deficient long-term potentiation at corticostriatal synapses, increased spontaneous excitatory post-synaptic current frequency, and enhanced locomotor activationin response to cocaine treatment. Exon 3 starts from about 42.59% of the coding region. The knockout of Exon 3 will result in frameshift of the gene. The size of intron 2 for 5'-loxP site insertion: 139091 bp, and the size of intron 3 for 3'-loxP site insertion: 11389 bp. The size of effective cKO region: ~633 bp. The cKO region does not have any other known gene. Page 1 of 8 https://www.alphaknockout.com Overview of the Targeting Strategy Wildtype allele gRNA region 5' gRNA region 3' 1 3 16 Targeting vector Targeted allele Constitutive KO allele (After Cre recombination) Legends Exon of mouse Ppp1r9a Homology arm cKO region loxP site Page 2 of 8 https://www.alphaknockout.com Overview of the Dot Plot Window size: 10 bp Forward Reverse Complement Sequence 12 Note: The sequence of homologous arms and cKO region is aligned with itself to determine if there are tandem repeats. -
Whole-Exome Sequencing of Metastatic Cancer and Biomarkers of Treatment Response
Supplementary Online Content Beltran H, Eng K, Mosquera JM, et al. Whole-exome sequencing of metastatic cancer and biomarkers of treatment response. JAMA Oncol. Published online May 28, 2015. doi:10.1001/jamaoncol.2015.1313 eMethods eFigure 1. A schematic of the IPM Computational Pipeline eFigure 2. Tumor purity analysis eFigure 3. Tumor purity estimates from Pathology team versus computationally (CLONET) estimated tumor purities values for frozen tumor specimens (Spearman correlation 0.2765327, p- value = 0.03561) eFigure 4. Sequencing metrics Fresh/frozen vs. FFPE tissue eFigure 5. Somatic copy number alteration profiles by tumor type at cytogenetic map location resolution; for each cytogenetic map location the mean genes aberration frequency is reported eFigure 6. The 20 most frequently aberrant genes with respect to copy number gains/losses detected per tumor type eFigure 7. Top 50 genes with focal and large scale copy number gains (A) and losses (B) across the cohort eFigure 8. Summary of total number of copy number alterations across PM tumors eFigure 9. An example of tumor evolution looking at serial biopsies from PM222, a patient with metastatic bladder carcinoma eFigure 10. PM12 somatic mutations by coverage and allele frequency (A) and (B) mutation correlation between primary (y- axis) and brain metastasis (x-axis) eFigure 11. Point mutations across 5 metastatic sites of a 55 year old patient with metastatic prostate cancer at time of rapid autopsy eFigure 12. CT scans from patient PM137, a patient with recurrent platinum refractory metastatic urothelial carcinoma eFigure 13. Tracking tumor genomics between primary and metastatic samples from patient PM12 eFigure 14. -
Detailed Characterization of Human Induced Pluripotent Stem Cells Manufactured for Therapeutic Applications
Stem Cell Rev and Rep DOI 10.1007/s12015-016-9662-8 Detailed Characterization of Human Induced Pluripotent Stem Cells Manufactured for Therapeutic Applications Behnam Ahmadian Baghbaderani 1 & Adhikarla Syama2 & Renuka Sivapatham3 & Ying Pei4 & Odity Mukherjee2 & Thomas Fellner1 & Xianmin Zeng3,4 & Mahendra S. Rao5,6 # The Author(s) 2016. This article is published with open access at Springerlink.com Abstract We have recently described manufacturing of hu- help determine which set of tests will be most useful in mon- man induced pluripotent stem cells (iPSC) master cell banks itoring the cells and establishing criteria for discarding a line. (MCB) generated by a clinically compliant process using cord blood as a starting material (Baghbaderani et al. in Stem Cell Keywords Induced pluripotent stem cells . Embryonic stem Reports, 5(4), 647–659, 2015). In this manuscript, we de- cells . Manufacturing . cGMP . Consent . Markers scribe the detailed characterization of the two iPSC clones generated using this process, including whole genome se- quencing (WGS), microarray, and comparative genomic hy- Introduction bridization (aCGH) single nucleotide polymorphism (SNP) analysis. We compare their profiles with a proposed calibra- Induced pluripotent stem cells (iPSCs) are akin to embryonic tion material and with a reporter subclone and lines made by a stem cells (ESC) [2] in their developmental potential, but dif- similar process from different donors. We believe that iPSCs fer from ESC in the starting cell used and the requirement of a are likely to be used to make multiple clinical products. We set of proteins to induce pluripotency [3]. Although function- further believe that the lines used as input material will be used ally identical, iPSCs may differ from ESC in subtle ways, at different sites and, given their immortal status, will be used including in their epigenetic profile, exposure to the environ- for many years or even decades. -
Mclean, Chelsea.Pdf
COMPUTATIONAL PREDICTION AND EXPERIMENTAL VALIDATION OF NOVEL MOUSE IMPRINTED GENES A Dissertation Presented to the Faculty of the Graduate School of Cornell University In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy by Chelsea Marie McLean August 2009 © 2009 Chelsea Marie McLean COMPUTATIONAL PREDICTION AND EXPERIMENTAL VALIDATION OF NOVEL MOUSE IMPRINTED GENES Chelsea Marie McLean, Ph.D. Cornell University 2009 Epigenetic modifications, including DNA methylation and covalent modifications to histone tails, are major contributors to the regulation of gene expression. These changes are reversible, yet can be stably inherited, and may last for multiple generations without change to the underlying DNA sequence. Genomic imprinting results in expression from one of the two parental alleles and is one example of epigenetic control of gene expression. So far, 60 to 100 imprinted genes have been identified in the human and mouse genomes, respectively. Identification of additional imprinted genes has become increasingly important with the realization that imprinting defects are associated with complex disorders ranging from obesity to diabetes and behavioral disorders. Despite the importance imprinted genes play in human health, few studies have undertaken genome-wide searches for new imprinted genes. These have used empirical approaches, with some success. However, computational prediction of novel imprinted genes has recently come to the forefront. I have developed generalized linear models using data on a variety of sequence and epigenetic features within a training set of known imprinted genes. The resulting models were used to predict novel imprinted genes in the mouse genome. After imposing a stringency threshold, I compiled an initial candidate list of 155 genes. -
Differential Expression of Thymic DNA Repair Genes in Low-Dose-Rate Irradiated AKR/J Mice
pISSN 1229-845X, eISSN 1976-555X JOURNAL OF J. Vet. Sci. (2013), 14(3), 271-279 http://dx.doi.org/10.4142/jvs.2013.14.3.271 Veterinary Received: 9 Mar. 2012, Revised: 19 Sep. 2012, Accepted: 23 Oct. 2012 Science Original Article Differential expression of thymic DNA repair genes in low-dose-rate irradiated AKR/J mice Jin Jong Bong1, Yu Mi Kang1, Suk Chul Shin1, Seung Jin Choi1, Kyung Mi Lee2,*, Hee Sun Kim1,* 1Radiation Health Research Institute, Korea Hydro and Nuclear Power, Seoul 132-703, Korea 2Global Research Lab, BAERI Institute, Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul 136-705, Korea We previously determined that AKR/J mice housed in a harmful to human life. For example, LDR irradiation low-dose-rate (LDR) (137Cs, 0.7 mGy/h, 2.1 Gy) γ-irradiation therapy for cancer is known to stimulate antioxidant facility developed less spontaneous thymic lymphoma and capacity, repair of DNA damage, apoptosis, and induction survived longer than those receiving sham or high-dose-rate of immune responses [4], and LDR irradiation has been (HDR) (137Cs, 0.8 Gy/min, 4.5 Gy) radiation. Interestingly, shown to mitigate lymphomagenesis and prolong the life histopathological analysis showed a mild lymphomagenesis in span of AKR/J mice [17,18]. Conversely, low-dose (LD) the thymus of LDR-irradiated mice. Therefore, in this study, we irradiation is reportedly involved in carcinogenesis, and LD investigated whether LDR irradiation could trigger the irradiation (lower than 2.0 Gy) has been shown to promote expression of thymic genes involved in the DNA repair process tumor growth and metastasis by enhancing angiogenesis of AKR/J mice. -
The Human Gene Connectome As a Map of Short Cuts for Morbid Allele Discovery
The human gene connectome as a map of short cuts for morbid allele discovery Yuval Itana,1, Shen-Ying Zhanga,b, Guillaume Vogta,b, Avinash Abhyankara, Melina Hermana, Patrick Nitschkec, Dror Friedd, Lluis Quintana-Murcie, Laurent Abela,b, and Jean-Laurent Casanovaa,b,f aSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065; bLaboratory of Human Genetics of Infectious Diseases, Necker Branch, Paris Descartes University, Institut National de la Santé et de la Recherche Médicale U980, Necker Medical School, 75015 Paris, France; cPlateforme Bioinformatique, Université Paris Descartes, 75116 Paris, France; dDepartment of Computer Science, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; eUnit of Human Evolutionary Genetics, Centre National de la Recherche Scientifique, Unité de Recherche Associée 3012, Institut Pasteur, F-75015 Paris, France; and fPediatric Immunology-Hematology Unit, Necker Hospital for Sick Children, 75015 Paris, France Edited* by Bruce Beutler, University of Texas Southwestern Medical Center, Dallas, TX, and approved February 15, 2013 (received for review October 19, 2012) High-throughput genomic data reveal thousands of gene variants to detect a single mutated gene, with the other polymorphic genes per patient, and it is often difficult to determine which of these being of less interest. This goes some way to explaining why, variants underlies disease in a given individual. However, at the despite the abundance of NGS data, the discovery of disease- population level, there may be some degree of phenotypic homo- causing alleles from such data remains somewhat limited. geneity, with alterations of specific physiological pathways under- We developed the human gene connectome (HGC) to over- come this problem. -
Integrated Analysis of Germline and Somatic Variants in Ovarian Cancer
ARTICLE Received 20 Sep 2013 | Accepted 19 Dec 2013 | Published 22 Jan 2014 DOI: 10.1038/ncomms4156 Integrated analysis of germline and somatic variants in ovarian cancer Krishna L. Kanchi1,*, Kimberly J. Johnson1,2,3,*, Charles Lu1,*, Michael D. McLellan1, Mark D.M. Leiserson4, Michael C. Wendl1,5,6, Qunyuan Zhang1,5, Daniel C. Koboldt1, Mingchao Xie1, Cyriac Kandoth1, Joshua F. McMichael1, Matthew A. Wyczalkowski1, David E. Larson1,5, Heather K. Schmidt1, Christopher A. Miller1, Robert S. Fulton1,5, Paul T. Spellman3, Elaine R. Mardis1,5,7, Todd E. Druley5,8, Timothy A. Graubert7,9, Paul J. Goodfellow10, Benjamin J. Raphael4, Richard K. Wilson1,5,7 & Li Ding1,5,7,9 We report the first large-scale exome-wide analysis of the combined germline–somatic landscape in ovarian cancer. Here we analyse germline and somatic alterations in 429 ovarian carcinoma cases and 557 controls. We identify 3,635 high confidence, rare truncation and 22,953 missense variants with predicted functional impact. We find germline truncation variants and large deletions across Fanconi pathway genes in 20% of cases. Enrichment of rare truncations is shown in BRCA1, BRCA2 and PALB2. In addition, we observe germline truncation variants in genes not previously associated with ovarian cancer susceptibility (NF1, MAP3K4, CDKN2B and MLL3). Evidence for loss of heterozygosity was found in 100 and 76% of cases with germline BRCA1 and BRCA2 truncations, respectively. Germline–somatic inter- action analysis combined with extensive bioinformatics annotation identifies 222 candidate functional germline truncation and missense variants, including two pathogenic BRCA1 and 1 TP53 deleterious variants. Finally, integrated analyses of germline and somatic variants identify significantly altered pathways, including the Fanconi, MAPK and MLL pathways. -
Decreased DNA Methylation at Promoters and Gene-Specific Neuronal
medRxiv preprint doi: https://doi.org/10.1101/2020.12.10.20246405; this version posted December 11, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Decreased DNA methylation at promoters and gene-specific neuronal hypermethylation in the prefrontal cortex of patients with bipolar disorder Miki Bundo1†, Junko Ueda1,2†, Yutaka Nakachi1, Kiyoto Kasai3,4, Tadafumi Kato2,5#, Kazuya Iwamoto1# 1Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University, Japan 2Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science, Japan 3Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Japan 4The International Research Center for Neurointelligence (WPI-IRCN) at The University of Tokyo Institutes for Advanced Study (UTIAS), 5Department of Psychiatry and Behavioral Science, Graduate School of Medicine, Juntendo University †contributed equally to this work #corresponding authors: Kazuya Iwamoto Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University. 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan [email protected] Tadadumi Kato Department of Psychiatry and Behavioral Science, Graduate School of Medicine, Juntendo University. 2-1-1 Hongo, Bunkyo, Tokyo 113-8421, Japan [email protected]. Running title: DNA methylation analysis in bipolar disorder 1 NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.12.10.20246405; this version posted December 11, 2020.