Association Weight Matrix for the Genetic Dissection of Puberty in Beef Cattle
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PARSANA-DISSERTATION-2020.Pdf
DECIPHERING TRANSCRIPTIONAL PATTERNS OF GENE REGULATION: A COMPUTATIONAL APPROACH by Princy Parsana A dissertation submitted to The Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland July, 2020 © 2020 Princy Parsana All rights reserved Abstract With rapid advancements in sequencing technology, we now have the ability to sequence the entire human genome, and to quantify expression of tens of thousands of genes from hundreds of individuals. This provides an extraordinary opportunity to learn phenotype relevant genomic patterns that can improve our understanding of molecular and cellular processes underlying a trait. The high dimensional nature of genomic data presents a range of computational and statistical challenges. This dissertation presents a compilation of projects that were driven by the motivation to efficiently capture gene regulatory patterns in the human transcriptome, while addressing statistical and computational challenges that accompany this data. We attempt to address two major difficulties in this domain: a) artifacts and noise in transcriptomic data, andb) limited statistical power. First, we present our work on investigating the effect of artifactual variation in gene expression data and its impact on trans-eQTL discovery. Here we performed an in-depth analysis of diverse pre-recorded covariates and latent confounders to understand their contribution to heterogeneity in gene expression measurements. Next, we discovered 673 trans-eQTLs across 16 human tissues using v6 data from the Genotype Tissue Expression (GTEx) project. Finally, we characterized two trait-associated trans-eQTLs; one in Skeletal Muscle and another in Thyroid. Second, we present a principal component based residualization method to correct gene expression measurements prior to reconstruction of co-expression networks. -
Mouse Spock1 Knockout Project (CRISPR/Cas9)
https://www.alphaknockout.com Mouse Spock1 Knockout Project (CRISPR/Cas9) Objective: To create a Spock1 knockout Mouse model (C57BL/6J) by CRISPR/Cas-mediated genome engineering. Strategy summary: The Spock1 gene (NCBI Reference Sequence: NM_009262 ; Ensembl: ENSMUSG00000056222 ) is located on Mouse chromosome 13. 12 exons are identified, with the ATG start codon in exon 2 and the TAG stop codon in exon 12 (Transcript: ENSMUST00000185502). Exon 5 will be selected as target site. Cas9 and gRNA will be co-injected into fertilized eggs for KO Mouse production. The pups will be genotyped by PCR followed by sequencing analysis. Note: Mice homozygous for a targeted null mutation display no obvious morphological or behavioral abnormalities, are fertile, and have normal life spans. Adult homozygotes exhibit normal brain morphology and EEG recordings. Exon 5 starts from about 18.25% of the coding region. Exon 5 covers 8.67% of the coding region. The size of effective KO region: ~115 bp. The KO 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 5 12 Legends Exon of mouse Spock1 Knockout region Page 2 of 8 https://www.alphaknockout.com Overview of the Dot Plot (up) Window size: 15 bp Forward Reverse Complement Sequence 12 Note: The 2000 bp section upstream of Exon 5 is aligned with itself to determine if there are tandem repeats. Tandem repeats are found in the dot plot matrix. The gRNA site is selected outside of these tandem repeats. -
Searching the Genomes of Inbred Mouse Strains for Incompatibilities That Reproductively Isolate Their Wild Relatives
Journal of Heredity 2007:98(2):115–122 ª The American Genetic Association. 2007. All rights reserved. doi:10.1093/jhered/esl064 For permissions, please email: [email protected]. Advance Access publication January 5, 2007 Searching the Genomes of Inbred Mouse Strains for Incompatibilities That Reproductively Isolate Their Wild Relatives BRET A. PAYSEUR AND MICHAEL PLACE From the Laboratory of Genetics, University of Wisconsin, Madison, WI 53706. Address correspondence to the author at the address above, or e-mail: [email protected]. Abstract Identification of the genes that underlie reproductive isolation provides important insights into the process of speciation. According to the Dobzhansky–Muller model, these genes suffer disrupted interactions in hybrids due to independent di- vergence in separate populations. In hybrid populations, natural selection acts to remove the deleterious heterospecific com- binations that cause these functional disruptions. When selection is strong, this process can maintain multilocus associations, primarily between conspecific alleles, providing a signature that can be used to locate incompatibilities. We applied this logic to populations of house mice that were formed by hybridization involving two species that show partial reproductive isolation, Mus domesticus and Mus musculus. Using molecular markers likely to be informative about species ancestry, we scanned the genomes of 1) classical inbred strains and 2) recombinant inbred lines for pairs of loci that showed extreme linkage disequi- libria. By using the same set of markers, we identified a list of locus pairs that displayed similar patterns in both scans. These genomic regions may contain genes that contribute to reproductive isolation between M. domesticus and M. -
Absence of the ER Cation Channel TMEM38B/TRIC-B Disrupts Intracellular Calcium Homeostasis and Dysregulates Collagen Synthesis in Recessive Osteogenesis Imperfecta
RESEARCH ARTICLE Absence of the ER Cation Channel TMEM38B/TRIC-B Disrupts Intracellular Calcium Homeostasis and Dysregulates Collagen Synthesis in Recessive Osteogenesis Imperfecta Wayne A. Cabral1, Masaki Ishikawa2¤a, Matthias Garten3, Elena N. Makareeva4, Brandi M. Sargent1, MaryAnn Weis5, Aileen M. Barnes1, Emma A. Webb6,7, Nicholas J. Shaw7, Leena Ala-Kokko8, Felicitas L. Lacbawan9¤b, Wolfgang Högler6,7, Sergey Leikin4, Paul a11111 S. Blank3, Joshua Zimmerberg3, David R. Eyre5, Yoshihiko Yamada2, Joan C. Marini1* 1 Section on Heritable Disorders of Bone and Extracellular Matrix, NICHD, NIH, Bethesda, Maryland, United States of America, 2 Molecular Biology Section, NIDCR, NIH, Bethesda, Maryland, United States of America, 3 Section on Integrative Biophysics, NICHD, NIH, Bethesda, Maryland, United States of America, 4 Section on Physical Biochemistry, NICHD, NIH, Bethesda, Maryland, United States of America, 5 Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, Washington, United States of America, 6 School of Clinical and Experimental Medicine, Institute of Biomedical Research, OPEN ACCESS University of Birmingham, Birmingham, United Kingdom, 7 Department of Endocrinology and Diabetes, Birmingham Children’s Hospital, Birmingham, United Kingdom, 8 Connective Tissue Gene Tests, Allentown, Citation: Cabral WA, Ishikawa M, Garten M, Pennsylvania, United States of America, 9 Department of Medical Genetics, Children’s National Medical Makareeva EN, Sargent BM, Weis M, et al. (2016) Center, Washington D.C., United States of America Absence of the ER Cation Channel TMEM38B/TRIC- B Disrupts Intracellular Calcium Homeostasis and ¤a Current address: Department of Restorative Dentistry, Division of Operative Dentistry, Tohoku University, Dysregulates Collagen Synthesis in Recessive Graduate School of Dentistry, Sendai, Japan ¤ Osteogenesis Imperfecta. -
Association Weight Matrix for the Genetic Dissection of Puberty in Beef Cattle
Association weight matrix for the genetic dissection of puberty in beef cattle Marina R. S. Fortesa,b,c, Antonio Revertera,b, Yuandan Zhanga,d, Eliza Collisa,b, Shivashankar H. Nagarajb,NickN.Jonssona,c,e, Kishore C. Prayagaa,b,1, Wes Barrisa,b, and Rachel J. Hawkena,b,2 aCooperative Research Centre for Beef Genetic Technologies; bCommonwealth Scientific and Industrial Research Organization, division of Livestock Industries, Queensland Bioscience Precinct, Brisbane QLD 4067, Australia; cThe University of Queensland, School of Veterinary Science, Gatton QLD 4343, Australia; dAnimal Genetics and Breeding Unit, University of New England, Armidale NSW 2351, Australia; and eFaculty of Veterinary Medicine, University of Glasgow, Glasgow G61 1QH, United Kingdom Edited by George Seidel, Colorado State University, Fort Collins, CO, and approved June 21, 2010 (received for review February 23, 2010) We describe a systems biology approach for the genetic dissection tional data on traits related to puberty are available. For example, of complex traits based on applying gene network theory to the re- weight and condition score are often measured on occasions sults from genome-wide associations. The associations of single- throughout an animal’s development. Hence, understanding ge- nucleotide polymorphisms (SNP) that were individually associated netics of cattle puberty and its biology serves two purposes: as with a primary phenotype of interest, age at puberty in our study, a strategy to develop efficient livestock resources and as a model were explored across 22 related traits. Genomic regions were sur- for human biology. veyed for genes harboring the selected SNP. As a result, an asso- The focus of this work is to demonstrate a unique systems ap- ciation weight matrix (AWM) was constructed with as many rows proach, which we call an association weight matrix (AWM), ap- as genes and as many columns as traits. -
Downloaded from Refseq Database ( Duct Development (After E7.5), in Which Both Ducts Re
Roly et al. BMC Genomics (2020) 21:688 https://doi.org/10.1186/s12864-020-07106-8 RESEARCH ARTICLE Open Access Transcriptional landscape of the embryonic chicken Müllerian duct Zahida Yesmin Roly, Rasoul Godini, Martin A. Estermann, Andrew T. Major, Roger Pocock and Craig A. Smith* Abstract Background: Müllerian ducts are paired embryonic tubes that give rise to the female reproductive tract in vertebrates. Many disorders of female reproduction can be attributed to anomalies of Müllerian duct development. However, the molecular genetics of Müllerian duct formation is poorly understood and most disorders of duct development have unknown etiology. In this study, we describe for the first time the transcriptional landscape of the embryonic Müllerian duct, using the chicken embryo as a model system. RNA sequencing was conducted at 1 day intervals during duct formation to identify developmentally-regulated genes, validated by in situ hybridization. Results: This analysis detected hundreds of genes specifically up-regulated during duct morphogenesis. Gene ontology and pathway analysis revealed enrichment for developmental pathways associated with cell adhesion, cell migration and proliferation, ERK and WNT signaling, and, interestingly, axonal guidance. The latter included factors linked to neuronal cell migration or axonal outgrowth, such as Ephrin B2, netrin receptor, SLIT1 and class A semaphorins. A number of transcriptional modules were identified that centred around key hub genes specifying matrix-associated signaling factors; SPOCK1, HTRA3 and ADGRD1. Several novel regulators of the WNT and TFG-β signaling pathway were identified in Müllerian ducts, including APCDD1 and DKK1, BMP3 and TGFBI.A number of novel transcription factors were also identified, including OSR1, FOXE1, PRICKLE1, TSHZ3 and SMARCA2. -
Osteogenesis Imperfecta
Osteogenesis imperfecta Description Osteogenesis imperfecta (OI) is a group of genetic disorders that mainly affect the bones. The term "osteogenesis imperfecta" means imperfect bone formation. People with this condition have bones that break (fracture) easily, often from mild trauma or with no apparent cause. Multiple fractures are common, and in severe cases, can occur even before birth. Milder cases may involve only a few fractures over a person's lifetime. There are at least 19 recognized forms of osteogenesis imperfecta, designated type I through type XIX. Several types are distinguished by their signs and symptoms, although their characteristic features overlap. Increasingly, genetic causes are used to define rarer forms of osteogenesis imperfecta. Type I (also known as classic non- deforming osteogenesis imperfecta with blue sclerae) is the mildest form of osteogenesis imperfecta. Type II (also known as perinatally lethal osteogenesis imperfecta) is the most severe. Other types of this condition, including types III ( progressively deforming osteogenesis imperfecta) and IV (common variable osteogenesis imperfecta with normal sclerae), have signs and symptoms that fall somewhere between these two extremes. The milder forms of osteogenesis imperfecta, including type I, are characterized by bone fractures during childhood and adolescence that often result from minor trauma, such as falling while learning to walk. Fractures occur less frequently in adulthood. People with mild forms of the condition typically have a blue or grey tint to the part of the eye that is usually white (the sclera), and about half develop hearing loss in adulthood. Unlike more severely affected individuals, people with type I are usually of normal or near normal height. -
Blueprint Genetics Comprehensive Growth Disorders / Skeletal
Comprehensive Growth Disorders / Skeletal Dysplasias and Disorders Panel Test code: MA4301 Is a 374 gene panel that includes assessment of non-coding variants. This panel covers the majority of the genes listed in the Nosology 2015 (PMID: 26394607) and all genes in our Malformation category that cause growth retardation, short stature or skeletal dysplasia and is therefore a powerful diagnostic tool. It is ideal for patients suspected to have a syndromic or an isolated growth disorder or a skeletal dysplasia. About Comprehensive Growth Disorders / Skeletal Dysplasias and Disorders This panel covers a broad spectrum of diseases associated with growth retardation, short stature or skeletal dysplasia. Many of these conditions have overlapping features which can make clinical diagnosis a challenge. Genetic diagnostics is therefore the most efficient way to subtype the diseases and enable individualized treatment and management decisions. Moreover, detection of causative mutations establishes the mode of inheritance in the family which is essential for informed genetic counseling. For additional information regarding the conditions tested on this panel, please refer to the National Organization for Rare Disorders and / or GeneReviews. Availability 4 weeks Gene Set Description Genes in the Comprehensive Growth Disorders / Skeletal Dysplasias and Disorders Panel and their clinical significance Gene Associated phenotypes Inheritance ClinVar HGMD ACAN# Spondyloepimetaphyseal dysplasia, aggrecan type, AD/AR 20 56 Spondyloepiphyseal dysplasia, Kimberley -
Blueprint Genetics Comprehensive Skeletal Dysplasias and Disorders
Comprehensive Skeletal Dysplasias and Disorders Panel Test code: MA3301 Is a 251 gene panel that includes assessment of non-coding variants. Is ideal for patients with a clinical suspicion of disorders involving the skeletal system. About Comprehensive Skeletal Dysplasias and Disorders This panel covers a broad spectrum of skeletal disorders including common and rare skeletal dysplasias (eg. achondroplasia, COL2A1 related dysplasias, diastrophic dysplasia, various types of spondylo-metaphyseal dysplasias), various ciliopathies with skeletal involvement (eg. short rib-polydactylies, asphyxiating thoracic dysplasia dysplasias and Ellis-van Creveld syndrome), various subtypes of osteogenesis imperfecta, campomelic dysplasia, slender bone dysplasias, dysplasias with multiple joint dislocations, chondrodysplasia punctata group of disorders, neonatal osteosclerotic dysplasias, osteopetrosis and related disorders, abnormal mineralization group of disorders (eg hypopohosphatasia), osteolysis group of disorders, disorders with disorganized development of skeletal components, overgrowth syndromes with skeletal involvement, craniosynostosis syndromes, dysostoses with predominant craniofacial involvement, dysostoses with predominant vertebral involvement, patellar dysostoses, brachydactylies, some disorders with limb hypoplasia-reduction defects, ectrodactyly with and without other manifestations, polydactyly-syndactyly-triphalangism group of disorders, and disorders with defects in joint formation and synostoses. Availability 4 weeks Gene Set Description -
Absence of the ER Cation Channel TMEM38B/TRIC-B Disrupts
University of Birmingham Absence of the ER Cation Channel TMEM38B/TRIC- B Disrupts Intracellular Calcium Homeostasis and Dysregulates Collagen Synthesis in Recessive Osteogenesis Imperfecta Cabral, Wayne A; Ishikawa, Masaki; Garten, Matthias; Makareeva, Elena N; Sargent, Brandi M; Weis, MaryAnn; Barnes, Aileen M; Webb, Emma; Shaw, Nicholas J; Ala-Kokko, Leena; Lacbawan, Felicitas L; Hoegler, Wolfgang; Leikin, Sergey; Blank, Paul S; Zimmerberg, Joshua; Eyre, David R; Yamada, Yoshihiko; Marini, Joan C DOI: 10.1371/journal.pgen.1006156 License: Creative Commons: Public Domain Dedication Document Version Publisher's PDF, also known as Version of record Citation for published version (Harvard): Cabral, WA, Ishikawa, M, Garten, M, Makareeva, EN, Sargent, BM, Weis, M, Barnes, AM, Webb, E, Shaw, NJ, Ala-Kokko, L, Lacbawan, FL, Hoegler, W, Leikin, S, Blank, PS, Zimmerberg, J, Eyre, DR, Yamada, Y & Marini, JC 2016, 'Absence of the ER Cation Channel TMEM38B/TRIC-B Disrupts Intracellular Calcium Homeostasis and Dysregulates Collagen Synthesis in Recessive Osteogenesis Imperfecta', PLoS Genetics, vol. 12, no. 7. https://doi.org/10.1371/journal.pgen.1006156 Link to publication on Research at Birmingham portal Publisher Rights Statement: Checked for eligibility: 03/11/2016. Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Citation: Cabral WA, Ishikawa M, Garten M, Makareeva EN, Sargent BM, Weis M, et al. (2016) Absence of the ER Cation Channel TMEM38B/TRICB Disrupts Intracellular Calcium Homeostasis and Dysregulates Collagen Synthesis in Recessive Osteogenesis Imperfecta. -
Of Small Intestine Harboring Driver Gene Mutations: a Case Report and a Literature Review
1161 Case Report A rare multiple primary sarcomatoid carcinoma (SCA) of small intestine harboring driver gene mutations: a case report and a literature review Zhu Zhu1#, Xinyi Liu2#, Wenliang Li1, Zhengqi Wen1, Xiang Ji1, Ruize Zhou1, Xiaoyu Tuo3, Yaru Chen2, Xian Gong2, Guifeng Liu2, Yanqing Zhou2, Shifu Chen2, Lele Song2#^, Jian Huang1 1Department of Oncology, First Affiliated Hospital of Kunming Medical University, Kunming, China; 2HaploX Biotechnology, Shenzhen, China; 3Department of Pathology, First Affiliated Hospital of Kunming Medical University, Kunming, China #These authors contributed equally to this work. Correspondence to: Jian Huang. Department of Oncology, First Affiliated Hospital of Kunming Medical University, No. 295, Xichang Road, Kunming 560032, Yunnan Province, China. Email: [email protected]; Lele Song. HaploX Biotechnology, 8th floor, Auto Electric Power Building, Songpingshan Road, Nanshan District, Shenzhen 518057, Guangdong Province, China. Email: [email protected]. Abstract: Primary sarcomatoid carcinoma (SCA) is a type of rare tumor consisting of both malignant epithelial and mesenchymal components. Only 32 cases of SCA of the small bowel have been reported in the literature to date. Due to its rarity and complexity, this cancer has not been genetically studied and its diagnosis and treatment remain difficult. Here we report a 54-year-old male underwent emergency surgical resection in the small intestine due to severe obstruction and was diagnosed with multiple SCA based on postoperative pathological examination. Over 100 polypoid tumors scattered along his whole jejunum and proximal ileum. Chemotherapy (IFO+Epirubicin) was performed after surgery while the patient died two months after the surgery due to severe malnutrition. Whole-exome sequencing was performed for the tumor tissue with normal tissue as the control. -
Molecular and Cytogenetic Analysis of the Spreading of X Inactivation in a Girl with Microcephaly, Mild Dysmorphic Features and T(X;5)(Q22.1;Q31.1)
European Journal of Human Genetics (2008) 16, 897–905 & 2008 Nature Publishing Group All rights reserved 1018-4813/08 $30.00 www.nature.com/ejhg ARTICLE Molecular and cytogenetic analysis of the spreading of X inactivation in a girl with microcephaly, mild dysmorphic features and t(X;5)(q22.1;q31.1) Roberto Giorda*,1,7, M Clara Bonaglia2,7, Greta Milani1, Anna Baroncini3, Francesca Spada3, Silvana Beri1, Giorgia Menozzi4, Marianna Rusconi1 and Orsetta Zuffardi5,6 1Molecular Biology Laboratory, ‘E. Medea’ Scientific Institute, Bosisio Parini, Lecco, Italy; 2Cytogenetics Laboratory, ‘E. Medea’ Scientific Institute, Bosisio Parini, Lecco, Italy; 3UO Genetica Medica, AUSL Imola, Imola, Italy; 4Bioinformatic Laboratory, ‘E. Medea’ Scientific Institute, Bosisio Parini, Lecco, Italy; 5Biologia Generale e Genetica Medica, Universita` di Pavia, Pavia, Italy; 6IRCCS Policlinico San Matteo, Pavia, Italy X chromosome inactivation involves initiation, propagation, and maintenance of gene inactivation. Studies of replication pattern and timing in X;autosome translocations have suggested that X inactivation may spread to autosomal DNA. To examine this phenomenon at the molecular level, we have tested the transcriptional activity of a number of chromosome 5 loci in a female subject with microcephaly, mild dysmorphic features and 46,X,der(X)t(X;5)(q22.1;q31.1) karyotype. RT-PCR analysis of 20 transcribed sequences spanning 5q31.1-qter revealed that nine of them were not expressed in somatic cell hybrid clones carrying the translocated chromosome. However, eight genes were expressed and therefore escaped inactivation. This direct expression test demonstrates that spreading of inactivation from the X chromosome to the adjoining autosomal DNA was incomplete and ‘patchy’.