Genetic Heterogeneity of Diffuse Large B-Cell Lymphoma

Total Page:16

File Type:pdf, Size:1020Kb

Genetic Heterogeneity of Diffuse Large B-Cell Lymphoma Genetic heterogeneity of diffuse large B-cell lymphoma Jenny Zhanga,b,1, Vladimir Grubora,1, Cassandra L. Lovea, Anjishnu Banerjeec, Kristy L. Richardsd, Piotr A. Mieczkowskid, Cherie Dunphyd, William Choie, Wing Yan Aue, Gopesh Srivastavae, Patricia L. Lugarf, David A. Rizzierif, Anand S. Lagoof, Leon Bernal-Mizrachig, Karen P. Manng, Christopher Flowersg, Kikkeri Nareshh, Andrew Evensi, Leo I. Gordonj, Magdalena Czaderk, Javed I. Gilll, Eric D. Hsim, Qingquan Liua, Alice Fana, Katherine Walsha, Dereje Jimaa, Lisa L. Smithn, Amy J. Johnsonn, John C. Byrdn, Micah A. Luftigf, Ting Nio, Jun Zhuo, Amy Chadburnj, Shawn Levyp, David Dunsonc, and Sandeep S. Davea,b,f,2 aDuke Institute for Genome Sciences and Policy, bDuke Cancer Institute and Department of Medicine, and cDepartment of Statistical Science, Duke University, Durham, NC 27710; dUniversity of North Carolina at Chapel Hill, Chapel Hill, NC 27599; eThe University of Hong Kong, Queen Mary Hospital, Hong Kong, China; fDuke University Medical Center, Durham NC 27710; gEmory University, Atlanta GA 30322; hImperial College, London, United Kingdom; iUniversity of Massachusetts, Worcester, MA 01655; jNorthwestern University, Chicago IL 60208; kIndiana University, Indianapolis IN 46202; lBaylor University Medical Center, Dallas TX 75246; mCleveland Clinic, Cleveland, OH 44195; nDivision of Hematology and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210; oGenetics and Development Biology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892; and pHudson Alpha Institute for Biotechnology, Huntsville, AL 35806 Edited* by Elliott Kieff, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, and approved November 27, 2012 (received for review April 2, 2012) Diffuse large B-cell lymphoma (DLBCL) is the most common form Results of lymphoma in adults. The disease exhibits a striking heteroge- Sequencing of a Lymphoma Genome Uncovers the Spectrum of neity in gene expression profiles and clinical outcomes, but its Somatic Variation in DLBCL. Lymphoma biopsy tissue and unaf- genetic causes remain to be fully defined. Through whole genome fected bone marrow were obtained from the same patient. Using and exome sequencing, we characterized the genetic diversity of the Illumina platform, we generated at total of 171 Gb of 100 bp DLBCL. In all, we sequenced 73 DLBCL primary tumors (34 with paired-end sequences from the tumor and matched normal ge- matched normal DNA). Separately, we sequenced the exomes of nomes corresponding to an average per-base sequencing cover- fi 21 DLBCL cell lines. We identi ed 322 DLBCL cancer genes that age of 37-fold and 20-fold, respectively. GENETICS were recurrently mutated in primary DLBCLs. We identified recur- We identified 23,214 somatic sequence alterations occurring rent mutations implicating a number of known and not previously throughout the lymphoma genome, summarized in Fig. 1 A and B identified genes and pathways in DLBCL including those related to and SI Appendix,TableS1. C chromatin modification (ARID1A and MEF2B), NF-κB(CARD11 and Transitions accounted for about 60% of these events (Fig. 1 ), TNFAIP3), PI3 kinase (PIK3CD, PIK3R1, and MTOR), B-cell lineage similar to patterns observed in a number of other malignancies – (IRF8, POU2F2, and GNA13), and WNT signaling (WIF1). We also (9 11) and suggest that the majority of these DLBCL mutations experimentally validated a mutation in PIK3CD, a gene not pre- arise from stochastic endogenous processes rather than envi- viously implicated in lymphomas. The patterns of mutation dem- ronmental exposures, for example, in the context of tobacco exposure and lung cancer (6). onstrated a classic long tail distribution with substantial variation Known oncogenes (12) found to be somatically mutated in this of mutated genes from patient to patient and also between pub- DLBCL patient included ARID1A, SETD2, CARD11,and lished studies. Thus, our study reveals the tremendous genetic PIK3R1. Of these genes, only CARD11 (13) has been previously heterogeneity that underlies lymphomas and highlights the need experimentally identified as an oncogene in DLBCL. We also for personalized medicine approaches to treating these patients. identified structural genetic alterations using approaches de- scribed previously (14, 15). In all, we identified seven deletions next-generation sequencing | cancer genetics | cancer heterogeneity and three amplifications. Known oncogenes that were implicated by these copy number alterations include PTEN (chromosome iffuse large B-cell lymphoma (DLBCL) is the most common 10) and CDKN2A (chromosome 9). Dform of lymphoma in adults (1). Although nearly half the patients can be cured with standard regimens, the majority of Exome Sequencing Defines the Spectrum of Coding Region Mutations relapsed patients succumb. Thus, there is an urgent need to in DLBCL. To identify recurrently mutated genes in DLBCLs, we identify the genetic underpinnings of the disease and to identify obtained a total of 73 cases of primary human samples. We di- n = novel treatment strategies. Gene expression profiling (2, 3) has vided the primary human cases into a discovery set ( 34) and n = uncovered distinct molecular signatures for DLBCL subtypes that a prevalence set ( 39). For each of the discovery set cases of have unique biology and prognoses. High-throughput sequencing primary DLBCLs, we also sequenced paired normal tissue. In has provided rich opportunities for the comprehensive identifi- addition, we sequenced the exomes of 21 DLBCL cell lines that cation of the genetic causes of cancer (4–6). Whereas exhaustive are widely used to model the disease. portraits of individual cancer genomes are emerging, the degree to which these genomes represent the disease is unclear. We generated a detailed analysis of a DLBCL genome by se- Author contributions: J. Zhang, V.G., C.L.L., A.J.J., J.C.B., M.A.L., and S.S.D. designed re- search; J. Zhang, V.G., C.L.L., K.L.R., P.A.M., C.D., W.C., W.Y.A., G.S., P.L.L., D.A.R., A.S.L., quencing a primary human tumor and paired normal tissue L.B.-M., K.P.M., C.F., K.N., A.E., L.I.G., M.C., J.I.G., E.D.H., Q.L., K.W., L.L.S., T.N., J. Zhu, A.C., (Dataset S1). We further characterized the genetic diversity of S.L., and S.S.D. performed research; J. Zhang, V.G., A.B., A.F., D.J., M.A.L., D.D., and S.S.D. DLBCL by sequencing the exomes of 73 DLBCL primary tumors analyzed data; and J. Zhang, V.G., C.L.L., and S.S.D. wrote the paper. (34 with matched normal DNA) and 21 DLBCL cell lines for The authors declare no conflict of interest. comparative purposes. This in-depth sequencing identified 322 *This Direct Submission article had a prearranged editor. DLBCL cancer genes that were recurrently mutated in DLBCLs. Data deposition: The data reported in this paper have been deposited in dbGap, http:// We also experimentally validated the effects of genetic alteration www.ncbi.nlm.nih.gov/gap (accession no. phs000573.v1.p1), and the Gene Expression of PIK3CD, an oncogene that we identified in DLBCL. Our work Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE22898). provides one of the largest genetic portraits yet of human 1J. Zhang and V.G. contributed equally to this work. DLBCLs and offers insights into the molecular heterogeneity of 2To whom correspondence should be addressed. E-mail: [email protected]. the disease, especially in the context of other recently published This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. studies in DLBCL (7, 8). 1073/pnas.1205299110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1205299110 PNAS Early Edition | 1of6 Downloaded by guest on September 26, 2021 A Somatically acquired genetic alterations Copy Number Alterations Intergenic Mutations Regulatory Region Mutations Coding Region Mutations Type of Mutation B Fig. 1. Results from sequencing a lymphoma ge- Nonsense nome. (A) Circos diagram (36) summarizing the Genomic Region Missense somatically acquired genetic variants in a DLBCL Frame Shift genome. The outermost ring depicts the chromo- Intronic Splice Site/Intronic some ideogram oriented clockwise, pter-qter. The Transcribed Region 5'UTR next ring indicates copy number alterations in the Regulatory Region 3'UTR DLCBL genome. The next three rings indicate so- matically acquired mutations in intergenic regions, Intergenic Synonymous potential regulatory regions, and the exome re- Non Coding RNAs spectively. (B) Pie chart depicts the relative number of somatically acquired mutations in the DLBCL C P<10-6 genome, which can be classified by their genomic 30% location as intergenic, intronic, potential regula- Transition tory, or transcribed regions (Left). (Right) Break- Proportion Transversion of alterations 20% down of different mutation types observed in the in transcribed regions. (C) Histogram depicts the mu- DLBCL Genome 10% tation profile of DLBCL. The proportion of muta- 0% tions in each of the six mutational classes is shown. G A A G T G G T T A C G Transitions represent the majority of the somati- − C T T C A C C A A T G C cally acquired mutations (P < 10 6). We performed whole-exome sequencing for all of these We empirically explored the power of our study to identify DLBCL and paired normal cases using the Agilent solution– novel genetic variants by plotting the expected number of new based system of exon capture, which targets the NCBI Consensus variants that would be discovered from each additional case of CDS database (CCDS) (16). We generated more than 500 Gb of DLBCL (SI Appendix). We found a progressively smaller number mappable sequence data and generated sequence data for 94% of unique variants by sequencing each additional sample (Fig. (median) of the targeted bases in each sample. Our average exome 2C).
Recommended publications
  • Meqtl and Ncrna Functional Analyses of 102 GWAS-Snps Associated with Depression Implicate HACE1 and SHANK2 Genes Diana M
    Ciuculete et al. Clinical Epigenetics (2020) 12:99 https://doi.org/10.1186/s13148-020-00884-8 RESEARCH Open Access meQTL and ncRNA functional analyses of 102 GWAS-SNPs associated with depression implicate HACE1 and SHANK2 genes Diana M. Ciuculete1* , Sarah Voisin2, Lara Kular3, Jörgen Jonsson1, Mathias Rask-Andersen4, Jessica Mwinyi1 and Helgi B. Schiöth1,5 Abstract Background: Little is known about how genetics and epigenetics interplay in depression. Evidence suggests that genetic variants may change vulnerability to depression by modulating DNA methylation (DNAm) and non-coding RNA (ncRNA) levels. Therefore, the aim of the study was to investigate the effect of the genetic variation, previously identified in the largest genome-wide association study for depression, on proximal DNAm and ncRNA levels. Results: We performed DNAm quantitative trait locus (meQTL) analysis in two independent cohorts (total n = 435 healthy individuals), testing associations between 102 single-nucleotide polymorphisms (SNPs) and DNAm levels in whole blood. We identified and replicated 64 SNP-CpG pairs (padj. < 0.05) with meQTL effect. Lower DNAm at cg02098413 located in the HACE1 promoter conferred by the risk allele (C allele) at rs1933802 was associated with higher risk for depression (praw = 0.014, DNAm = 2.3%). In 1202 CD14+ cells sorted from blood, DNAm at cg02088412 positively correlated with HACE1 mRNA expression. Investigation in postmortem brain tissue of adults diagnosed with major depressive disorder (MDD) indicated 1% higher DNAm at cg02098413 in neurons and lower HACE1 mRNA expression in CA1 hippocampus of MDD patients compared with healthy controls (p = 0.008 and 0.012, respectively). Expression QTL analysis in blood of 74 adolescent revealed that hsa-miR-3664-5p was associated with rs7117514 (SHANK2)(padj.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • 4-6 Weeks Old Female C57BL/6 Mice Obtained from Jackson Labs Were Used for Cell Isolation
    Methods Mice: 4-6 weeks old female C57BL/6 mice obtained from Jackson labs were used for cell isolation. Female Foxp3-IRES-GFP reporter mice (1), backcrossed to B6/C57 background for 10 generations, were used for the isolation of naïve CD4 and naïve CD8 cells for the RNAseq experiments. The mice were housed in pathogen-free animal facility in the La Jolla Institute for Allergy and Immunology and were used according to protocols approved by the Institutional Animal Care and use Committee. Preparation of cells: Subsets of thymocytes were isolated by cell sorting as previously described (2), after cell surface staining using CD4 (GK1.5), CD8 (53-6.7), CD3ε (145- 2C11), CD24 (M1/69) (all from Biolegend). DP cells: CD4+CD8 int/hi; CD4 SP cells: CD4CD3 hi, CD24 int/lo; CD8 SP cells: CD8 int/hi CD4 CD3 hi, CD24 int/lo (Fig S2). Peripheral subsets were isolated after pooling spleen and lymph nodes. T cells were enriched by negative isolation using Dynabeads (Dynabeads untouched mouse T cells, 11413D, Invitrogen). After surface staining for CD4 (GK1.5), CD8 (53-6.7), CD62L (MEL-14), CD25 (PC61) and CD44 (IM7), naïve CD4+CD62L hiCD25-CD44lo and naïve CD8+CD62L hiCD25-CD44lo were obtained by sorting (BD FACS Aria). Additionally, for the RNAseq experiments, CD4 and CD8 naïve cells were isolated by sorting T cells from the Foxp3- IRES-GFP mice: CD4+CD62LhiCD25–CD44lo GFP(FOXP3)– and CD8+CD62LhiCD25– CD44lo GFP(FOXP3)– (antibodies were from Biolegend). In some cases, naïve CD4 cells were cultured in vitro under Th1 or Th2 polarizing conditions (3, 4).
    [Show full text]
  • 1 Supporting Information for a Microrna Network Regulates
    Supporting Information for A microRNA Network Regulates Expression and Biosynthesis of CFTR and CFTR-ΔF508 Shyam Ramachandrana,b, Philip H. Karpc, Peng Jiangc, Lynda S. Ostedgaardc, Amy E. Walza, John T. Fishere, Shaf Keshavjeeh, Kim A. Lennoxi, Ashley M. Jacobii, Scott D. Rosei, Mark A. Behlkei, Michael J. Welshb,c,d,g, Yi Xingb,c,f, Paul B. McCray Jr.a,b,c Author Affiliations: Department of Pediatricsa, Interdisciplinary Program in Geneticsb, Departments of Internal Medicinec, Molecular Physiology and Biophysicsd, Anatomy and Cell Biologye, Biomedical Engineeringf, Howard Hughes Medical Instituteg, Carver College of Medicine, University of Iowa, Iowa City, IA-52242 Division of Thoracic Surgeryh, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Canada-M5G 2C4 Integrated DNA Technologiesi, Coralville, IA-52241 To whom correspondence should be addressed: Email: [email protected] (M.J.W.); yi- [email protected] (Y.X.); Email: [email protected] (P.B.M.) This PDF file includes: Materials and Methods References Fig. S1. miR-138 regulates SIN3A in a dose-dependent and site-specific manner. Fig. S2. miR-138 regulates endogenous SIN3A protein expression. Fig. S3. miR-138 regulates endogenous CFTR protein expression in Calu-3 cells. Fig. S4. miR-138 regulates endogenous CFTR protein expression in primary human airway epithelia. Fig. S5. miR-138 regulates CFTR expression in HeLa cells. Fig. S6. miR-138 regulates CFTR expression in HEK293T cells. Fig. S7. HeLa cells exhibit CFTR channel activity. Fig. S8. miR-138 improves CFTR processing. Fig. S9. miR-138 improves CFTR-ΔF508 processing. Fig. S10. SIN3A inhibition yields partial rescue of Cl- transport in CF epithelia.
    [Show full text]
  • Análise Integrativa De Perfis Transcricionais De Pacientes Com
    UNIVERSIDADE DE SÃO PAULO FACULDADE DE MEDICINA DE RIBEIRÃO PRETO PROGRAMA DE PÓS-GRADUAÇÃO EM GENÉTICA ADRIANE FEIJÓ EVANGELISTA Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas Ribeirão Preto – 2012 ADRIANE FEIJÓ EVANGELISTA Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas Tese apresentada à Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo para obtenção do título de Doutor em Ciências. Área de Concentração: Genética Orientador: Prof. Dr. Eduardo Antonio Donadi Co-orientador: Prof. Dr. Geraldo A. S. Passos Ribeirão Preto – 2012 AUTORIZO A REPRODUÇÃO E DIVULGAÇÃO TOTAL OU PARCIAL DESTE TRABALHO, POR QUALQUER MEIO CONVENCIONAL OU ELETRÔNICO, PARA FINS DE ESTUDO E PESQUISA, DESDE QUE CITADA A FONTE. FICHA CATALOGRÁFICA Evangelista, Adriane Feijó Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas. Ribeirão Preto, 2012 192p. Tese de Doutorado apresentada à Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo. Área de Concentração: Genética. Orientador: Donadi, Eduardo Antonio Co-orientador: Passos, Geraldo A. 1. Expressão gênica – microarrays 2. Análise bioinformática por module maps 3. Diabetes mellitus tipo 1 4. Diabetes mellitus tipo 2 5. Diabetes mellitus gestacional FOLHA DE APROVAÇÃO ADRIANE FEIJÓ EVANGELISTA Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas.
    [Show full text]
  • Mir-15A and Mir-16-1 Cluster Functions in Human Leukemia
    MiR-15a and miR-16-1 cluster functions in human leukemia George A. Calin*†‡, Amelia Cimmino*§, Muller Fabbri*, Manuela Ferracin¶, Sylwia E. Wojcik*, Masayoshi Shimizu*§, Cristian Taccioli*, Nicola Zanesi*, Ramiro Garzon*, Rami I. Aqeilan*, Hansjuerg Alder*, Stefano Volinia*ʈ, Laura Rassenti**, Xiuping Liu*, Chang-gong Liu*, Thomas J. Kipps**, Massimo Negrini¶, and Carlo M. Croce*†† *Human Cancer Genetics Program and †Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University, Columbus, OH 43210; §Department of Biochemistry and Biophysics ‘‘F. Cedrangolo,’’ Medical School, Second University of Naples, 80138 Naples, Italy; ¶Department of Experimental and Diagnostic Medicine, Interdepartment Center for Cancer Research and ʈMorphology and Embryology Department, University of Ferrara, 44100 Ferrara, Italy; and **Department of Medicine, University of California at San Diego, La Jolla, CA 92093 Contributed by Carlo M. Croce, January 16, 2008 (sent for review December 6, 2007) MicroRNAs (miRNAs) are short noncoding RNAs regulating gene megakaryocytic leukemia (22). These data support a role for expression that play roles in human diseases, including cancer. Each miR-15a and miR-16-1 as tumor-suppressor genes (TSGs) in CLLs miRNA is predicted to regulate hundreds of transcripts, but only few and perhaps in other malignancies in which these genes are lost or have experimental validation. In chronic lymphocytic leukemia (CLL), down-regulated. the most common adult human leukemia, miR-15a and miR-16-1 are Here, to investigate the mechanism of action of miR-15a and lost or down-regulated in the majority of cases. After our previous miR-16-1 as tumor suppressors in leukemias, we analyzed the work indicating a tumor suppressor function of miR-15a/16-1 by effects of miR-15a and miR-16-1 on transcriptome and proteome in targeting the BCL2 oncogene, here, we produced a high-throughput MEG-01 leukemic cells.
    [Show full text]
  • The Genetics of Bipolar Disorder
    Molecular Psychiatry (2008) 13, 742–771 & 2008 Nature Publishing Group All rights reserved 1359-4184/08 $30.00 www.nature.com/mp FEATURE REVIEW The genetics of bipolar disorder: genome ‘hot regions,’ genes, new potential candidates and future directions A Serretti and L Mandelli Institute of Psychiatry, University of Bologna, Bologna, Italy Bipolar disorder (BP) is a complex disorder caused by a number of liability genes interacting with the environment. In recent years, a large number of linkage and association studies have been conducted producing an extremely large number of findings often not replicated or partially replicated. Further, results from linkage and association studies are not always easily comparable. Unfortunately, at present a comprehensive coverage of available evidence is still lacking. In the present paper, we summarized results obtained from both linkage and association studies in BP. Further, we indicated new potential interesting genes, located in genome ‘hot regions’ for BP and being expressed in the brain. We reviewed published studies on the subject till December 2007. We precisely localized regions where positive linkage has been found, by the NCBI Map viewer (http://www.ncbi.nlm.nih.gov/mapview/); further, we identified genes located in interesting areas and expressed in the brain, by the Entrez gene, Unigene databases (http://www.ncbi.nlm.nih.gov/entrez/) and Human Protein Reference Database (http://www.hprd.org); these genes could be of interest in future investigations. The review of association studies gave interesting results, as a number of genes seem to be definitively involved in BP, such as SLC6A4, TPH2, DRD4, SLC6A3, DAOA, DTNBP1, NRG1, DISC1 and BDNF.
    [Show full text]
  • Intrinsic Disorder in Tetratricopeptide Repeat Proteins
    International Journal of Molecular Sciences Article Intrinsic Disorder in Tetratricopeptide Repeat Proteins 1, 1, 1, 2 Nathan W. Van Bibber y, Cornelia Haerle y, Roy Khalife y, Bin Xue and Vladimir N. Uversky 1,3,4,* 1 Department of Molecular Medicine Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, USA; [email protected] (N.W.V.B.); [email protected] (C.H.); [email protected] (R.K.) 2 Department of Cell Biology, Microbiology and Molecular Biology, School of Natural Sciences and Mathematics, College of Arts and Sciences, University of South Florida, Tampa, FL 33620, USA; [email protected] 3 USF Health Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, USA 4 Institute for Biological Instrumentation, Russian Academy of Sciences, Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”, 4 Institutskaya St., Pushchino, 142290 Moscow Region, Russia * Correspondence: [email protected]; Tel.: +1-813-974-5816; Fax: +1-813-974-7357 These authors contributed equally to this work. y Received: 21 April 2020; Accepted: 22 May 2020; Published: 25 May 2020 Abstract: Among the realm of repeat containing proteins that commonly serve as “scaffolds” promoting protein-protein interactions, there is a family of proteins containing between 2 and 20 tetratricopeptide repeats (TPRs), which are functional motifs consisting of 34 amino acids. The most distinguishing feature of TPR domains is their ability to stack continuously one upon the other, with these stacked repeats being able to affect interaction with binding partners either sequentially or in combination.
    [Show full text]
  • Elucidating Biological Roles of Novel Murine Genes in Hearing Impairment in Africa
    Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 19 September 2019 doi:10.20944/preprints201909.0222.v1 Review Elucidating Biological Roles of Novel Murine Genes in Hearing Impairment in Africa Oluwafemi Gabriel Oluwole,1* Abdoulaye Yal 1,2, Edmond Wonkam1, Noluthando Manyisa1, Jack Morrice1, Gaston K. Mazanda1 and Ambroise Wonkam1* 1Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, South Africa. 2Department of Neurology, Point G Teaching Hospital, University of Sciences, Techniques and Technology, Bamako, Mali. *Correspondence to: [email protected]; [email protected] Abstract: The prevalence of congenital hearing impairment (HI) is highest in Africa. Estimates evaluated genetic causes to account for 31% of HI cases in Africa, but the identification of associated causative genes mutations have been challenging. In this study, we reviewed the potential roles, in humans, of 38 novel genes identified in a murine study. We gathered information from various genomic annotation databases and performed functional enrichment analysis using online resources i.e. genemania and g.proflier. Results revealed that 27/38 genes are express mostly in the brain, suggesting additional cognitive roles. Indeed, HERC1- R3250X had been associated with intellectual disability in a Moroccan family. A homozygous 216-bp deletion in KLC2 was found in two siblings of Egyptian descent with spastic paraplegia. Up to 27/38 murine genes have link to at least a disease, and the commonest mode of inheritance is autosomal recessive (n=8). Network analysis indicates that 20 other genes have intermediate and biological links to the novel genes, suggesting their possible roles in HI.
    [Show full text]
  • Supplementary Table 1
    Supplementary Table 1. 492 genes are unique to 0 h post-heat timepoint. The name, p-value, fold change, location and family of each gene are indicated. Genes were filtered for an absolute value log2 ration 1.5 and a significance value of p ≤ 0.05. Symbol p-value Log Gene Name Location Family Ratio ABCA13 1.87E-02 3.292 ATP-binding cassette, sub-family unknown transporter A (ABC1), member 13 ABCB1 1.93E-02 −1.819 ATP-binding cassette, sub-family Plasma transporter B (MDR/TAP), member 1 Membrane ABCC3 2.83E-02 2.016 ATP-binding cassette, sub-family Plasma transporter C (CFTR/MRP), member 3 Membrane ABHD6 7.79E-03 −2.717 abhydrolase domain containing 6 Cytoplasm enzyme ACAT1 4.10E-02 3.009 acetyl-CoA acetyltransferase 1 Cytoplasm enzyme ACBD4 2.66E-03 1.722 acyl-CoA binding domain unknown other containing 4 ACSL5 1.86E-02 −2.876 acyl-CoA synthetase long-chain Cytoplasm enzyme family member 5 ADAM23 3.33E-02 −3.008 ADAM metallopeptidase domain Plasma peptidase 23 Membrane ADAM29 5.58E-03 3.463 ADAM metallopeptidase domain Plasma peptidase 29 Membrane ADAMTS17 2.67E-04 3.051 ADAM metallopeptidase with Extracellular other thrombospondin type 1 motif, 17 Space ADCYAP1R1 1.20E-02 1.848 adenylate cyclase activating Plasma G-protein polypeptide 1 (pituitary) receptor Membrane coupled type I receptor ADH6 (includes 4.02E-02 −1.845 alcohol dehydrogenase 6 (class Cytoplasm enzyme EG:130) V) AHSA2 1.54E-04 −1.6 AHA1, activator of heat shock unknown other 90kDa protein ATPase homolog 2 (yeast) AK5 3.32E-02 1.658 adenylate kinase 5 Cytoplasm kinase AK7
    [Show full text]
  • Nº Ref Uniprot Proteína Péptidos Identificados Por MS/MS 1 P01024
    Document downloaded from http://www.elsevier.es, day 26/09/2021. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. Nº Ref Uniprot Proteína Péptidos identificados 1 P01024 CO3_HUMAN Complement C3 OS=Homo sapiens GN=C3 PE=1 SV=2 por 162MS/MS 2 P02751 FINC_HUMAN Fibronectin OS=Homo sapiens GN=FN1 PE=1 SV=4 131 3 P01023 A2MG_HUMAN Alpha-2-macroglobulin OS=Homo sapiens GN=A2M PE=1 SV=3 128 4 P0C0L4 CO4A_HUMAN Complement C4-A OS=Homo sapiens GN=C4A PE=1 SV=1 95 5 P04275 VWF_HUMAN von Willebrand factor OS=Homo sapiens GN=VWF PE=1 SV=4 81 6 P02675 FIBB_HUMAN Fibrinogen beta chain OS=Homo sapiens GN=FGB PE=1 SV=2 78 7 P01031 CO5_HUMAN Complement C5 OS=Homo sapiens GN=C5 PE=1 SV=4 66 8 P02768 ALBU_HUMAN Serum albumin OS=Homo sapiens GN=ALB PE=1 SV=2 66 9 P00450 CERU_HUMAN Ceruloplasmin OS=Homo sapiens GN=CP PE=1 SV=1 64 10 P02671 FIBA_HUMAN Fibrinogen alpha chain OS=Homo sapiens GN=FGA PE=1 SV=2 58 11 P08603 CFAH_HUMAN Complement factor H OS=Homo sapiens GN=CFH PE=1 SV=4 56 12 P02787 TRFE_HUMAN Serotransferrin OS=Homo sapiens GN=TF PE=1 SV=3 54 13 P00747 PLMN_HUMAN Plasminogen OS=Homo sapiens GN=PLG PE=1 SV=2 48 14 P02679 FIBG_HUMAN Fibrinogen gamma chain OS=Homo sapiens GN=FGG PE=1 SV=3 47 15 P01871 IGHM_HUMAN Ig mu chain C region OS=Homo sapiens GN=IGHM PE=1 SV=3 41 16 P04003 C4BPA_HUMAN C4b-binding protein alpha chain OS=Homo sapiens GN=C4BPA PE=1 SV=2 37 17 Q9Y6R7 FCGBP_HUMAN IgGFc-binding protein OS=Homo sapiens GN=FCGBP PE=1 SV=3 30 18 O43866 CD5L_HUMAN CD5 antigen-like OS=Homo
    [Show full text]
  • In Silico Prediction and Experimental Validation of Natural Antisense Transcripts in Two Cancer-Associated Regions of Human Chromosome 6
    1099-1108 27/2/2009 01:48 ÌÌ ™ÂÏ›‰·1099 INTERNATIONAL JOURNAL OF ONCOLOGY 34: 1099-1108, 2009 In silico prediction and experimental validation of natural antisense transcripts in two cancer-associated regions of human chromosome 6 LAURA MONTI1*, RAFFAELLA CINQUETTI1*, ALESSANDRO GUFFANTI2*, FRANCESCO NICASSIO3, MATTIA CREMONA4, GIOVANNI LAVORGNA5, FABRIZIO BIANCHI3, FRANCESCA VIGNATI1, DAVIDE CITTARO6, ROBERTO TARAMELLI1 and FRANCESCO ACQUATI1 1Department of Biotechnology and Molecular Sciences, University of Insubria, Via JH Dunant 3, I-21100 Varese; 2Nanotechnologies Group, Institute of Biomedical Technologies, CNR, Via Fantoli 16/15, I-20138 Milano; 3IFOM - FIRC Institute of Molecular Oncology, Via Adamello 16, I-20139 Milano; 4Proteomic Unit, Department of Experimental Oncology, National Institute of Cancer, Via Venezian 21, I-20133 Milano; 5DIBIT, San Raffaele Hospital, Via Olgettina 58, I-20132 Milano; 6HPC and Bioinformatics Systems @ Informatics Core, FIRC Insitute of Molecular Oncology (IFOM), Via Adamello 16, I-20139 Milano, Italy Received August 28, 2008; Accepted October 27, 2008 DOI: 10.3892/ijo_00000237 Abstract. Antisense transcription has long been recognized human malignancies, such as non-Hodgkin's lymphomas, as a mechanism involved in the regulation of gene expression. melanoma and carcinomas of the mammary gland, ovary, Therefore, several human diseases associated with abnormal uterus, stomach, kidney and salivary gland (1-3). The involve- patterns of gene expression might display antisense RNA- ment of this chromosome in the pathogenesis of the above- mediated pathogenetic mechanisms. Such issue could be mentioned cancer types has been demonstrated by LOH particularly relevant for cancer pathogenesis, since deregulated studies and chromosome-transfer assays, which led to the gene expression has long been established as a hallmark of identification of several regions of minimal deletion spanning cancer cells.
    [Show full text]