Project

Back to overview

Chromosome 21: functional genomics and molecular pathophysiology of its disorders

English title Chromosome 21: functional genomics and molecular pathophysiology of its disorders
Applicant Antonarakis Stylianos
Number 144082
Funding scheme Project funding
Research institution Dépt de Médecine Génétique & Développement Faculté de Médecine
Institution of higher education University of Geneva - GE
Main discipline Genetics
Start/End 01.10.2012 - 30.09.2015
Approved amount 930'000.00
Show all

Lay Summary (English)

Lead
Lay summary

Trisomy 21 (Down syndrome; DS; T21) is the most common known cause of mental retardation and also provides a model for the study of genomic aneuploidies. The knowledge of the molecular pathogenesis of T21 is poor (even after 50 years from the discovery of T21 by Jerome Lejeune), and does not yet allow effective treatment of this common genomic abnormality. Many advances of the last 10 years, however, provide a reasonable enthusiasm for the understanding of this common, and yet “orphan” disease. These advances include the i) completion of the high quality DNA sequence of the 33,5 Mb long arm of chromosome 21 (HSA21), ii) the sequence of additional mammalian genomes that allows the description of the various evolutionary conserved and functional components of the genome; iii) the description of the common polymorphic variability of the human genomes and the appreciation of the individuality of gene expression variation, iv) the development of high throughput methods for genome analysis, v) the recent advances in high throughput sequencing, vi) the advances in computational biology, vii) the capability of producing induced pluripotent stem cells (iPS), viii) and the use of mouse and other models. The elucidation of the molecular pathogenesis of the multiple, heterogeneous, and variable T21 phenotypes will also be of importance in the understanding of many other genetic disorders due to genomic dosage imbalance. In this grant application we propose to continue the functional genome analysis of HSA21, characterize the molecular basis of one of the most characteristic and tractable phenotypes of T21, and explore the power of stem cell biology to understand the cellular specificity of the genome dysfunction due to the supernumerary HSA21. The specific aims of the proposal are to: 1) Discover the molecular basis of the Congenital Heart Defects in Trisomy 21. 2) Determine the functional genomic connectivity of Conserved Non-Coding Sequences (CNCS) of HSA21. 3) Assess the transcriptome dysregulation of T21 by RNAseq. 4) Study the epigenetic modifications related to HSA21 and T21. 5) Establish and study T21 iPS (induced pluripotent stem cells). The results of this research will contribute to the elucidation of the complex mechanisms of the phenotypic consequences of genomic dosage imbalance, which is likely to be related to the variability of the functional components of the genome.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD)
Giorgio Elisa, Robyr Daniel, Spielmann Malte, Ferrero Enza, Di Gregorio Eleonora, Imperiale Daniele, Vaula Giovanna, Stamoulis Georgios, Santoni Federico, Atzori Cristiana, Gasparini Laura, Ferrera Denise, Canale Claudio, Guipponi Michel, Pennacchio Len A., Antonarakis Stylianos E., Brussino Alessandro, Brusco Alfredo (2015), A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), in HUMAN MOLECULAR GENETICS, 24(11), 3143-3154.
Biased allelic expression in human primary fibroblast single cells
Borel C., Ferreira P.G., Santoni F., Delaneau O., Fort A., Popadin K.Y., Garieri M., Falconnet E., Ribaux P., Guipponi M., Padioleau I., Carninci P., Dermitzakis E.T., Antonarakis S.E. (2015), Biased allelic expression in human primary fibroblast single cells, in American Journal of Human Genetics, 96(1), 70-80.
Brief Report: Isogenic Induced Pluripotent Stem Cell Lines From an Adult With Mosaic Down Syndrome Model Accelerated Neuronal Ageing and Neurodegeneration
Murray Aoife, Letourneau Audrey, Canzonetta Claudia, Stathaki Elisavet, Gimelli Stefania, Sloan-Bena Frederique, Abrehart Robert, Goh Pollyanna, Lim Shuhui, Baldo Chiara, Dagna-Bricarelli Franca, Hannan Saad, Mortensen Martin, Ballard David, Court Denise Syndercombe, Fusaki Noemi, Hasegawa Mamoru, Smart Trevor G., Bishop Cleo, Antonarakis Stylianos E., Groet Juergen, Nizetic Dean (2015), Brief Report: Isogenic Induced Pluripotent Stem Cell Lines From an Adult With Mosaic Down Syndrome Model Accelerated Neuronal Ageing and Neurodegeneration, in STEM CELLS, 33(6), 2077-2084.
CATCHing putative causative variants in consanguineous families
Santoni Federico Andrea, Makrythanasis Periklis, Antonarakis Stylianos E. (2015), CATCHing putative causative variants in consanguineous families, in BMC BIOINFORMATICS, 16, 1-1.
DNA-Methylation Patterns in Trisomy 21 Using Cells from Monozygotic Twins
Sailani M. Reza, Santoni Federico A., Letourneau Audrey, Borel Christelle, Makrythanasis Periklis, Hibaoui Youssef, Popadin Konstantin, Bonilla Ximena, Guipponi Michel, Gehrig Corinne, Vannier Anne, Carre-Pigeon Frederique, Feki Anis, Nizetic Dean, Antonarakis Stylianos E. (2015), DNA-Methylation Patterns in Trisomy 21 Using Cells from Monozygotic Twins, in PLOS ONE, 10(8), 1-1.
Exome Sequencing in 53 Sporadic Cases of Schizophrenia Identifies 18 Putative Candidate Genes (vol 9, e112745, 2014)
Guipponi Michel, Santoni Federico A., Setola Vincent, Gehrig Corinne, Rotharmel Maud, Cuenca Macarena, Guillin Olivier, Dikeos Dimitris, Georgantopoulos Georgios, Papadimitriou George, Curtis Logos, Meary Alexandre, Schuerhoff Franck, Jamain Stephane, Avramopoulos Dimitri, Leboyer Marion, Rujescu Dan, Pulver Ann, Campion Dominique, Siderovski David P., Antonarakis Stylianos E. (2015), Exome Sequencing in 53 Sporadic Cases of Schizophrenia Identifies 18 Putative Candidate Genes (vol 9, e112745, 2014), in PLOS ONE, 10(10), 1-1.
Exome sequencing reveals pathogenic mutations in 91 strains of mice with Mendelian disorders
Fairfield Heather, Srivastava Anuj, Ananda Guruprasad, Liu Rangjiao, Kircher Martin, Lakshminarayana Anuradha, Harris Belinda S., Karst Son Yong, Dionne Louise A., Kane Coleen C., Curtain Michelle, Berry Melissa L., Ward-Bailey Patricia F., Greenstein Ian, Byers Candice, Czechanski Anne, Sharp Jocelyn, Palmer Kristina, Gudis Polyxeni, Martin Whitney, Tadenev Abby, Bogdanik Laurent, Pratt C. Herbert, Chang Bo, Schroeder David G. (2015), Exome sequencing reveals pathogenic mutations in 91 strains of mice with Mendelian disorders, in GENOME RESEARCH, 25(7), 948-957.
Galanin pathogenic mutations in temporal lobe epilepsy
Guipponi Michel, Chentouf Amina, Webling Kristin E. B., Freimann Krista, Crespel Arielle, Nobile Carlo, Lemke Johannes R., Hansen Jorg, Dorn Thomas, Lesca Gaetan, Ryvlin Philippe, Hirsch Edouard, Rudolf Gabrielle, Rosenberg Dominique Sarah, Weber Yvonne, Becker Felicitas, Helbig Ingo, Muhle Hiltrud, Salzmann Annick, Chaouch Malika, Oubaiche Mohand Laid, Ziglio Serena, Gehrig Corinne, Santoni Federico, Pizzato Massimo (2015), Galanin pathogenic mutations in temporal lobe epilepsy, in HUMAN MOLECULAR GENETICS, 24(11), 3082-3091.
HIV-1 Nef promotes infection by excluding SERINC5 from virion incorporation
Rosa Annachiara, Chande Ajit, Ziglio Serena, De Sanctis Veronica, Bertorelli Roberto, Goh Shih Lin, McCauley Sean M., Nowosielska Anetta, Antonarakis Stylianos E., Luban Jeremy, Santoni Federico Andrea, Pizzato Massimo (2015), HIV-1 Nef promotes infection by excluding SERINC5 from virion incorporation, in NATURE, 526(7572), 212-212.
Opposite Phenotypes of Muscle Strength and Locomotor Function in Mouse Models of Partial Trisomy and Monosomy 21 for the Proximal Hspa13-App Region
Brault Véronique, Brault Véronique, Brault Véronique, Brault Véronique, Duchon Arnaud, Duchon Arnaud, Duchon Arnaud, Duchon Arnaud, Romestaing Caroline, Sahun Ignasi, Pothion Stéphanie, Karout Mona, Karout Mona, Karout Mona, Karout Mona, Borel Christelle, Dembele Doulaye, Dembele Doulaye, Dembele Doulaye, Dembele Doulaye, Bizot Jean Charles, Messaddeq Nadia, Messaddeq Nadia, Messaddeq Nadia, Messaddeq Nadia (2015), Opposite Phenotypes of Muscle Strength and Locomotor Function in Mouse Models of Partial Trisomy and Monosomy 21 for the Proximal Hspa13-App Region, in PLoS Genetics, 11(3), 1-1.
Diagnostic Exome Sequencing to Elucidate the Genetic Basis of Likely Recessive Disorders in Consanguineous Families
Makrythanasis Periklis, Nelis Mari, Santoni Federico A., Guipponi Michel, Vannier Anne, Bena Frederique, Gimelli Stefania, Stathaki Elisavet, Temtamy Samia, Megarbane Andre, Masri Amira, Aglan Mona S., Zaki Maha S., Bottani Armand, Fokstuen Siv, Gwanmesia Lorraine, Aliferis Konstantinos, Eduardo Mariana Bustamante, Stamoulis Georgios, Psoni Stavroula, Kitsiou-Tzeli Sofia, Fryssira Helen, Kanavakis Emmanouil, Al-Allawi Nasir, Sefiani Abdelaziz (2014), Diagnostic Exome Sequencing to Elucidate the Genetic Basis of Likely Recessive Disorders in Consanguineous Families, in HUMAN MUTATION, 35(10), 1203-1210.
Domains of genome-wide gene expression dysregulation in Down's syndrome
Letourneau A (2014), Domains of genome-wide gene expression dysregulation in Down's syndrome, in Nature, 508(7496), 345-350.
Extrachromosomal driver mutations in glioblastoma and low-grade glioma
Nikolaev Sergey, Santoni Federico, Garieri Marco, Makrythanasis Periklis, Falconnet Emilie, Guipponi Michel, Vannier Anne, Radovanovic Ivan, Bena Frederique, Forestier Francoise, Schaller Karl, Dutoit Valerie, Clement-Schatlo Virginie, Dietrich Pierre-Yves, Antonarakis Stylianos E. (2014), Extrachromosomal driver mutations in glioblastoma and low-grade glioma, in NATURE COMMUNICATIONS, 5, 1-1.
Extrachromosomal driver mutations in glioblastoma and low-grade glioma
Nikolaev Sergey, Santoni Federico, Garieri Marco, Makrythanasis Periklis, Falconnet Emilie, Guipponi Michel, Vannier Anne, Radovanovic Ivan, Bena Frederique, Forestier Francoise, Schaller Karl, Dutoit Valerie, Clement-Schatlo Virginie, Dietrich Pierre-Yves, Antonarakis Stylianos E. (2014), Extrachromosomal driver mutations in glioblastoma and low-grade glioma, in NATURE COMMUNICATIONS, 5, 1-1.
Gene Age Predicts the Strength of Purifying Selection Acting on Gene Expression Variation in Humans
Popadin Konstantin Y., Gutierrez-Arcelus Maria, Lappalainen Tuuli, Buil Alfonso, Steinberg Julia, Nikolaev Sergey I., Lukowski Samuel W., Bazykin Georgii A., Seplyarskiy Vladimir B., Ioannidis Panagiotis, Zdobnov Evgeny M., Dermitzakis Emmanouil T., Antonarakis Stylianos E. (2014), Gene Age Predicts the Strength of Purifying Selection Acting on Gene Expression Variation in Humans, in AMERICAN JOURNAL OF HUMAN GENETICS, 95(6), 660-674.
Guidelines for investigating causality of sequence variants in human disease
MacArthur D.G., Manolio T.A., Dimmock D.P., Rehm H.L., Shendure J., Abecasis G.R., Adams D.R., Altman R.B., Antonarakis S.E., Ashley E.A., Barrett J.C., Biesecker L.G., Conrad D.F., Cooper G.M., Cox N.J., Daly M.J., Gerstein M.B., Goldstein D.B., Hirschhorn J.N., Leal S.M., Pennacchio L.A., Stamatoyannopoulos J.A., Sunyaev S.R., Valle D., Voight B.F. (2014), Guidelines for investigating causality of sequence variants in human disease, in Nature, 508(7497), 469-476.
Modelling and rescuing neurodevelopmental defect of Down syndrome using induced pluripotent stem cells from monozygotic twins discordant for trisomy 21
Hibaoui Y., Grad I., Letourneau A., Sailani M.R., Dahoun S., Santoni F.A., Gimelli S., Guipponi M., Pelte M.F., Béna F., Antonarakis S.E., Feki A. (2014), Modelling and rescuing neurodevelopmental defect of Down syndrome using induced pluripotent stem cells from monozygotic twins discordant for trisomy 21, in EMBO Molecular Medicine, 6(2), 259-277.
Perturbations of heart development and function in cardiomyocytes from human embryonic stem cells with trisomy 21
Bosman Alexis, Bosman Alexis, Letourneau Audrey, Sartiani Laura, Del Lungo Martina, Ronzoni Flavio, Kuziakiv Rostyslav, Tohonen Virpi, Zucchelli Marco, Santoni Federico, Guipponi Michel, Dumevska Biljana, Hovatta Outi, Antonarakis Stylianos E., Antonarakis Stylianos E., Jaconi Marisa E. (2014), Perturbations of heart development and function in cardiomyocytes from human embryonic stem cells with trisomy 21, in Stem Cells, 33(5), 1434-1446.
Simultaneous identification and prioritization of variants in familial, de novo, and somatic genetic disorders with VariantMaster
Santoni F.A., Makrythanasis P., Nikolaev S., Guipponi M., Robyr D., Bottani A., Antonarakis S.E. (2014), Simultaneous identification and prioritization of variants in familial, de novo, and somatic genetic disorders with VariantMaster, in Genome Research, 24(2), 349-355.
Simultaneous identification and prioritization of variants in familial, de novo, and somatic genetic disorders with VariantMaster
Santoni F.A., Makrythanasis P., Nikolaev S., Guipponi M., Robyr D., Bottani A., Antonarakis S.E. (2014), Simultaneous identification and prioritization of variants in familial, de novo, and somatic genetic disorders with VariantMaster, in Genome Research, 24(2), 349-355.
Transcriptome profiling by RNAseq of single human islet cells reveals unique features of individual alpha and beta cells
Garieri M., Borel C., Ribaux P., Antonarakis S. E., Dermitzakis E. T., Halban P. A. (2014), Transcriptome profiling by RNAseq of single human islet cells reveals unique features of individual alpha and beta cells, in DIABETOLOGIA, 57, 18-19.
Transcriptome profiling by RNAseq of single human islet cells reveals unique features of individual alpha and beta cells
Garieri M., Borel C., Ribaux P., Antonarakis S. E., Dermitzakis E. T., Halban P. A. (2014), Transcriptome profiling by RNAseq of single human islet cells reveals unique features of individual alpha and beta cells, in DIABETOLOGIA, 57, 18-19.

Collaboration

Group / person Country
Types of collaboration
I Xenarios Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
A Feki, M Jaconi Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dean Nizetic Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
E Dermitzakis Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Yann Herault France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Associated projects

Number Title Start Funding scheme
163180 Chromosome 21: functional genomics and molecular pathophysiology of trisomy 21 01.10.2015 Project funding
105602 Chromosome 21: functional genomics and molecular pathophysiology of its disorders 01.10.2004 Project funding
127375 Chromosome 21: functional genomics and molecular pathophysiology of its disorders 01.10.2009 Project funding
164091 Identifying environmental controls over the transcriptional activity of single cells across organs and systems 01.12.2015 R'EQUIP

Abstract

Trisomy 21 (Down syndrome; DS; T21) is the most common known cause of mental retardation and also provides a model for the study of genomic aneuploidies. The knowledge of the molecular pathogenesis of T21 is poor (even after 50 years from the discovery of T21 by Jerome Lejeune), and does not yet allow effective treatment of this common genomic abnormality. Many advances of the last 10 years, however, provide a reasonable enthusiasm for the understanding of this common, and yet “orphan” disease. These advances include the i) completion of the high quality DNA sequence of the 33,5 Mb long arm of chromosome 21 (HSA21), ii) the sequence of additional mammalian genomes that allows the description of the various evolutionary conserved and functional components of the genome; iii) the description of the common polymorphic variability of the human genomes and the appreciation of the individuality of gene expression variation, iv) the development of high throughput methods for genome analysis, v) the recent advances in high throughput sequencing, vi) the advances in computational biology, vii) the capability of producing induced pluripotent stem cells (iPS), viii) and the use of mouse and other models. The elucidation of the molecular pathogenesis of the multiple, heterogeneous, and variable T21 phenotypes will also be of importance in the understanding of many other genetic disorders due to genomic dosage imbalance.In this grant application we propose to continue the functional genome analysis of HSA21, characterize the molecular basis of one of the most characteristic and tractable phenotypes of T21, and explore the power of stem cell biology to understand the cellular specificity of the genome dysfunction due to the supernumerary HSA21.The specific aims of the proposal are to:1) Discover the molecular basis of the Congenital Heart Defects in Trisomy 21.2) Determine the functional genomic connectivity of Conserved Non-Coding Sequences (CNCS) of HSA21.3) Assess the transcriptome dysregulation of T21 by RNAseq.4) Study the epigenetic modifications related to HSA21 and T21.5) Establish and study T21 iPS (induced pluripotent stem cells).6) Study the somatic mutations in the Leukemia of Down syndromeThe results of this research will contribute to the elucidation of the complex mechanisms of the phenotypic consequences of genomic dosage imbalance, which is likely to be related to the variability of the functional components of the genome.
-