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 127375
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 01.10.2009 - 30.09.2012
Approved amount 930'000.00
Show all

Keywords (12)

Chromosome 21; Trisomy 21; DNA sequences; Gene expression variation; Conserved non-coding sequences; Transgenic mice; Congenital heart defect; Epigenetics; microRNAs; transcriptome; epigenetic modifications; iPS

Lay Summary (English)

Lead
Lay summary
Trisomy 21 (Down syndrome; DS; T21) is the most common known cause of mental retardation. 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) sequence of additional mammalian genomes that allows by comparative genome analysis the description of the various evolutionary conserved and functional components of the genome; iii) description of the common polymorphic variability of the human genomes and the appreciation of the individuality of gene expression variation, iv) development of high throughput methods for genome analysis, v) recent advances in high throughput sequencing, vi) advances in computational biology, vii) 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
Extensive natural variation for cellular hydrogen peroxide release is genetically controlled.
Attar Homa, Bedard Karen, Migliavacca Eugenia, Gagnebin Maryline, Dupré Yann, Descombes Patrick, Borel Christelle, Deutsch Samuel, Prokisch Holger, Meitinger Thomas, Mehta Divya, Wichmann Erich, Delabar Jean Maurice, Dermitzakis Emmanouil T, Krause Karl-Heinz, Antonarakis Stylianos E (2012), Extensive natural variation for cellular hydrogen peroxide release is genetically controlled., in PloS one, 7(8), 43566-43566.
Genomic determinants in the phenotypic variability of Down syndrome.
Letourneau Audrey, Antonarakis Stylianos E (2012), Genomic determinants in the phenotypic variability of Down syndrome., in Progress in brain research, 197, 15-28.
BDNF and DYRK1A Are Variable and Inversely Correlated in Lymphoblastoid Cell Lines from Down Syndrome Patients
Tlili A, Hoischen A, Ripoll C, Benabou E, Badel A, Ronan A, Touraine R, Grattau Y, Stora S, van Bon B, de Vries B, Menten B, Bockaert N, Gecz J, Antonarakis SE, Campion D, Potier MC, Blehaut H, Delabar JM, Janel N (2012), BDNF and DYRK1A Are Variable and Inversely Correlated in Lymphoblastoid Cell Lines from Down Syndrome Patients, in MOLECULAR NEUROBIOLOGY, 46(2), 297-303.
Novel homozygous, heterozygous and hemizygous FRMD7 gene mutations segregated in the same consanguineous family with congenital X-linked nystagmus
Radhakrishna U, Ratnamala U, Deutsch S, Bartoloni L, Kuracha MR, Singh R, Banwait J, Bastola DK, Johar K, Nath SK, Antonarakis SE (2012), Novel homozygous, heterozygous and hemizygous FRMD7 gene mutations segregated in the same consanguineous family with congenital X-linked nystagmus, in EUROPEAN JOURNAL OF HUMAN GENETICS, 20(10), 1032-1036.
An integrated encyclopedia of DNA elements in the human genome
Dunham I, Kundaje A, Aldred SF, Collins PJ, Davis C, Doyle F, Epstein CB, Frietze S, Harrow J, Kaul R, Khatun J, Lajoie BR, Landt SG, Lee BK, Pauli F, Rosenbloom KR, Sabo P, Safi A, Sanyal A, Shoresh N, Simon JM, Song L, Trinklein ND, Altshuler RC, Birney E (2012), An integrated encyclopedia of DNA elements in the human genome, in NATURE, 489(7414), 57-74.
Landscape of transcription in human cells
Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, Tanzer A, Lagarde J, Lin W, Schlesinger F, Xue CH, Marinov GK, Khatun J, Williams BA, Zaleski C, Rozowsky J, Roder M, Kokocinski F, Abdelhamid RF, Alioto T, Antoshechkin I, Baer MT, Bar NS, Batut P, Bell K (2012), Landscape of transcription in human cells, in NATURE, 489(7414), 101-108.
Genome-wide linkage and copy number variation analysis reveals 710 kb duplication on chromosome 1p31.3 responsible for autosomal dominant omphalocele
Radhakrishna U, Nath SK, McElreavey K, Ratnamala U, Sun C, Maiti AK, Gagnebin M, Bena F, Newkirk HL, Sharp AJ, Everman DB, Murray JC, Schwartz CE, Antonarakis SE, Butler MG (2012), Genome-wide linkage and copy number variation analysis reveals 710 kb duplication on chromosome 1p31.3 responsible for autosomal dominant omphalocele, in JOURNAL OF MEDICAL GENETICS, 49(4), 270-276.
BLUEPRINT to decode the epigenetic signature written in blood
Adams D, Altucci L, Antonarakis SE, Ballesteros J, Beck S, Bird A, Bock C, Boehm B, Campo E, Caricasole A, Dahl F, Dermitzakis ET, Enver T, Esteller M, Estivill X, Ferguson-Smith A, Fitzgibbon J, Flicek P, Giehl C, Graf T, Grosveld F, Guigo R, Gut I, Helin K, Jarvius J (2012), BLUEPRINT to decode the epigenetic signature written in blood, in NATURE BIOTECHNOLOGY, 30(3), 224-226.
Duplications of BHLHA9 are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion
Klopocki E, Lohan S, Doelken SC, Stricker S, Ockeloen CW, de Aguiar RST, Lezirovitz K, Netto RCM, Jamsheer A, Shah H, Kurth I, Habenicht R, Warman M, Devriendt K, Kordass U, Hempel M, Rajab A, Makitie O, Naveed M, Radhakrishna U, Antonarakis SE, Horn D, Mundlos S (2012), Duplications of BHLHA9 are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion, in JOURNAL OF MEDICAL GENETICS, 49(2), 119-125.
Duplications of BHLHA9 are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion.
Klopocki Eva, Lohan Silke, Doelken Sandra C, Stricker Sigmar, Ockeloen Charlotte W, Soares Thiele de Aguiar Renata, Lezirovitz Karina, Mingroni Netto Regina Celia, Jamsheer Aleksander, Shah Hitesh, Kurth Ingo, Habenicht Rolf, Warman Matthew, Devriendt Koenraad, Kordass Ulrike, Hempel Maja, Rajab Anna, Mäkitie Outi, Naveed Mohammed, Radhakrishna Uppala, Antonarakis Stylianos E, Horn Denise, Mundlos Stefan (2012), Duplications of BHLHA9 are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion., in Journal of medical genetics, 49(2), 119-25.
Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma
Nikolaev SI, Rimoldi D, Iseli C, Valsesia A, Robyr D, Gehrig C, Harshman K, Guipponi M, Bukach O, Zoete V, Michielin O, Muehlethaler K, Speiser D, Beckmann JS, Xenarios I, Halazonetis TD, Jongeneel CV, Stevenson BJ, Antonarakis SE (2012), Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma, in NATURE GENETICS, 44(2), 133-139.
Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma.
Nikolaev Sergey I, Rimoldi Donata, Iseli Christian, Valsesia Armand, Robyr Daniel, Gehrig Corinne, Harshman Keith, Guipponi Michel, Bukach Olesya, Zoete Vincent, Michielin Olivier, Muehlethaler Katja, Speiser Daniel, Beckmann Jacques S, Xenarios Ioannis, Halazonetis Thanos D, Jongeneel C Victor, Stevenson Brian J, Antonarakis Stylianos E (2012), Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma., in Nature genetics, 44(2), 133-9.
Evidence for Transcript Networks Composed of Chimeric RNAs in Human Cells
Djebali S, Lagarde J, Kapranov P, Lacroix V, Borel C, Mudge JM, Howald C, Foissac S, Ucla C, Chrast J, Ribeca P, Martin D, Murray RR, Yang XP, Ghamsari L, Lin CW, Bell I, Dumais E, Drenkow J, Tress ML, Gelpi JL, Orozco M, Valencia A, van Berkum NL, Lajoie BR (2012), Evidence for Transcript Networks Composed of Chimeric RNAs in Human Cells, in PLOS ONE, 7(1), 1-10.
From sequence to functional understanding: the difficult road ahead.
Makrythanasis Periklis, Antonarakis Stylianos E (2011), From sequence to functional understanding: the difficult road ahead., in Genome medicine, 3(4), 21-21.
Mouse Models for Down Syndrome-Associated Developmental Cognitive Disabilities
Liu CH, Belichenko PV, Zhang L, Fu DW, Kleschevnikov AM, Baldini A, Antonarakis SE, Mobley WC, Yu YE (2011), Mouse Models for Down Syndrome-Associated Developmental Cognitive Disabilities, in DEVELOPMENTAL NEUROSCIENCE, 33(5), 404-413.
Mouse models for Down syndrome-associated developmental cognitive disabilities.
Liu Chunhong, Belichenko Pavel V, Zhang Li, Fu Dawei, Kleschevnikov Alexander M, Baldini Antonio, Antonarakis Stylianos E, Mobley William C, Yu Y Eugene (2011), Mouse models for Down syndrome-associated developmental cognitive disabilities., in Developmental neuroscience, 33(5), 404-13.
NANOG priming before full reprogramming may generate germ cell tumours.
Grad I, Hibaoui Y, Jaconi M, Chicha L, Bergström-Tengzelius R, Sailani M R, Pelte M F, Dahoun S, Mitsiadis T A, Töhönen V, Bouillaguet S, Antonarakis S E, Kere J, Zucchelli M, Hovatta O, Feki A (2011), NANOG priming before full reprogramming may generate germ cell tumours., in European cells & materials, 22, 258-258.
DNA methylation profiles of human active and inactive X chromosomes
Sharp AJ, Stathaki E, Migliavacca E, Brahmachary M, Montgomery SB, Dupre Y, Antonarakis SE (2011), DNA methylation profiles of human active and inactive X chromosomes, in GENOME RESEARCH, 21(10), 1592-1600.
Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus
Jacquemont S, Reymond A, Zufferey F, Harewood L, Walters RG, Kutalik Z, Martinet D, Shen YP, Valsesia A, Beckmann ND, Thorleifsson G, Belfiore M, Bouquillon S, Campion D, de Leeuw N, de Vries BBA, Esko T, Fernandez BA, Fernandez-Aranda F, Fernandez-Real JM, Gratacos M, Guilmatre A, Hoyer J, Jarvelin MR, Kooy RF (2011), Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus, in NATURE, 478(7367), 97-97.
Consanguineous marriages, pearls and perils: Geneva International Consanguinity Workshop Report
Hamamy H, Antonarakis SE, Cavalli-Sforza LL, Temtamy S, Romeo G, Ten Kate LP, Bennett RL, Shaw A, Megarbane A, van Duijn C, Bathija H, Fokstuen S, Engel E, Zlotogora J, Dermitzakis E, Bottani A, Dahoun S, Morris MA, Arsenault S, Aglan MS, Ajaz M, Alkalamchi A, Alnaqeb D, Alwasiyah MK, Anwer N (2011), Consanguineous marriages, pearls and perils: Geneva International Consanguinity Workshop Report, in GENETICS IN MEDICINE, 13(9), 841-847.
Rapid detection of genetic variants in hypertrophic cardiomyopathy by custom DNA resequencing array in clinical practice
Fokstuen S, Munoz A, Melacini P, Iliceto S, Perrot A, Ozcelik C, Jeanrenaud X, Rieubland C, Farr M, Faber L, Sigwart U, Mach FO, Lerch R, Antonarakis SE, Blouin JL (2011), Rapid detection of genetic variants in hypertrophic cardiomyopathy by custom DNA resequencing array in clinical practice, in JOURNAL OF MEDICAL GENETICS, 48(8), 572-576.
Refinement of the X-linked Nonsyndromic High-Grade Myopia Locus MYP1 on Xq28 and Exclusion of 13 Known Positional Candidate Genes by Direct Sequencing
Ratnamala U, Lyle R, Rawal R, Singh R, Vishnupriya S, Himabindu P, Rao V, Aggarwal S, Paluru P, Bartoloni L, Young TL, Paoloni-Giacobino A, Morris MA, Nath SK, Antonarakis SE, Radhakrishna U (2011), Refinement of the X-linked Nonsyndromic High-Grade Myopia Locus MYP1 on Xq28 and Exclusion of 13 Known Positional Candidate Genes by Direct Sequencing, in INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 52(9), 6814-6819.
A User's Guide to the Encyclopedia of DNA Elements (ENCODE)
Myers RM, Stamatoyannopoulos J, Snyder M, Dunham I, Hardison RC, Bernstein BE, Gingeras TR, Kent WJ, Birney E, Wold B, Crawford GE, Bernstein BE, Epstein CB, Shoresh N, Ernst J, Mikkelsen TS, Kheradpour P, Zhang XL, Wang L, Issner R, Coyne MJ, Durham T, Ku MC, Truong T, Ward LD (2011), A User's Guide to the Encyclopedia of DNA Elements (ENCODE), in PLOS BIOLOGY, 9(4), 1-15.
Network-Guided Analysis of Genes with Altered Somatic Copy Number and Gene Expression Reveals Pathways Commonly Perturbed in Metastatic Melanoma
Valsesia A, Rimoldi D, Martinet D, Ibberson M, Benaglio P, Quadroni M, Waridel P, Gaillard M, Pidoux M, Rapin B, Rivolta C, Xenarios I, Simpson AJG, Antonarakis SE, Beckmann JS, Jongeneel CV, Iseli C, Stevenson BJ (2011), Network-Guided Analysis of Genes with Altered Somatic Copy Number and Gene Expression Reveals Pathways Commonly Perturbed in Metastatic Melanoma, in PLOS ONE, 6(4), 1-10.
Chromosome Conformation Capture Uncovers Potential Genome-Wide Interactions between Human Conserved Non-Coding Sequences
Robyr D, Friedli M, Gehrig C, Arcangeli M, Marin M, Guipponi M, Farinelli L, Barde I, Verp S, Trono D, Antonarakis SE (2011), Chromosome Conformation Capture Uncovers Potential Genome-Wide Interactions between Human Conserved Non-Coding Sequences, in PLOS ONE, 6(3), 1-12.
A de novo 12q13.11 microdeletion in a patient with severe mental retardation, cleft palate, and high myopia
Gimelli S, Makrythanasis P, Stouder C, Antonarakis SE, Bottani A, Bena F (2011), A de novo 12q13.11 microdeletion in a patient with severe mental retardation, cleft palate, and high myopia, in EUROPEAN JOURNAL OF MEDICAL GENETICS, 54(1), 94-96.
A de novo 12q13.11 microdeletion in a patient with severe mental retardation, cleft palate, and high myopia.
Gimelli S, Makrythanasis P, Stouder C, Antonarakis S E, Bottani A, Béna F (2011), A de novo 12q13.11 microdeletion in a patient with severe mental retardation, cleft palate, and high myopia., in European journal of medical genetics, 54(1), 94-6.
A High-Resolution Anatomical Atlas of the Transcriptome in the Mouse Embryo
Diez-Roux G, Banfi S, Sultan M, Geffers L, Anand S, Rozado D, Magen A, Canidio E, Pagani M, Peluso I, Lin-Marq N, Koch M, Bilio M, Cantiello I, Verde R, De Masi C, Bianchi SA, Cicchini J, Perroud E, Mehmeti S, Dagand E, Schrinner S, Nurnberger A, Schmidt K, Metz K (2011), A High-Resolution Anatomical Atlas of the Transcriptome in the Mouse Embryo, in PLOS BIOLOGY, 9(1), 1-15.
Identification of cis- and trans- regulatory variation modulating microRNA expression levels in human fibroblasts
Borel C, Deutsch S, Letourneau A, Migliavacca E, Montgomery SB, Dimas AS, Vejnar CE, Attar H, Gagnebin M, Gehrig C, Falconnet E, Dupre Y, Dermitzakis ET, Antonarakis SE (2011), Identification of cis- and trans- regulatory variation modulating microRNA expression levels in human fibroblasts, in GENOME RESEARCH, 21(1), 68-73.
A mouse embryonic stem cell bank for inducible overexpression of human chromosome 21 genes
De Cegli R, Romito A, Iacobacci S, Mao L, Lauria M, Fedele AO, Klose J, Borel C, Descombes P, Antonarakis SE, di Bernardo D, Banfi S, Ballabio A, Cobellis G (2010), A mouse embryonic stem cell bank for inducible overexpression of human chromosome 21 genes, in GENOME BIOLOGY, 11(6), 1-10.
A systematic enhancer screen using lentivector transgenesis identifies conserved and non-conserved functional elements at the Olig1 and Olig2 locus.
Friedli Marc, Barde Isabelle, Arcangeli Mélanie, Verp Sonia, Quazzola Alexandra, Zakany Jozsef, Lin-Marq Nathalie, Robyr Daniel, Attanasio Catia, Spitz François, Duboule Denis, Trono Didier, Antonarakis Stylianos E (2010), A systematic enhancer screen using lentivector transgenesis identifies conserved and non-conserved functional elements at the Olig1 and Olig2 locus., in PloS one, 5(12), 15741-15741.
A teratocarcinoma-like human embryonic stem cell (hESC) line and four hESC lines reveal potentially oncogenic genomic changes.
Hovatta Outi, Jaconi Marisa, Töhönen Virpi, Béna Frédérique, Gimelli Stefania, Bosman Alexis, Holm Frida, Wyder Stefan, Zdobnov Evgeny M, Irion Olivier, Andrews Peter W, Antonarakis Stylianos E, Zucchelli Marco, Kere Juha, Feki Anis (2010), A teratocarcinoma-like human embryonic stem cell (hESC) line and four hESC lines reveal potentially oncogenic genomic changes., in PloS one, 5(4), 10263-10263.
Down syndrome: from understanding the neurobiology to therapy.
Gardiner Katheleen, Herault Yann, Lott Ira T, Antonarakis Stylianos E, Reeves Roger H, Dierssen Mara (2010), Down syndrome: from understanding the neurobiology to therapy., in The Journal of neuroscience : the official journal of the Society for Neuroscience, 30(45), 14943-5.
Regulation of fibrinogen production by microRNAs
Fort A, Borel C, Migliavacca E, Antonarakis SE, Fish RJ, Neerman-Arbez M (2010), Regulation of fibrinogen production by microRNAs, in BLOOD, 116(14), 2608-2615.
Methylation profiling in individuals with uniparental disomy identifies novel differentially methylated regions on chromosome 15
Sharp AJ, Migliavacca E, Dupre Y, Stathaki E, Sailani MR, Baumer A, Schinzel A, Mackay DJ, Robinson DO, Cobellis G, Cobellis L, Brunner HG, Steiner B, Antonarakis SE (2010), Methylation profiling in individuals with uniparental disomy identifies novel differentially methylated regions on chromosome 15, in GENOME RESEARCH, 20(9), 1271-1278.
Array-CGH Analysis in a Patient With WAGR Syndrome and a Reciprocal Translocation t(2;11) Inherited From the Normal Father With Double Translocation
Gimelli S, Divizia MT, Lerone M, Bricco L, Bena F, Antonarakis SE, Ravazzolo R, Gimelli G (2010), Array-CGH Analysis in a Patient With WAGR Syndrome and a Reciprocal Translocation t(2;11) Inherited From the Normal Father With Double Translocation, in AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 152A(8), 2130-2133.
A spectrum of LMX1B mutations in Nail-Patella syndrome: New point mutations, deletion, and evidence of mosaicism in unaffected parents
Marini M, Bocciardi R, Gimelli S, Di Duca M, Divizia MT, Baban A, Gaspar H, Mammi I, Garavelli L, Cerone R, Emma F, Bedeschi MF, Tenconi R, Sensi A, Salmaggi A, Bengala M, Mari F, Colussi G, Szczaluba K, Antonarakis SE, Seri M, Lerone M, Ravazzolo R (2010), A spectrum of LMX1B mutations in Nail-Patella syndrome: New point mutations, deletion, and evidence of mosaicism in unaffected parents, in GENETICS IN MEDICINE, 12(7), 431-439.
Eye Gaze During Face Processing in Children and Adolescents With 22q11.2 Deletion Syndrome
Glaser B, Debbane M, Ottet MC, Vuilleumier P, Zesiger P, Antonarakis SE, Eliez S (2010), Eye Gaze During Face Processing in Children and Adolescents With 22q11.2 Deletion Syndrome, in JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY, 49(7), 665-674.
Mendelian disorders and multifactorial traits: the big divide or one for all?
Antonarakis SE, Chakravarti A, Cohen JC, Hardy J (2010), Mendelian disorders and multifactorial traits: the big divide or one for all?, in NATURE REVIEWS GENETICS, 11(5), 380-384.
A recurrent 14q32.2 microdeletion mediated by expanded TGG repeats
Bena F, Gimelli S, Migliavacca E, Brun-Druc N, Buiting K, Antonarakis SE, Sharp AJ (2010), A recurrent 14q32.2 microdeletion mediated by expanded TGG repeats, in HUMAN MOLECULAR GENETICS, 19(10), 1967-1973.
A Teratocarcinoma-Like Human Embryonic Stem Cell (hESC) Line and Four hESC Lines Reveal Potentially Oncogenic Genomic Changes
Hovatta O, Jaconi M, Tohonen V, Bena F, Gimelli S, Bosman A, Holm F, Wyder S, Zdobnov EM, Irion O, Andrews PW, Antonarakis SE, Zucchelli M, Kere J, Feki A (2010), A Teratocarcinoma-Like Human Embryonic Stem Cell (hESC) Line and Four hESC Lines Reveal Potentially Oncogenic Genomic Changes, in PLOS ONE, 5(4), 1-10.
Detection of genomic variation by selection of a 9 mb DNA region and high throughput sequencing.
Nikolaev Sergey I, Iseli Christian, Sharp Andrew J, Robyr Daniel, Rougemont Jacques, Gehrig Corinne, Farinelli Laurent, Antonarakis Stylianos E (2009), Detection of genomic variation by selection of a 9 mb DNA region and high throughput sequencing., in PloS one, 4(8), 6659-6659.
Genetic structure of Europeans: a view from the North-East.
Nelis Mari, Esko Tõnu, Mägi Reedik, Zimprich Fritz, Zimprich Alexander, Toncheva Draga, Karachanak Sena, Piskácková Tereza, Balascák Ivan, Peltonen Leena, Jakkula Eveliina, Rehnström Karola, Lathrop Mark, Heath Simon, Galan Pilar, Schreiber Stefan, Meitinger Thomas, Pfeufer Arne, Wichmann H-Erich, Melegh Béla, Polgár Noémi, Toniolo Daniela, Gasparini Paolo, D'Adamo Pio, Klovins Janis (2009), Genetic structure of Europeans: a view from the North-East., in PloS one, 4(5), 5472-5472.
Identifying protein-coding genes in genomic sequences.
Harrow Jennifer, Nagy Alinda, Reymond Alexandre, Alioto Tyler, Patthy Laszlo, Antonarakis Stylianos E, Guigó Roderic (2009), Identifying protein-coding genes in genomic sequences., in Genome biology, 10(1), 201-201.
A new mouse model for the trisomy of the Abcg1-U2af1 region reveals the complexity of the combinatorial genetic code of down syndrome.
Pereira Patricia Lopes, Magnol Laetitia, Sahún Ignasi, Brault Véronique, Duchon Arnaud, Prandini Paola, Gruart Agnès, Bizot Jean-Charles, Chadefaux-Vekemans Bernadette, Deutsch Samuel, Trovero Fabrice, Delgado-García José María, Antonarakis Stylianos E, Dierssen Mara, Herault Yann (2009), A new mouse model for the trisomy of the Abcg1-U2af1 region reveals the complexity of the combinatorial genetic code of down syndrome., in Human molecular genetics, 18(24), 4756-69.
Transcriptional and post-transcriptional profile of human chromosome 21.
Nikolaev Sergey I, Deutsch Samuel, Genolet Raphael, Borel Christelle, Parand Leila, Ucla Catherine, Schütz Frederic, Duriaux Sail Genevieve, Dupré Yann, Jaquier-Gubler Pascale, Araud Tanguy, Conne Beatrice, Descombes Patrick, Vassalli Jean-Dominique, Curran Joseph, Antonarakis Stylianos E (2009), Transcriptional and post-transcriptional profile of human chromosome 21., in Genome research, 19(8), 1471-9.
Common regulatory variation impacts gene expression in a cell type-dependent manner.
Dimas Antigone S, Deutsch Samuel, Stranger Barbara E, Montgomery Stephen B, Borel Christelle, Attar-Cohen Homa, Ingle Catherine, Beazley Claude, Gutierrez Arcelus Maria, Sekowska Magdalena, Gagnebin Marilyne, Nisbett James, Deloukas Panos, Dermitzakis Emmanouil T, Antonarakis Stylianos E (2009), Common regulatory variation impacts gene expression in a cell type-dependent manner., in Science (New York, N.Y.), 325(5945), 1246-50.
Disease-causing 7.4 kb cis-regulatory deletion disrupting conserved non-coding sequences and their interaction with the FOXL2 promotor: implications for mutation screening.
D'haene Barbara, Attanasio Catia, Beysen Diane, Dostie Josée, Lemire Edmond, Bouchard Philippe, Field Michael, Jones Kristie, Lorenz Birgit, Menten Björn, Buysse Karen, Pattyn Filip, Friedli Marc, Ucla Catherine, Rossier Colette, Wyss Carine, Speleman Frank, De Paepe Anne, Dekker Job, Antonarakis Stylianos E, De Baere Elfride (2009), Disease-causing 7.4 kb cis-regulatory deletion disrupting conserved non-coding sequences and their interaction with the FOXL2 promotor: implications for mutation screening., in PLoS genetics, 5(6), 1000522-1000522.
The genome sequence of taurine cattle: a window to ruminant biology and evolution.
Bovine Genome Sequencing and Analysis Consortium, Elsik Christine G, Tellam Ross L, Worley Kim C, Gibbs Richard A, Muzny Donna M, Weinstock George M, Adelson David L, Eichler Evan E, Elnitski Laura, Guigó Roderic, Hamernik Debora L, Kappes Steve M, Lewin Harris A, Lynn David J, Nicholas Frank W, Reymond Alexandre, Rijnkels Monique, Skow Loren C, Zdobnov Evgeny M, Schook Lawrence, Womack James, Alioto Tyler, Antonarakis Stylianos E, Astashyn Alex (2009), The genome sequence of taurine cattle: a window to ruminant biology and evolution., in Science (New York, N.Y.), 324(5926), 522-8.
Proliferation deficits and gene expression dysregulation in Down's syndrome (Ts1Cje) neural progenitor cells cultured from neurospheres.
Moldrich Randal X, Dauphinot Luce, Laffaire Julien, Vitalis Tania, Hérault Yann, Beart Philip M, Rossier Jean, Vivien Denis, Gehrig Corinne, Antonarakis Stylianos E, Lyle Robert, Potier Marie-Claude (2009), Proliferation deficits and gene expression dysregulation in Down's syndrome (Ts1Cje) neural progenitor cells cultured from neurospheres., in Journal of neuroscience research, 87(14), 3143-52.

Collaboration

Group / person Country
Types of collaboration
D Duboule, UNIGE, EPFL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
M Dermitzakis, Sanger Great Britain and Northern Ireland (Europe)
- Publication
X Estivill, CGR Spain (Europe)
- in-depth/constructive exchanges on approaches, methods or results
I Xenarios, SIB Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
T Gingeras, CSHL United States of America (North America)
- Publication
M Jaconi, A Feki, UniGE Switzerland (Europe)
- Publication
C Iseli, LICR Switzerland (Europe)
- Publication
R Guigo, CGR Spain (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
American Society of Human Genetics 01.11.2012 USA
American Society of Human Genetics 01.11.2011 USA
American Society of human Genetics 01.11.2010 USA


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Genome Exposition Western Switzerland

Associated projects

Number Title Start Funding scheme
113127 Genotyping and transcriptome analyses; illumina platform 01.10.2006 R'EQUIP
144082 Chromosome 21: functional genomics and molecular pathophysiology of its disorders 01.10.2012 Project funding
105602 Chromosome 21: functional genomics and molecular pathophysiology of its disorders 01.10.2004 Project funding
121418 Ultra High Throughput sequencing platform for functional genome analysis 01.08.2008 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 by comparative genome analysis 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.
-