Project

genomic variability; trisomy 21; transcriptome; chromatin; mouse models; single cell genomics; transcription factors; zebrafish models; DNA Sequence

Lead
Le syndrome de Down est la plus fréquente des anomalies génomiques liées aux troubles de la déficience intellectuelle ; celui-ci est causé par la présence d’une copie numérique du chromosome 21 (trisomie 21) dans le génome des personnes atteintes. Bien que cette anomalie chromosomique ait été décrite en 1959 et que le séquençage du contenu du chromosome 21 a été finalisé en 2002, les causes moléculaires des différents symptômes de ce syndrome sont encore méconnues à ce jour et il n’existe toujours pas de traitement connu. Au cours des dernières décennies, les méthodes de diagnostic ont connu d’importants progrès ; un nouveau test non invasif sur le sang maternel permet de dépister de façon précise et fiable les trisomies 21 fœtales pendant la grossesse.
Lay summary
Les progrès récents en génétique/génomique et en bioinformatique permettent actuellement l'étude des mécanismes moléculaires conduisant à une aneuploïdie des différents symptômes du syndrome de Down tels que la déficience intellectuelle, les malformations cardiaques congénitales, la leucémie, l’apparition précoce de la maladie d'Alzheimer, ainsi que le vieillissement prématuré. Les objectifs de ce projet sont de comprendre les mécanismes moléculaires responsables du syndrome de Down. Les méthodologies expérimentales sont basées sur l'analyse génomique des échantillons des patients, des expériences en laboratoire et une analyse bioinformatique. Les retombées de ces études seront transposables à d’autres anomalies chromosomiques et à chacun des symptômes du syndrome de Down. De plus, les résultats de nos investigations généreront de nouveaux axes de recherche pour de futurs traitements encore impensables il y a quelques années.

Direct link to Lay Summary

Last update: 19.10.2015

Title	Year

Number	Title	Start	Funding scheme

Trisomy 21 (Down syndrome; DS; T21) is the most common known cause of mental retardation and it also provides a model for the study of genomic aneuploidies. The knowledge of the molecular pathogenesis of T21 is poor (even after 55 years from the discovery of T211), and does not yet allow effective treatment of this common genomic disorder. Many advances of the last 15 years, however, provide a reasonable enthusiasm for the understanding of this “model” 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 for comparative genome analysis and 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 advances in computational biology, vi) the capability of producing induced pluripotent stem cells (iPS), vii) the use of mouse and other models, viii) the recent advances in genome editing, ix) the ability to perform genomic studies in single cells. 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. T21 remains the model for aneuploidies and gene dosage imbalance; in addition T21 is associated with several phenotypes such as intellectual disability, accelerated ageing, Alzheimer disease, developmental abnormalities including heart defects, leukemias, and thus could be considered as a model to also understand certain aspects of these disorders. Thus, the fundamental understanding of the genomic dosage imbalance in T21 is applicable to numerous other genomic alterations.In this grant application we propose to continue the functional genome analysis of HSA21 and the genome dysfunction due to the supernumerary HSA21, explore the power of single cell genomic analysis to understand the cellular impact of aneuploidy, and elucidate the molecular basis of one of the most characteristic and tractable phenotypes of T21, the congenital heart defects. The specific aims of the proposal are to: 1) Study the molecular causes of Gene Expression Dysregulation in T21. 2) Discover the molecular basis of the Congenital Heart Defects in T21.3) Use single cell genomic analysis to study the cellular impact of aneuploidy. 4) Identify the regulatory networks of the transcription factors encoded by HSA21The results of this research will contribute to the elucidation of the complex mechanisms of the phenotypic consequences of genomic dosage imbalance, that are likely to be related to the variability of the functional components of the genome.