Solving the genomic jigsaw: Causes and consequences of complex genomic structural variations

Samenvatting

Genomic mutations and chromosomal rearrangements drive a wide range of diseases, including congenital disorders and cancer. Complex genomic structural variations (SVs), including recently discovered chromothripsis events that scramble large genomic regions, contribute to this landscape by reshuffling and disturbing both coding and regulatory elements. Currently, there are two main outstanding questions: What are the pathogenic mechanisms resulting from such rearrangements and what triggers these potentially highly pathogenic events?
To understand how rearrangements drive pathology, I will study the consequences of complex de novo SVs in patients with congenital disorders by family-based molecular profiling using next-generation sequencing (NGS) techniques. Preliminary work unexpectedly identified chromosomal alterations that were also observed in cancer. Here, I will apply this approach to additional patient cases to systematically identify disease genes and the pathways involved (Aim 1). I will specifically dissect the molecular mechanisms by which recurrent SVs both drive congenital disorders and contribute to tumorigenesis using patient cell-based, zebrafish, and mouse models (Aim 2). These efforts will improve current current diagnostic for congenital disorders and improve our abilities to interpret whole-genome sequencing data (personal genomes) in relation to disease and disease susceptibilities.
To understand how complex structural arrangements arise, I will build on the observation that chromosome missegregation during cell division can result in aneuploidies and structural rearrangements. I will construct an optogenetic system to allow labelling, tracking and sorting of cultured cells with missegregating or damaged chromosomes (Aim 3). Individual and pooled cells will be collected at various time-points and cellular responses will be characterized at both the genomic and transcriptomic levels using NGS-based techniques. Molecular mechanisms will be unravelled by the functional manipulation of DNA-damage response systems and perturbation of environmental conditions. These experiments will provide novel fundamental insight in complex SVs and chromothripsis processes and may provide leads for cancer treatment strategies.

Producten

Wetenschappelijk artikel

Kenmerken

Projectnummer

865.13.004

Hoofdaanvrager

Prof. dr. ir. E.P.J.G. Cuppen

Verbonden aan

Koninklijke Nederlandse Akademie van Wetenschappen, Hubrecht Instituut voor Ontwikkelingsbiologie en Stamcelonderzoek, Genregulatie

Uitvoerders

Prof. dr. ir. E.P.J.G. Cuppen, L. de la Fonteijne, Ing. RRE Janssen, Dr. J.P. Korzelius, Dr. J.P. Korzelius, Dr. E.W. Kuijk, Drs. S. Middelkamp, Drs. S Middelkamp, N.B. Niet Bekend en Niet Gebruiken, N.B. Niet Bekend en Niet Gebruiken, Drs. J Vlaar

Looptijd

01/07/2014 tot 30/06/2019