• Le 09 octobre 2018
    Institut de Recherche en Santé - 8 quai Moncousu - Nantes
    Amphithéâtre Denis Escande
  • 11h30

Functional dissection of pediatric genetic disease

Functional dissection of pediatric genetic disease

Erica DAVIS, PhD, invited by Stéphane Bezieau (Eq Emergente)
Associate Professor, Center for Human Disease Modeling
Departments of Pediatrics and Cell Biology
Duke University Medical Center
Durham, NC, USA


ABSTRACT

The current ability to sequence whole exomes and genomes has reached an unprecedented pace. Variant data have been cataloged for over one million humans, representative of Mendelian disease cohorts, complex trait consortia, and healthy populations. This flood of information, expected to grow hyper-exponentially in the coming years, has already fueled the development of animal models to assign physiological relevance of genotype to phenotype; to inform variant pathogenicity; and to dissect multi-locus interactions. Here, we discuss our experience with the zebrafish model and its refined molecular toolkit to conduct scalable throughput analyses of novel disease genes implicated in rare pediatric disease in humans. We have placed particular emphasis on congenital anomalies in children impacting the structure of the brain, face, and kidney due to their direct anatomical surrogates in the developing zebrafish. Recent exemplars that we will highlight include: (1) the use of zebrafish to provide supporting data for rare human cases in which genetic evidence from population datasets is insufficient to support causality of novel disease genes; (2) application of zebrafish models to determine direction of allele effect for genes impacted by either copy number variants or missense mutations; and (3) validation of functional networks contributing to overlapping human phenotypes. In addition to the application of our work to inform human health, we will discuss our implementation of automated image acquisition platforms, as well as comparisons between transient and CRISPR/Cas9 zebrafish mutant models.