UDN

Solving Medical Mysteries
Through Team Science

Model Organisms

Overview

The Model Organisms Screening Center (MOSC) for the Undiagnosed Diseases Network (UDN) is composed of two Centers that use fruit fly (Drosophila melanogaster), nematode worm (Caenorhabditis elegans) and zebrafish (Danio rerio) genetics and biology to tackle rare and undiagnosed diseases. By combining state-of-the-art genetic and genomic technologies, the MOSCs investigate whether a rare variant identified in the genomes of UDN participants may contribute to disease pathogenesis. The Baylor College of Medicine (BCM)-University of Oregon (UO) MOSC is led by Drs. Hugo J. Bellen (BCM), Michael F. Wangler (BCM), Shinya Yamamoto (BCM), Monte Westerfield (UO) and John Postlethwait (UO). The Washington University in St. Louis (WUSTL) MOSC is led by Drs. Tim Schedl, Lilianna Solnica-Krezel, Dustin Baldridge, Angela Bowman and Stephen C. Pak.

BCM-UO MOSC Leadership
WUSTL MOSC Leadership
Why flies, worms and zebrafish?

Over the past century, genetic model organisms have taught us so much about human biology and disease mechanisms. Although these organisms (e.g. bacteria, yeast, worm, fly, zebrafish, mouse) may look very different from us, fundamental biological mechanisms and genes are well conserved throughout evolution. To investigate the functional consequences of hundreds of rare variants found through sequencing UDN participants’ and their family members’ genomes, the MOSCs use three model organisms, fruit fly (Drosophila melanogaster), nematode worm (Caenorhabditis elegans) and zebrafish (Danio rerio). These animals are cost efficient, have short life-cycles and are amenable to sophisticated genetic manipulations to “model” a human disease condition. DrosophilaC. elegans and zebrafish are complementary to one another, providing synergistic strengths. Candidate genes and variants that are shown to have functional impacts can be further pursued in mammalian model systems, such as mouse and human pluripotent stem cells, for further translational studies.

Workflow

When a diagnosis is not reached after performing a thorough clinical, genetic and/or metabolomic workup, the UDN Clinical Sites submit candidate gene(s)/variant(s) to the MOSCs together with a brief description of the participant’s condition. The MOSCs then perform database searches using a number of bioinformatics tools, including the MARRVEL tool (marrvel.org, see below), to aggregate existing information on the human gene/variant and its model organism orthologs. The MOSCs also try to identify other individuals with similar genotype and phenotype in other cohorts, a practice known as “matchmaking”. Once a variant is considered to be a high priority candidate, experiments to assess gene and variant function are designed by MOSC investigators and pursued in the C. elegans Core, Drosophila Core or Zebrafish Cores.

MARRVEL

In collaboration with Drs. Zhandong Liu’s (BCM) and Norbert Perrimon’s (Harvard Medical School) bioinformatics team, the BCM-UO MOSC developed a powerful online tool that allows anyone to quickly gather gene and variant function information. MARRVEL (Model organism Aggregated Resources for Rare Variant ExpLoration) is a novel web-based tool that integrates human and model organism databases to facilitate molecular diagnosis. MARRVEL can also be used by model organism researchers to assess whether specific model organism genes of interest may have links to human diseases. MARRVEL is publicly available for clinicians and researchers worldwide at marrvel.org, and we will be continuously updating and upgrading this tool for the community.

Publications
Research Articles

A Recurrent De Novo Heterozygous COG4 Substitution Leads to Saul-Wilson Syndrome, Disrupted Vesicular Trafficking, and Altered Proteoglycan Glycosylation

IRF2BPL Is Associated with Neurological Phenotypes

Functional variants in TBX2 are associated with a syndromic cardiovascular and skeletal developmental disorder

Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder

Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially

MARRVEL: Integration of Human and Model Organism Genetic Resources to Facilitate Functional Annotation of the Human Genome

A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3

A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay

Review Articles

Fruit flies in biomedical research

Morgan’s legacy: fruit flies and the functional annotation of conserved genes 

Bedside Back to Bench: Building Bridges between Basic and Clinical Genomic Research

Model Organisms Facilitate Rare Disease Diagnosis and Therapeutic Research

Funding

RFAs: RFA-RM-14-016 and RFA-RM-17-017

Grant numbers: 1U54NS093793-01, 2U54NS093793-04, 1U54NS108251-01

External links

BCM MOSC website

Photos