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 Hugo J. Bellen (BCM), Michael F. Wangler (BCM), Shinya Yamamoto (BCM), Monte Westerfield (UO), and John Postlethwait (UO). The Washington University in St. Louis (WashU) MOSC is led by Lilianna Solnica-Krezel, Tim Schedl, Dustin Baldridge, and Stephen C. Pak.

BCM-UO MOSC Leadership

WashU 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. Drosophila, C. 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

Loss-of-function in RBBP5 results in a syndromic neurodevelopmental disorder associated with microcephaly

AI-MARRVEL – A Knowledge-Driven AI System for Diagnosing Mendelian Disorders

Dominant missense variants in SREBF2 are associated with complex dermatological, neurological, and skeletal abnormalities

Loss of function of FAM177A1, a Golgi complex localized protein, causes a novel neurodevelopmental disorder

Loss of the endoplasmic reticulum protein Tmem208 affects cell polarity, development, and viability

Rare de novo gain-of-function missense variants in DOT1L are associated with developmental delay and congenital anomalies

Macrocephaly and developmental delay caused by missense variants in RAB5C

Bi-allelic variants in INTS11 are associated with a complex neurological disorder

De novo variants in MRTFB have gain-of-function activity in Drosophila and are associated with a novel neurodevelopmental phenotype with dysmorphic features

A de novo missense variant in EZH1 associated with developmental delay exhibits functional deficits in Drosophila melanogaster

SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia

The recurrent de novo c.2011C>T missense variant in MTSS2 causes syndromic intellectual disability

The microRNA processor DROSHA is a candidate gene for a severe progressive neurological disorder

ModelMatcher: A scientist-centric online platform to facilitate collaborations between stakeholders of rare and undiagnosed disease research

Functional analysis of a novel de novo variant in PPP5C associated with microcephaly, seizures, and developmental delay

A dominant negative variant of RAB5B disrupts maturation of surfactant protein B and surfactant protein C

Heterozygous loss-of-function variants significantly expand the phenotypes associated with loss of GDF11

Functional analysis of a de novo variant in the neurodevelopment and generalized epilepsy disease gene NBEA

TNPO2 variants associate with human developmental delays, neurologic deficits, and dysmorphic features and alter TNPO2 activity in Drosophila

Rare deleterious de novo missense variants in Rnf2/Ring2 are associated with a neurodevelopmental disorder with unique clinical features

BICRA, a SWI/SNF Complex Member, Is Associated with BAF-Disorder Related Phenotypes in Humans and Model Organisms

De novo mutations in TOMM70, a receptor of the mitochondrial import translocase, cause neurological impairment

De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy

Loss- or Gain-of-Function Mutations in ACOX1 Cause Axonal Loss via Different Mechanisms

De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia

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

Tutorial Articles

Using MARRVEL v1.2 for Bioinformatics Analysis of Human Genes and Variant Pathogenicity

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila

Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information

Review Articles

Integrating non-mammalian model organisms in the diagnosis of rare genetic diseases in humans

Sphingolipids in neurodegenerative diseases

Drosophila as a diet discovery tool for treating amino acid disorders

‘Fly-ing’ from rare to common neurodegenerative disease mechanisms

Recent insights into the role of glia and oxidative stress in Alzheimer’s disease gained from Drosophila

Model organisms contribute to diagnosis and discovery in the Undiagnosed Diseases Network: current state and a future vision

Using Drosophila to drive the diagnosis and understand the mechanisms of rare human diseases.

The fruit fly at the interface of diagnosis and pathogenic mechanisms of rare and common human diseases

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

U54NS093793

U54NS108251

U2CNS132415

Photos