Date of Award
8-2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Genetics and Biochemistry
Committee Chair/Advisor
Trudy F. C. Mackay
Committee Member
Robert R. H. Anholt
Committee Member
Frank Alexander Feltus
Committee Member
Jennifer Mason
Abstract
Fetal Alcohol Spectrum Disorders are a group of disorders resulting from prenatal alcohol exposure, presenting with neurodevelopmental and facial abnormalities of varying severity. SSRIDDs and CdLS are rare disorders of chromatin modification, resulting in patients with a wide range of craniofacial, digit and/or neurodevelopmental abnormalities. All of these disorders have a wide range of clinical phenotypes and disease severity, yet the role of potential genetic modifiers and gene-gene or gene-environment interactions in disease pathogenesis is largely unknown and cannot be studied in humans. Insufficient numbers of patients with a single rare disorder prevent investigation of genetic factors beyond the focal disease-associated variant, while experimental study of the more common FASD using human subjects is prohibited due to ethical constraints. Drosophila melanogaster is an excellent model system for neurodevelopmental disorders, as Drosophila neurobiology is largely conserved in humans and experiments performed in Drosophila are low-cost, easily controlled, and exempt from regulation. Here, we take advantage of the Drosophila model system and identify genetic factors contributing to these neurodevelopmental disorders. Specifically, we used the Drosophila Genetic Reference Panel (DGRP) of inbred lines with full genome sequences and single cell RNA sequencing to identify genetic networks in adult Drosophila after developmental ethanol exposure and demonstrate that changes in sleep, activity, and time to sedation as a result of the developmental ethanol exposure are dependent on genetic background. We also developed a novel assay measuring time to ethanol-induced sedation of individual flies to better assess this phenotype in our research and characterized a previously unstudied long noncoding RNA critical for Drosophila fitness and stress-response. We then established Drosophila models for multiple SSRIDD and CdLS subtypes and determined the extent to which behavioral and transcriptomic phenotypes vary within and across these rare disorders. Finally, we used SSRIDD Drosophila models to present evidence for the role of genetic modifiers in ARID1B-associated SSRIDD and identify candidate genetic modifiers for multiple SSRIDD subtypes. Taken together, these results show that the Drosophila model system is a powerful tool for investigating the genetic underpinnings of both rare and common neurodevelopmental disorders that cannot be currently identified using human populations.
Recommended Citation
MacPherson, Rebecca, "A Systems Genetics Approach to Drosophila melanogaster Models of Rare and Common Neurodevelopmental Disorders" (2023). All Dissertations. 3386.
https://tigerprints.clemson.edu/all_dissertations/3386
Author ORCID Identifier
0000-0002-3597-4097