PROJECT SUMMARY Down syndrome (DS) is the most common genetic cause of intellectual disability. While societal improvements have enhanced the quality of life for those with DS, which 21st chromosome (Hsa21) genes are responsible for the multitude of characteristic phenotypes that accompany DS remains unknown. These include intellectual disability, motor incoordination, low muscle tone, and craniofacial abnormalities, which are consistent across people with DS, as well as other variably-occurring co-morbid conditions such as congenital heart disease and autism, to name just a few. Although mouse models have shed light on the role some Hsa21 genes play in some phenotypes, such as Alzheimer’s pathology (APP) and leukemia (GATA1), most Hsa21 genes have not been studied in detail. This study will circumvent the time-consuming and costly use of mouse models for the study of individual Hsa21 genes by systematically investigating which Hsa21 genes cause behavioral deficits when overexpressed in the efficient model Caenorhabditis elegans. Our lab found that C. elegans shares 51 highly-conserved genes with the human 21st chromosome. Through the study of mutants for these genes, we found that in worm 14 Hsa21 orthologs are essential genes and 10 Hsa21 orthologs are required for neural or muscular function, 3 of which had not previously been studied. This study will use epistasis analysis to further functionally characterize one of those novel genes, mtq-2, which appears to be an important novel modifier of synaptic G-protein signaling. Additionally, to probe how overexpression (OE) of individual Hsa21 genes contributes to DS phenotypes, a set of 51 C. elegans transgenic strains that each overexpresses a different conserved Hsa21 ortholog will be generated. This set will be assessed one-by-one using high-throughput, quantitative behavioral analyses to deduce which genes cause neural or muscular dysfunction when overexpressed. This research will be conducted through the University of Texas’s highly supportive and well-resourced Institute for Neuroscience graduate program, under the direction of a PI who has ample experience mentoring successful PhD students. The trainee has demonstrated leadership by founding a large women’s STEM professional organization. Inspired by a sister with DS, the trainee plans to apply her leadership, scientific expertise, and personal insights to run a DS lab following postdoctoral training. By identifying Hsa21 genes that cause phenotypes when overexpressed in C. elegans, this study will spotlight genes to prioritize for further study by her and others in mouse and human stem-cell models of DS. The set of Hsa21 OE strains produced will be shared freely around the world to establish C. elegans as the first mechanistic in vivo model to conveniently study consequences of individual Hsa21 gene OE. This will promote DS research by additional worm labs and allow other DS labs to expand their repertoire of model systems for studying spec...