Systematic Functional Characterization of Human 21st Chromosome Orthologs in .

Individuals with Down syndrome have neurological and muscle impairments due to an additional copy of the human 21st chromosome (HSA21). Only a few of ∼200 HSA21 genes encoding proteins have been linked to specific Down syndrome phenotypes, while the remainder are understudied. To identify poorly characterized HSA21 genes required for nervous system function, we studied behavioral phenotypes caused by loss-of-function mutations in conserved HSA21 orthologs in the nematode We identified 10 HSA21 orthologs that are required for neuromuscular behaviors: (), (), (), (), (), (), (), (), (), and (). We also found that three of these genes are required for normal release of the neurotransmitter acetylcholine. This includes a known synaptic gene (), as well as uncharacterized genes () and (). As the first systematic functional analysis of HSA21 orthologs, this study may serve as a platform to understand genes that underlie phenotypes associated with Down syndrome.