Systematic Functional Characterization of Human 21st Chromosome Orthologs inCaenorhabditis elegans

Abstract

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 Caenorhabditis elegans. We identified 10 HSA21 orthologs that are required for neuromuscular behaviors: cle-1 (COL18A1), cysl-2 (CBS), dnsn-1 (DONSON), eva-1 (EVA1C), mtq-2 (N6ATM1), ncam-1 (NCAM2), pad-2 (POFUT2), pdxk-1 (PDXK), rnt-1 (RUNX1), and unc-26 (SYNJ1). We also found that three of these genes are required for normal release of the neurotransmitter acetylcholine. This includes a known synaptic gene unc-26 (SYNJ1), as well as uncharacterized genes pdxk-1 (PDXK) and mtq-2 (N6ATM1). 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.

Survey of Human Chromosome 21 Gene Expression Effects on Early Development in Danio rerio

“…For example, sod1 , rrp1 and ybey are expressed in somites, cct8 is expressed ubiquitously, jam2 shows expression in the region of the developing heart and erg is expressed in the vasculature ( Table 2 ). pofut2 is expressed in the brain and eye ( Ohata et al 2009 ); knockdown of a C. elegans homolog of this gene produced a neuromuscular phenotype ( Nordquist et al 2018 ). pcbp3 is expressed in the retina and telencephalon beginning at the Prim-15 stage ( Thisse and Thisse 2004 ).…”

“…Recently, a screen to examine the effects of down-regulating orthologs of 47 Hsa21 genes was performed in Caenorhabditis elegans ( Nordquist et al 2018 ). Ten of these conserved genes exhibited neurobehavioral phenotypes: COL18A1 , CBS , DONSON , EVA1C , N6AMT , NCAM2 , POFUT2 , PDXK , RUNX1 and SYNJ1 ( Nordquist et al 2018 ). Of these ten genes, five were shown to be essential for development based on the lethality phenotype seen in mouse knock-out models.…”

OrthoList 2: A New Comparative Genomic Analysis of Human and Caenorhabditis elegans Genes

“…Subsequently, we created a minimal, unpublished, online tool distributed through informal C. elegans community channels to enhance its accessibility and utility. OrthoList has indeed both facilitated the identification of orthology (e.g., Firnhaber and Hammarlund 2013;Du et al 2015;Vahdati Nia et al 2017) and has been used as the basis for streamlining RNAi screens (e.g., Gillard et al 2015;Hernando-Rodríguez et al 2018;Nordquist et al 2018).…”

“…OrthoList has already been used to design streamlined RNAi screens that yielded important discoveries (e.g., Gillard et al 2015;Hernando-Rodríguez et al 2018;Nordquist et al 2018). To further facilitate the design of such screens, our new Web-based tool not only includes the most up-to-date version of the widely used C. elegans feeding RNAi library, but it also allows users to focus their screens even further by generating lists based on protein domains and/or human disease associations.…”

Modeling Down syndrome in animals from the early stage to the 4.0 models and next

“…elegans is a well-established genetic model and shows homology with 13.7 % of the genes from HSA21. To identify poorly characterized HSA21 genes required for nervous system function, Norquist and collaborators (Nordquist et al, 2018) performed a systematic functional characterization of HSA21 orthologs in C. elegans. They did a knockdown screen (RNA interference) and studied behavioural phenotypes caused by loss-of-function mutations in conserved HSA21 orthologs in the nematode.…”