Caernorhabditis elegans model for 16p11.2 recurrent microdeletion suggests differential effects of conserved genes to knockdown
Area of Honors:
Biochemistry and Molecular Biology
Bachelor of Science
Dr. Santhosh Girirajan, Thesis Supervisor David Scott Gilmour, Honors Advisor
C. elegans 16p11.2 Autism Genetics
The 16p11.2 deletion syndrome is a rare (<1% of population) copy number variation (CNV) associated with a wide range of neurodevelopmental disorders, with a prevalence of 0.6% of patients for Autism Spectrum Disorder (ASD), 0.4% of patients with intellectual disability, and developmental birth defects. , , Such neurodevelopmental disorders are characterized by diminished cognitive functionality and motor defects. The extensive genetic diversity associated with neurodevelopmental disorders causes their underlying functionality to remain unknown. In this study, one-hit and two-hit knockdown of orthologous 16p11.2 genes in C. elegans models elucidated the cellular and behavioral phenotypes and trends associated with each individual gene. We tested eight neurodevelopmental genes to document differential sensitivities of these genes in dosage alterations. Of the eight orthologous genes present between C. elegans and H. Sapiens, motor defects and body area phenotypes were commonly associated with the suppression of aldo-1, k09a9.6, and mpk-1 human orthologs. Following the neurodevelopmental two-hit model proposed by Girirajan et. al., two-hit knockdowns of the eight orthologous genes were paired systematically, and revealed that two-hit pairings with aldo-1, k09a9.6, and mpk-1 demonstrated increased sensitivity in neurodevelopmental and behavioral phenotypes in relation to one-hit models. These results suggest the importance of further studies of the mechanistic factors associated with morphological changes and motor dysfunction within the 16p11.2 region.