Abstract
While rare pathogenic copy-number variants (CNVs) are associated with both neuronal and non-neuronal phenotypes, functional studies evaluating these regions have focused on the molecular basis of neuronal defects. We report a systematic functional analysis of non-neuronal defects for homologs of 59 genes within ten pathogenic CNVs and 20 neurodevelopmental genes in Drosophila melanogaster. Using wing-specific knockdown of 136 RNA interference lines, we identified qualitative and quantitative phenotypes in 72/79 homologs, including 21 lines with severe wing defects and six lines with lethality. In fact, we found that 10/31 homologs of CNV genes also showed complete or partial lethality at larval or pupal stages with ubiquitous knockdown. Comparisons between eye and wing-specific knockdown of 37/45 homologs showed both neuronal and non-neuronal defects, but with no correlation in the severity of defects. We further observed disruptions in cell proliferation and apoptosis in larval wing discs for 23/27 homologs, and altered Wnt, Hedgehog and Notch signaling for 9/14 homologs, including AATF/Aatf, PPP4C/Pp4-19C, and KIF11/Klp61F. These findings were further supported by tissue-specific differences in expression patterns of human CNV genes, as well as connectivity of CNV genes to signaling pathway genes in brain, heart and kidney-specific networks. Our findings suggest that multiple genes within each CNV differentially affect both global and tissue-specific developmental processes within conserved pathways, and that their roles are not restricted to neuronal functions.
Highlights
Rare copy-number variants (CNVs), or deletions and duplications in the genome, are associated with neurodevelopmental disorders such as autism, intellectual disability (ID), and schizophrenia [1,2]
While dosage alteration of CNV regions contribute predominantly to defects in nervous system development, several CNV-associated disorders lead to early developmental features involving other organ systems [3,4], including cardiac defects [5,6], kidney malformations [7], craniofacial features [3], and skeletal abnormalities [8]
We categorized adult female wing phenotypes based on their severity, and performed k-means clustering analysis to categorize each RNA interference (RNAi) line by their overall phenotypic severity (Fig 2A and 2B)
Summary
Rare copy-number variants (CNVs), or deletions and duplications in the genome, are associated with neurodevelopmental disorders such as autism, intellectual disability (ID), and schizophrenia [1,2]. The 1q21.1 deletion causes variable expression of multiple neuronal and non-neuronal phenotypes, including developmental delay, autism, and schizophrenia as well as craniofacial features, cataracts, cardiac defects, and skeletal abnormalities [10,11,12]. Despite the prevalence of non-neuronal phenotypes among CNV carriers, functional studies of CNV genes have primarily focused on detailed assessments of neuronal and behavioral phenotypes in model systems. While Haller and colleagues showed that mice with knockdown of MAZ, a gene within the 16p11.2 deletion region, exhibit genitourinary defects observed in individuals with the deletion [20], mouse studies for other homologs of 16p11.2 genes, including TAOK2, KCTD13, and MAPK3, have only focused on assessing neuronal defects [21,22,23,24,25]. Dickinson and colleagues reported a high-throughput analysis of essential genes in mice and identified both neuronal and non-neuronal phenotypes for individual gene knockouts, including more
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