Developmental Biology - CNV Genes
CNV Genes Affecting Brains and Brawn?
Genes located in 'copy number variants' (CNVs) - parts of chromosomes missing in some people and duplicated in others - are now associated with neurodevelopmental disorders more than brain development...
These new findings, by a team of Penn State researchers, appeared June 24 in the journal PLOS Genetics, and could have important implications in clinical and genetic counseling, where it's vital to have a full understanding of potential impacts of CNVs.
"Copy number variants have been studied extensively, and are often associated with neurodevelopmental disorders such as autism. But, many disorders associated with CNVs also result in heart, kidney, or skeletal defects. Although most research only looks for behavioral or cognitive effects in animal models, we looked at how genes in CNVs affect development outside of the nervous system."
Santhosh Girirajan PhD, Associate Professor, Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania; Department of Anthropology, Pennsylvania State University, University Park, Pennsylvania, USA.
The research team tested the effect of reducing the expression of dozens of genes located within CNVs, mimicking the effect of deletions in developing fruit-fly wings. Most of these genes, thought of mainly in terms of neurodevelopment, had also disrupted wing development.
The team identified fruit-fly gene counterparts in ten different human copy number variants. Then, using a technique called "RNA interference" reduced the function of these genes in developing fruit-fly wings. Referred to as "knocking down" gene expression [function] - this process mimics deletion of that gene on one chromosome of a chromosome pair, the same as found in human copy number variants.
"We tested 59 genes from human CNVs that cause neurodevelopment disorders, plus 20 other genes that have important roles in neurodevelopment.
We found decreased dosage of 72 of 79 genes had measurable effects on wing development, including six lethal to the developing fly. This indicates their critical role in early development across multiple organ systems."
Tanzeen Yusuff PhD, Postdoctoral Researcher, Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania, USA.
Researchers also compared the impact of knocking out genes in the wing to the effect of knocking them down in the fly eye, used as an experimental system for identifying neurodevelopmental defects.
While reduced dosage of most genes caused defects in both the eye and wing, there was no correlation between the severity of the effects, suggesting that genes that caused major disruptions to eye development, and therefore would likely have a major impact on brain development, could have only slight effects on wing development and vice versa.
"We also found CNV genes are expressed in many other organs in both flies and humans, including heart, kidney, liver, and muscle. Our analysis of gene interaction networks also showed that CNV genes are likely to affect different cellular mechanisms across these organs."
Matthew Jensen, Graduate Student, Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania, USA, and co-first author of the paper.
"Researchers had primarily thought that genes associated with autism and intellectual disability are specific to neurodevelopment, but most of them are not. When a child is diagnosed with one of these disorders, the focus has usually been on cognition and behavior, but our study suggests that we should take a more global approach to catch potential heart or kidney defects, for example, as early as possible."
Santhosh Girirajan PhD.
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.
Rare copy-number variants (CNVs), or large deletions and duplications in the genome, are associated with both neuronal and non-neuronal clinical features. Previous functional studies for these disorders have primarily focused on understanding the cellular mechanisms for neurological and behavioral phenotypes. To understand how genes within these CNVs contribute to developmental defects in non-neuronal tissues, we assessed 79 homologs of CNV and known neurodevelopmental genes in Drosophila models. We found that most homologs showed developmental defects when knocked down in the adult fly wing, ranging from mild size changes to severe wrinkled wings or lethality. Although a majority of tested homologs showed defects when knocked down specifically in wings or eyes, we found no correlation in the severity of the observed defects in these two tissues. A subset of the homologs showed disruptions in cellular processes in the developing fly wing, including alterations in cell proliferation, apoptosis, and cellular signaling pathways. Furthermore, human CNV genes also showed differences in gene expression patterns and interactions with signaling pathway genes across multiple human tissues. Our findings suggest that genes within CNV disorders affect global developmental processes in both neuronal and non-neuronal tissues.
Tanzee Yusuff, Matthew Jensen, Sneha Yennawar, Lucilla Pizzo, Siddharth Karthikeyan, Dagny J. Gould, Avik Sarker, Erika Gedvilaite, Yurika Matsui, Janani Iyer, Zhi-Chun Lai and Santhosh Girirajan.
The research was supported by U.S. National Institutes of Health with additional support from Penn State Huck Institutes of Life Sciences.
The authors thank Drs. Scott Selleck and Claire Thomas for providing fly lines for the experiments, and members of the Girirajan Lab for their helpful discussions and comments on the manuscript. This study makes use of data generated by the DECIPHER community. A full list of centers who contributed to the generation of the data is available from http://decipher.sanger.ac.uk and via email from firstname.lastname@example.org. Funding for the DECIPHER project was provided by the Wellcome Trust.
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Jul 22 2020 Fetal Timeline Maternal Timeline News
Genes in copy number variant (CNV) regions of the human genome - typically associated with neurodevelopment - cause defects in both the fly eye (neuronal) and wing (non-neuronal) tissues. Although, severity did not correlate between the two tissues. CNV genes globally affect biological processes important to development, causing different effects across multiple organs.
CREDIT Girirajan Laboratory, Penn State