Studying synthetic lethal interactions in the zebrafish system: insight into disease genes and mechanisms

Hajeri, Vinita A.; Amatruda, James F.

doi:10.1242/dmm.007989

Cited by 10 publications

(8 citation statements)

References 56 publications

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“…Future studies using PLA might pinpoint the subcellular localization of their interaction with CPAP. Genetic interaction studies have been successfully used to study cellular pathways in model systems, for example zebrafish [63]. They can provide useful information about protein-protein complexes, downstream pathways and parallel pathways.…”

Section: Discussionmentioning

confidence: 99%

Genetic and protein interaction studies between the ciliary dyslexia candidate genes DYX1C1 and DCDC2

Bieder

Chandrasekar

Wason

et al. 2023

BMC Mol and Cell Biol

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Background DYX1C1 (DNAAF4) and DCDC2 are two of the most replicated dyslexia candidate genes in genetic studies. They both have demonstrated roles in neuronal migration, in cilia growth and function and they both are cytoskeletal interactors. In addition, they both have been characterized as ciliopathy genes. However, their exact molecular functions are still incompletely described. Based on these known roles, we asked whether DYX1C1 and DCDC2 interact on the genetic and the protein level. Results Here, we report the physical protein-protein interaction of DYX1C1 and DCDC2 as well as their respective interactions with the centrosomal protein CPAP (CENPJ) on exogenous and endogenous levels in different cell models including brain organoids. In addition, we show a synergistic genetic interaction between dyx1c1 and dcdc2b in zebrafish exacerbating the ciliary phenotype. Finally, we show a mutual effect on transcriptional regulation among DYX1C1 and DCDC2 in a cellular model. Conclusions In summary, we describe the physical and functional interaction between the two genes DYX1C1 and DCDC2. These results contribute to the growing understanding of the molecular roles of DYX1C1 and DCDC2 and set the stage for future functional studies.

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Section: Discussionmentioning

confidence: 99%

Genetic and protein interaction studies between the ciliary dyslexia candidate genes DYX1C1 and DCDC2

Bieder

Chandrasekar

Wason

et al. 2023

BMC Mol and Cell Biol

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“…Several challenges still remain for understanding compensation mechanisms under different environmental and genetic variations. Functional compensation in SSL pairs might follow the four different mechanisms proposed by Kaelin: inclusion of direct surrogacy, subunits of an essential multiprotein complex, an essential linear pathway, and parallel pathways [ 56 , 57 ]. Furthermore, the biological robustness of more organisms can be investigated through the concept of synthetic lethality, such as Drosophila melanogaster , Caenorhabditis elegans, and Danio rerio [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

Feature Identification of Compensatory Gene Pairs without Sequence Homology in Yeast

Peng

Lin

Peng

et al. 2012

Comparative and Functional Genomics

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Genetic robustness refers to a compensatory mechanism for buffering deleterious mutations or environmental variations. Gene duplication has been shown to provide such functional backups. However, the overall contribution of duplication-based buffering for genetic robustness is rather small. In this study, we investigated whether transcriptional compensation also exists among genes that share similar functions without sequence homology. A set of nonhomologous synthetic-lethal gene pairs was assessed by using a coexpression network, protein-protein interactions, and other types of genetic interactions in yeast. Our results are notably different from those of previous studies on buffering paralogs. The low expression similarity and the conditional coexpression alone do not play roles in identifying the functionally compensatory genes. Additional properties such as synthetic-lethal interaction, the ratio of shared common interacting partners, and the degree of coregulation were, at least in part, necessary to extract functional compensatory genes. Our network-based approach is applicable to select several well-documented cases of compensatory gene pairs and a set of new pairs. The results suggest that transcriptional reprogramming plays a limited role in functional compensation among nonhomologous genes. Our study aids in understanding the mechanism and features of functional compensation more in detail.

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“…For instance, the phenomenon of synthetic lethality occurs when two genetic mutations, which by themselves cause no effect, are both present in the same gene and their presence together results in a defective protein product. 87 Furthermore, genetic interactions appear to be ubiquitous throughout the genome. 88 However, predicting how independent genes combine with each other to create emergent properties is not straightforward.…”

Section: Gene Network In the Developing Human Brainmentioning

confidence: 99%

Functional genomics of human brain development and implications for autism spectrum disorders

2015

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Transcription of the inherited DNA sequence into copies of messenger RNA is the most fundamental process by which the genome functions to guide development. Encoded sequence information, inherited epigenetic marks and environmental influences all converge at the level of mRNA gene expression to allow for cell-type-specific, tissue-specific, spatial and temporal patterns of expression. Thus, the transcriptome represents a complex interplay between inherited genomic structure, dynamic experiential demands and external signals. This property makes transcriptome studies uniquely positioned to provide insight into complex genetic–epigenetic–environmental processes such as human brain development, and disorders with non-Mendelian genetic etiologies such as autism spectrum disorders. In this review, we describe recent studies exploring the unique functional genomics profile of the human brain during neurodevelopment. We then highlight two emerging areas of research with great potential to increase our understanding of functional neurogenomics—non-coding RNA expression and gene interaction networks. Finally, we review previous functional genomics studies of autism spectrum disorder in this context, and discuss how investigations at the level of functional genomics are beginning to identify convergent molecular mechanisms underlying this genetically heterogeneous disorder.

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Studying synthetic lethal interactions in the zebrafish system: insight into disease genes and mechanisms

Cited by 10 publications

References 56 publications

Genetic and protein interaction studies between the ciliary dyslexia candidate genes DYX1C1 and DCDC2

Genetic and protein interaction studies between the ciliary dyslexia candidate genes DYX1C1 and DCDC2

Feature Identification of Compensatory Gene Pairs without Sequence Homology in Yeast

Functional genomics of human brain development and implications for autism spectrum disorders

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