Deciphering Plasticity of Essentiality

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Identifying the essential set of genes had been the focus of many studies with the aim to decipher core processes critical for survival and fertility of an organism. Typically, various types of mutagenes (e.g. transposons, chemicals, X-rays), RNA interference and more recently CRISPR/Cas9 are used to either disrupt the function of the gene or deplete the gene product, and assess the effect of this on survival/fitness. Reverse genetic screens (e.g. RNAi), in particular, had accelerated the quest for essential genes by circumventing the genome-wide search for the mutation identity, a common bottleneck of the mutagenesis screens. Although, essential gene sets had been successfully determined in a number of different model organisms, mostly under the laboratory conditions and in laboratory strains, it is clear that the essentiality is conditional state. For example, a gene that appears to be essential under a specific condition (e.g. limited nutrition) may not be essential in a different environment (standard laboratory). Importantly, different strains have different genetic variants in the genome that may influence the level at which genes are critical for survival and fertility. The long-term goal of our NSERC Discovery program is to study how the natural context of Caenorhabditis elegans' genomes shapes the essentiality. About 15% of C. elegans genes are identified as essential for development in a widely used N2 strain under laboratory conditions ("N2 essentialome"). To further understand the essentialome, we will: (1)Introduce the existing lethal alleles using CRISPR/Cas9 approaches to a variety of natural C. elegans genetic backgrounds compiled from the Caenorhabditis elegans Natural Diversity Resource (CeNDR) (https://www.elegansvariation.org/) (2)Study the effect of these natural genomes on development and fitness of known lethal alleles (3)Employ high throughput genome-wide approaches to identify natural genome variations capable of modulating the lethality (4)Study the effect of these natural genomes on genetic interaction networks My NSERC discovery program will advance our knowledge on genetic interactions and the nature of essential processes given the effect of natural variations of genomes. Starting with the state-of-the field genomics and bioinformatics methods while developing modern future approaches, this program has an unprecedented potential to establish an analytical/comparative approach to untangling the outstanding questions on plasticity of essentialomes, but also providing an insight on plasticity of interactomes. Importantly, the NSERC support for this program will help foster the multidisciplinary environment for next generation of Highly Qualified Personnel (HQP) skilled in molecular genetics, genomics, bioinformatics and systems biology, an outstanding need in Canada.