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Emerging and evolving concepts in gene essentiality

Key Points

  • A gene is considered essential if it is required for the reproductive success of a cell or an organism. Gene essentiality is a core concept of genetics, with repercussions in evolutionary, systems and synthetic biology and with applications in drug development.

  • The 'essentialome' is defined as the complete set of genes that are individually essential in a given organism. Recent genome sequencing and editing technologies are enabling the identification of essentialomes in a progressively larger number of non-model organisms and higher eukaryotes.

  • The essentiality of many genes is dependent on the environment and/or genetic context and can be altered in the course of both short-term and long-term evolutionary processes. Hence it is not an absolute and static property of a gene.

  • There seems to be a gradient of gene essentiality among genes in each genome, with some essential genes being more prone to losing their essentiality than others. Hence essentiality is not a binary but a quantitative property of a gene.

  • The context-dependent nature of gene essentiality can be exploited to develop more effective or more specific antimicrobials and provides avenues for patient-tailored anticancer therapies.

  • The evolvable nature of gene essentiality has implications for drug target prioritization: genes that are less likely to lose their essentiality should be associated with a lower incidence of resistance when targeted by a drug.

Abstract

Gene essentiality is a founding concept of genetics with important implications in both fundamental and applied research. Multiple screens have been performed over the years in bacteria, yeasts, animals and more recently in human cells to identify essential genes. A mounting body of evidence suggests that gene essentiality, rather than being a static and binary property, is both context dependent and evolvable in all kingdoms of life. This concept of a non-absolute nature of gene essentiality changes our fundamental understanding of essential biological processes and could directly affect future treatment strategies for cancer and infectious diseases.

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Figure 1: Milestones of technological and biological breakthroughs in gene essentiality research.
Figure 2: Scaling of essential gene number with genome size.
Figure 3: Emerging properties of essential genes.
Figure 4: Context-dependent gene essentiality.
Figure 5: Exploiting the non-absolute nature of gene essentiality for drug targeting.

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Acknowledgements

The authors thank H. Luo (Tianjin University, China) and K. Raman (Indian Institute of Technology, Madras, India) for providing raw data from references 110 and 206 for use in Fig. 3. This work was supported by an A*STAR Investigatorship to G.R. (1437a00119), a Sofja Kovaleskaja Award from Humboldt Foundation to A.T., the Canadian Institutes of Health Research (MOP-142375) to J.M. and by an A*STAR Investigatorship to N.P. (1437a00117).

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All authors researched data for the article, substantially contributed to discussions of content and contributed to writing the manuscript. G.R., A.T. and N.P. contributed to reviewing and editing the manuscript before submission.

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Correspondence to Norman Pavelka.

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Essentialomes of selected organisms (XLSX 56 kb)

Glossary

Gene essentiality

The extent to which a gene is required for the reproductive success of a living system, for example, a virus, a single-celled organism, a cell line or a multicellular organism.

Reproductive success

The ability of a living system to generate fertile progeny, that is, viable offspring that can themselves generate further viable offspring.

Cellular gene essentiality

The extent to which a gene is required for the reproductive success of a single-celled organism or of a cell line derived from a multicellular organism.

Organismal gene essentiality

The extent to which a gene is required for the reproductive success of a multicellular organism, that is, for it to grow and develop from a zygote into a fertile adult.

Viral gene essentiality

The extent to which a gene is required for the reproductive success of a virus.

Essentialomes

Comprehensive sets of essential genes in genomes.

RNA interference

(RNAi). A technique to inhibit the production of a protein by destabilizing a target mRNA molecule.

Minimal genome

A genome consisting solely of a minimal set of genes that are required and sufficient to sustain cellular life.

Evolvable

Able to change via a process of adaptive evolution, that is, via acquisition and fixation of genetic mutations that confer selective advantages.

Transposon mutagenesis

A gene disruption strategy based on random insertion of transposable genetic elements into a host genome.

Shotgun sequencing

A sequencing method based on sequencing several random fragments from a long DNA molecule followed by bioinformatic assembly of the fragments based on similarity of overlapping ends.

Gene traps

High-throughput approaches to introduce genome-wide insertional mutations in mammalian genomes. They inactivate the trapped gene by introducing a premature polyadenylation site.

Next-generation sequencing

A term used to describe different high-throughput sequencing technologies that became available over the past decade.

Genetic interactions

(GIs). Phenomena by which concomitant mutations in two genes result in a phenotype that is not readily predictable from the phenotype of the two individual mutations.

Signature mutagenesis

A genetic technique based on transposon mutagenesis, where each transposable element contains a different molecular tag that uniquely identifies it. This allows the phenotype of pools of mutants to be analysed en masse.

Purifying selection

Negative selection against deleterious alleles.

Phyletic retention

The tendency of genes to be retained in genomes along phylogenetic lineages.

Orthologue

Orthologues are genes found in different species that have evolved from a common ancestor.

Interactomes

Complete sets of genetic, protein–protein, metabolic or other types of molecular interaction within a given genome.

Degree

Within the context of biological networks, the number of genetic or physical interactions a gene or protein is involved in.

Pleiotropy

The production of two or more apparently unrelated phenotypes or traits by a single gene.

Epistasis

A form of genetic interaction, whereby an allele of one gene influences non-additively the phenotype associated with the allele of another gene. Positive or negative epistasis exists when a double mutant is fitter or less fit than the sum of the fitness effects of the two single mutants, respectively.

Synthetic lethality

An extreme form of negative epistasis, whereby the combination of mutations in two or more genes causes cell death, whereas none of the single mutations are lethal in isolation.

Ploidy

The number of sets (that is, full complements) of chromosomes in a genome.

Syntrophic relationships

A phenomenon by which one species requires the product of another species to survive.

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Rancati, G., Moffat, J., Typas, A. et al. Emerging and evolving concepts in gene essentiality. Nat Rev Genet 19, 34–49 (2018). https://doi.org/10.1038/nrg.2017.74

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