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Dr. Li-Lin Du’s laboratory reveals the prevalence and principles of bypassable gene essentiality

Publication Date:2019/03/03

On March 1, 2019, Dr. Li-Lin Du’s laboratory published a paper titled “Systematic analysis reveals the prevalence and principles of bypassable gene essentiality” in Nature Communications. In this study, the authors for the first time systematically investigated the phenomenon of bypassable gene essentiality.

Genes can be classified as either essential genes or non-essential genes according to whether a gene is required for cell growth or not. Essential genes are usually involved in more fundamental biological processes and are more conserved in evolution. Gene essentiality is also a key criterion when selecting drug targets for combating pathogens and cancer cells. However, essentiality is not a static gene feature. It can sometimes be lost, i.e. an essential gene can become non-essential. What percentage of essential genes can lose essentiality? How does essentiality loss happen? Are there common principles behind essentiality loss? These are not only fundamental questions in biology, but are also of practical values to drug development.

It has been sporadically reported in the literature that the lethality of deleting an essential gene can sometimes be rescued by mutating or overexpressing another gene. This type of genetic interaction, which results in essentiality loss, has not previously been analyzed in a systematic and unbiased manner. It also lacks a name. Dr. Li-Lin Du’s laboratory names this type of digenic interaction bypass of essentiality (BOE). The genetic changes that cause essentiality loss are termed BOE suppressors, and the essential genes that can be rendered non-essential by BOE interactions are termed bypassable essential genes (Figure 1).

Figure 1. Three types of monogenic changes that can cause bypass of essentiality (BOE).

In the paper “Systematic analysis reveals the prevalence and principles of bypassable gene essentiality”, Dr. Li-Lin Du’s laboratory applied chemical mutagenesis, transposon mutagenesis, and overexpression plasmid library to systematically screen for BOE suppressors of essential genes on the left arm of chromosome II in the unicellular model organism the fission yeast Schizosaccharomyces pombe (Figure 2). Among the 142 analyzed essential genes, as many as 27% of them were found to be bypassable. This finding indicates that bypassable essential gene are not rare, but rather quite prevalent.

Figure 2. Systematic BOE analysis of the essential genes on the left arm of chromosome II in fission yeast.

Through analyzing the differences between bypassable and non-bypassable essential genes among the 142 screened genes, the authors identified three principles of bypassable gene essentiality. Firstly, bypassable essential genes tend to be of lower importance, with their loss in general causing lower degrees of system perturbation than the loss of non-bypassable genes. This principle manifests as a longer time it usually takes for the cell to cease growth upon the disruption of a bypassable essential gene (slow lethality) (Figure 2). Secondly, a majority of bypassable essential genes exhibit differential essentiality between species, suggesting that essentiality bypass is relevant to evolution. Lastly, the constituent subunits of an essential protein complex tend to be either all bypassable or all non-bypassable. Based on these principles, the authors made predictions on gene bypassability.

Figure 3. A diagram explaining the relationship between the rapidity of lethality upon gene disruption and gene bypassability.

In the paper, the authors also investigated the mechanisms underlying bypassable gene essentiality, and found that activating dormant redundancy is a common bypassing mechanism for essential genes that have paralogs. In addition, BOE interactions are shown to have predictive power for the functional connections between genes, and the authors used this power to uncover the functions of several genes.

After the paper’s acceptance, the authors were invited to write an online article for the Behind the Paper channel of the Nature Research Ecology & Evolution Community. The article is titled “A ten-year pursuit of bypassable gene essentiality” and can be found at https://natureecoevocommunity.nature.com/channels/521-behind-the-paper/posts/43892-a-ten-year-pursuit-of-bypassable-gene-essentiality.

Drs. Jun Li, Hai-Tao Wang, and Wei-Tao Wang from the Du laboratory are co-first authors of this paper. Dr. Li-Lin Du is the corresponding author. Other contributing authors include Dr. Xiao-Ran Zhang, Fang Suo, Jing-Yi Ren, Ying Bi, Ying-Xi Xue, Dr. Wen Hu, and Dr. Meng-Qiu Dong. This study was supported by National Natural Science Foundation of China, Chinese Ministry of Science and Technology, and the Beijing municipal government.

Web address of the paper: https://www.nature.com/articles/s41467-019-08928-1