The nonessentiality of essential genes in yeast provides therapeutic insights into a human disease

Abstract

Essential genes refer to those whose null mutation leads to lethality or sterility. Theoretical reasoning and empirical data both suggest that the fatal effect of inactivating an essential gene can be attributed to either the loss of indispensable core cellular function (Type I), or the gain of fatal side effects after losing dispensable periphery function (Type II). In principle, inactivation of Type I essential genes can be rescued only by re-gain of the core functions, whereas inactivation of Type II essential genes could be rescued by a further loss of function of another gene to eliminate the otherwise fatal side effects. Because such loss-of-function rescuing mutations may occur spontaneously, Type II essential genes may become nonessential in a few individuals of a large population. Motivated by this reasoning, we here carried out a systematic screening for Type II essentiality in the yeast Saccharomyces cerevisiae. Large-scale whole-genome sequencing of essentiality-reversing mutants reveals 14 cases whereby the inactivation of an essential gene is rescued by loss-of-function mutations on another gene. In particular, the essential gene encoding the enzyme adenylosuccinate lyase (ADSL) is shown to be Type II, suggesting a loss-of-function therapeutic strategy for the human disorder ADSL deficiency. A proof-of-principle test of this strategy in the nematode Caenorhabditis elegans shows promising results.

Mechanisms of suppression: The wiring of genetic resilience

“…Unbiased suppression analysis in yeast showed that loss of any of the genes upstream of ADE13 in the pathway can rescue the lethality caused by loss of ADE13 , while deletion of downstream genes could not (Fig. C) . None of the other genes in the pathway are essential, suggesting that loss of Ade13 leads to the accumulation of a toxic intermediate, in this case (S)‐2‐[5‐Amino‐1‐(5‐phospho‐D‐ribosyl)imidazole‐4‐carboxamido]succinate or SAICAR, which can be prevented by inactivation of any of the upstream pathway members.…”

“…Note that the distinction between genomic and dosage suppression largely relies on the method of isolation of the suppressor genes, and that genomic suppressor mutations can include dosage events, such as gene duplications. Single suppressor events have the potential to overcome extreme growth defects, and mutations have been isolated that can suppress the lethality of complete loss of function of an essential gene in yeast . Suppression interactions tend to occur between genes that have a close functional connection, and suppressor screens have been widely used to identify genes involved in a variety of biological pathways in bacteria, yeast, fly, and worm .…”

Genetic compensation in a stable slc25a46 mutant zebrafish: A case for using F0 CRISPR mutagenesis to study phenotypes caused by inherited disease

“…Male flies showed an up-regulated transcription from their X chromosome, resulting in similar gene expression as in female fruit flies, which possess two X chromosomes [1]. Since then genetic compensation has been shown to be a wide-spread phenomenon having been reported in diverse phyla including fly [1][2][3][4][5], plants [6,7], yeast [8], zebrafish [9][10][11][12], and mice [13][14][15]. There is also evidence from genome-wide association studies suggesting that genetic compensation, by way of genetic modifiers, may explain the absence of affected status in some humans carrying deleterious mutations [16,17], and thus is of great interest for potential medical applications.…”

Systematic analysis of bypass suppression of essential genes

“…Although essential genes tend to play highly conserved roles in a cell (Giaever et al , ; Costanzo et al , ), genetic variants can sometimes lead to a rewiring of cellular processes that bypass the fundamental requirement for otherwise essential genes (Dowell et al , ; Sanchez et al , ). Spontaneous suppressor mutations can be isolated by selecting for faster growing mutants from large populations of cells that are compromised for the function of an essential gene (Van Leeuwen et al , ) and can identify bypass suppressors (Liu et al , ; Chen et al , 2016a). Here, we describe the construction of a collection of haploid yeast strains, each carrying a single deletion allele of a different essential gene.…”