title: 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.
authors.affiliation: Key Laboratory of Gene Engineering of Ministry of Education, Collaborative Innovation Center for Cancer Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
authors.forename: Piaopiao
authors.initials: P
authors.lastname: Chen
authors.affiliation: Key Laboratory of Gene Engineering of Ministry of Education, Collaborative Innovation Center for Cancer Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Wang
authors.affiliation: Key Laboratory of Gene Engineering of Ministry of Education, Collaborative Innovation Center for Cancer Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
authors.forename: Han
authors.initials: H
authors.lastname: Chen
authors.affiliation: Key Laboratory of Gene Engineering of Ministry of Education, Collaborative Innovation Center for Cancer Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Gene Engineering of Ministry of Education, Collaborative Innovation Center for Cancer Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China; State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
authors.forename: Xionglei
authors.initials: X
authors.lastname: He
mesh_terms: D000264:Adenylosuccinate Lyase / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics* / Q000628:therapy; D017173:Caenorhabditis elegans / Q000235:genetics; D020043:Genes, Essential; D015316:Genetic Therapy; D006801:Humans; D000073658:Loss of Function Mutation; D011686:Purine-Pyrimidine Metabolism, Inborn Errors / Q000235:genetics* / Q000628:therapy; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*
chemical_list: D029701:Saccharomyces cerevisiae Proteins; D000264:Adenylosuccinate Lyase