RT Journal
A1 Chen, Piaopiao
A1 Wang, Dandan
A1 Chen, Han
A1 Zhou, Zhenzhen
A1 He, Xionglei
T1 The nonessentiality of essential genes in yeast provides therapeutic insights into a human disease
JF Genome Research 
JO Genome Research 
YR 2016 
FD October 01 
VO 26 
IS 10 
SP 1355 
OP 1362 
DO 10.1101/gr.205955.116 
UL http://genome.cshlp.org/content/26/10/1355.abstract 
AB 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.