TY - JOUR T1 - The non-essentiality of essential genes suggests a loss-of-function therapeutic strategy for loss-of-function human diseases JF - bioRxiv DO - 10.1101/040568 SP - 040568 AU - Piaopiao Chen AU - Dandan Wang AU - Han Chen AU - Zhenzhen Zhou AU - Xionglei He Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/02/22/040568.abstract N2 - Essential genes refer to those whose null mutation leads to lethality or sterility. We propose 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 the type I essential genes can be rescued only by regain of the core functions, whereas inactivation of the 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 non-essential in a few individuals of a large population. We tested this idea in the yeast Sacchromyces cerevisiae. Large-scale whole genome sequencing of such essentiality-reversing mutants reveals 14 cases where 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. ER -