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.

journal_name

Genome Res

journal_title

Genome research

authors

Chen P,Wang D,Chen H,Zhou Z,He X

doi

10.1101/gr.205955.116

subject

Has Abstract

pub_date

2016-10-01 00:00:00

pages

1355-1362

issue

10

eissn

1088-9051

issn

1549-5469

pii

gr.205955.116

journal_volume

26

pub_type

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