Genetic compensation: A phenomenon in search of mechanisms

Abstract

Several recent studies in a number of model systems including zebrafish, Arabidopsis, and mouse have revealed phenotypic differences between knockouts (i.e., mutants) and knockdowns (e.g., antisense-treated animals). These differences have been attributed to a number of reasons including off-target effects of the antisense reagents. An alternative explanation was recently proposed based on a zebrafish study reporting that genetic compensation was observed in egfl7 mutant but not knockdown animals. Dosage compensation was first reported in Drosophila in 1932, and genetic compensation in response to a gene knockout was first reported in yeast in 1969. Since then, genetic compensation has been documented many times in a number of model organisms; however, our understanding of the underlying molecular mechanisms remains limited. In this review, we revisit studies reporting genetic compensation in higher eukaryotes and outline possible molecular mechanisms, which may include both transcriptional and posttranscriptional processes.

Fig 1. Proposed models of transcriptional adaptation.

(A) DNA damage response can induce chromatin reorganization, increasing chromatin accessibility at the compensatory genes’ regulatory regions. (B) Mutations can lead to transcripts that are targeted for degradation through mRNA surveillance pathways. The resulting RNA fragments may trigger the compensatory response. As a secondary effect of the mutated gene’s mRNA degradation, RBPs or miRNAs normally acting on the mutated as well as the compensating genes’ mRNAs become more available to exert their stabilizing effects on the compensating genes’ mRNAs. Abbreviations: miRNAs, microRNAs; RBPs, RNA-binding proteins; TFs, transcription factors.