Genetics in Light of Transcriptional Adaptation

Abstract

Genetics has recently benefited from the genome engineering revolution: genes can be knocked out, knocked down, or activated more easily than ever before. This range of genetic manipulations has also provided a range of outcomes, sometimes contradictory. But how much interesting biology hides within these discrepancies? Recent studies have shown that genetic compensation can be activated by some gene perturbations and not others, hinting that this phenomenon might skew our understanding of the genotype-phenotype relationship. We review the main findings regarding transcriptional adaptation, a newly discovered form of genetic compensation, and discuss their possible implications for establishing and analyzing animal and plant models to study gene function. We also touch upon how this new knowledge could benefit our understanding of disease-causing mutations and help explain cases of low penetrance or variable expressivity in human genetics.

Keywords: animal models; gene expression; genetic compensation; genome engineering; transcriptional adaptation.

Figure 1

Data from key studies {(i), Rossi et al. [39]; (ii), El-Brolosy et al. [48]; (iii), Ma et al. [49]; (iv), Serobyan et al. [52]} have helped build a basic framework for transcriptional adaptation: a frameshift mutation in gene X can activate the transcription of similar genes in trans [39,48,49,52]. This activation is not dependent on loss of protein activity as transcriptional [39,48,49,52] or translational [39] inhibition of gene X, or dominant negative alleles [39], do not trigger this response. The mRNA quality control (QC) mechanism of the cell determines whether an mRNA is used for protein production or is recycled [48,49,52]. If not used for translation, mRNAs can also enter the transcriptional adaptation pathway, either repurposed as long noncoding RNAs [49] or by contributing small degradation intermediates [48,52]. Different processes have been implicated in transcriptional adaptation, either upstream or downstream of the QC step [48,49,52]. Better understanding of the crosstalk between these processes will help explain different transcriptional adaptation responses and allow modulation of this pathway. Abbreviation: PTC, premature termination codon.