The genetic compensation response (GCR), triggered by deleterious mutations but not by gene knockdown, has been proposed to explain many phenotypic discrepancies between gene-knockout and gene-knockdown models. GCRs have been observed in many model organisms from mice to Arabidopsis. Although the GCR is beneficial for organism survival, it impedes the exploration of gene function as many knockout mutants do not display discernible phenotypes due to the GCR. Uncovering how the mechanism of GCR operates is not only a fundamental goal in biology but also may provide a key solution in the unmasking of phenotypes in mutants displaying GCRs. Using zebrafish as the model, two recent studies have provided a molecular basis to explain this genetic paradox by demonstrating that the nonsense-mediated mRNA decay pathway is essential for nonsense mRNA to upregulate the expression of its homologous genes through an enhancement of histone H3 Lys4 trimethylation (H3K4me3) at the transcription start site regions of the compensatory genes. Here, we summarize the progress on the molecular mechanism of the GCR and make suggestions on how to overcome GCRs in the generation of genetic mutants.

中文翻译：

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过早终止带有密码子的mRNA介导遗传补偿反应。

已经提出了由有害突变而不是基因敲低引发的遗传补偿反应（GCR），以解释基因敲除模型与基因敲除模型之间的许多表型差异。在从小鼠到拟南芥的许多模式生物中均已观察到GCR。尽管GCR对生物体生存有利，但由于许多基因敲除突变体由于GCR而无法显示可辨别的表型，因此它阻碍了基因功能的探索。揭示GCR机制的运作方式不仅是生物学的基本目标，而且可以为揭示GCR突变体表型的揭示提供关键解决方案。以斑马鱼为模型，最近的两项研究通过证明无义介导的mRNA衰变途径对于无意义mRNA通过增强组蛋白H3 Lys4三甲基化来上调其同源基因的表达是必不可少的，为解释这种遗传悖论提供了分子基础。 （H3K4me3）位于补偿性基因的转录起始位点区域。这里，