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Analysis of an apparent mutant/morphant disagreement

Barthelson K, Baer L, Dong Y, Hand M, Pujic Z, Newman M, Goodhill GJ, Richards RI, Pederson SM, Lardelli M. Zebrafish Chromosome 14 Gene Differential Expression in the fmr1 (h u2787) Model of Fragile X Syndrome. Front Genet. 2021 May 31;12:625466. doi: 10.3389/fgene.2021.625466. eCollection 2021.

Interesting analysis of an apparent mutant/morphant disagreement finding no genetic compensation experimentally.

"Kok et al. (2015) summarised the puzzling, frequent discordance between phenotypes caused by gene mutations compared to morphant phenotypes caused by reduction of gene expression due to injection of morpholinos. Rossi et al. (2015), then described the phenomenon of “genetic compensation” (now referred to as “transcriptional adaptation” Kontarakis and Stainier, 2020) as contributing to this discordance. As elaborated in a subsequent paper from that laboratory (El-Brolosy et al., 2019), non-sense-medicated decay (NMD) of transcripts with premature termination codons can (in a manner independent of protein feedback loops) increase the abundance of transcripts of genes with homologous sequences that, presumably, are partially functionally redundant and ameliorate the effects of the mutation. The discovery of this phenomenon raises questions regarding the definition of “null” mutant phenotypes and reveals that reducing gene expression using morpholinos may, in some cases, provide more focussed functional effects at the molecular level that are simpler to interpret than those caused by mutations inducing NMD."

"Despite the apparent NMD of fmr1hu2787 transcripts, and the reported milder developmental phenotype of fmr1hu2787 homozygotes relative to individuals in which the function of this gene is suppressed using morpholinos, we did not see evidence for transcriptional adaptation by increased transcription of genes possessing sequences with homology to fmr1, at least at 2 dpf. This illustrates possible variability of the occurrence of the recently discovered transcriptional adaptation mechanism, and that more research is required to understand the factors modulating it."

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