RNA modifications unlock the hidden code of synonymous mutations in crop domestication

Abstract

Synonymous mutations have traditionally been regarded as functionally neutral because they do not alter protein sequences. However, growing evidence suggests these variants can affect gene expression, RNA structure, and protein function, ultimately influencing phenotypes. A recent study by Xin et al. (2025) provides strong evidence that synonymous mutations can exert regulatory effects through epitranscriptomic mechanisms, particularly m⁶A RNA methylation. The authors identify a synonymous 1287C > T mutation in the ACS2 gene that reduces m⁶A methylation at the adjacent A¹²⁸⁶ site. This reduction alters RNA secondary structure, creating a more compact conformation that impairs translation efficiency, leading to decreased ACS2 protein levels and promoting fruit elongation in cultivated cucumbers. The mutation lies within a domestication sweep region and ACS2^1287C is exclusively found in wild cucumber populations, suggesting that ACS2^1287T has been favored during domestication for its agronomic benefits. Notably, the study also uncovers a genotype-dependent interaction between ACS2 and the m⁶A reader protein YTH1, which binds only to methylated transcripts, further illustrating how genetic background modulates epitranscriptomic regulation. These findings challenge the long-standing assumption that synonymous variants are biologically irrelevant and introduce RNA methylation as a key, dynamic regulatory layer in crop domestication and breeding, offering new opportunities for RNA-based precision breeding.