Translational buffering tunes gene expression in mouse and human

Translational buffering refers to the regulation of ribosome occupancy to offset the effects of transcriptional variation. Previous studies have primarily investigated translational buffering in yeast due to genetic variation or environmental stress. However, it remains unclear how widespread translational buffering is across mammalian genes in various cellular contexts. In this study, we uniformly analyzed 1515 matched ribosome profiling and RNA-seq datasets from human and mouse. This resource enabled us to assess translational buffering by comparative analysis of variation at ribosome occupancy and the RNA expression and by examining the relationship between mRNA abundance and translation efficiency. We found that translational buffering is partly conserved between human and mouse, with homologous genes showing a moderate cross-species correlation in mRNA–translation efficiency relationships and a strong enrichment of shared buffered genes, particularly those encoding ribosomal, RNA-binding, and proteasomal proteins. Although the identified buffered genes show association with some sequence features, these alone are insufficient to predict translational buffering, highlighting the importance of cellular context. Genes exhibiting translational buffering have lower variation in protein abundance in cancer cell lines as well as human and mouse tissues. We also observed that translationally buffered genes are more likely to be haploinsufficient and triplosensitive suggesting a demand for stringent dosage limits in these genes. We hypothesize two models of translational buffering, namely “differential accessibility model” and “translation initiation rate model” with our analysis suggesting that some transcripts conform to the former and others align with the latter. Our study explores the translational buffering potential of genes across diverse cellular conditions, elucidates the distinctive features of genes that exhibit this phenomenon, and provides insights into the possible mechanisms driving this effect.