Translational buffering tunes gene expression in mice and humans

Translational buffering refers to the regulation of ribosome occupancy to offset the effects of transcriptional variation. While previous studies have primarily investigated translational buffering in yeast under genetic variation or environmental stress, it remains unclear how widespread this is across mammalian genes in various cellular contexts.

We performed a uniform analysis of 1,515 matched ribosome profiling and RNA-seq datasets from humans and mice. This resource enabled us to assess translational buffering through comparative analysis of variation in ribosome occupancy and RNA expression, and by examining the relationship between mRNA abundance and translation efficiency. We found that translational buffering is partly conserved between humans and mice; homologous genes showed moderate cross-species correlation in mRNA-translation efficiency relationships and strong enrichment of shared buffered genes, particularly those encoding ribosomal, RNA-binding, and proteasomal proteins. Although identified buffered genes associate with specific sequence features, these alone are insufficient to predict translational buffering, highlighting the importance of cellular context. Genes exhibiting translational buffering show lower variation in protein abundance in cancer cell lines and tissues. We also observed that translationally buffered genes are more likely to be haploinsufficient and triplosensitive, suggesting a demand for stringent dosage limits.

We hypothesize two models of translational buffering, namely the "differential accessibility model" and the "translation initiation rate model", suggesting that different transcripts align with one or the other. Our study explores the translational buffering potential of genes across diverse conditions, elucidates their distinctive features, and provides insights into the mechanisms driving this effect.