# Mapping the inter- and intra-genic codon-usage landscape in Homo sapiens

## TL;DR

This study explores how codon usage affects gene function in humans, showing that it influences protein production and folding.

## Contribution

The paper provides a comprehensive analysis of codon usage in humans, revealing its role in translational regulation and protein structure.

## Key findings

- Highly biased codon usage is linked to genes involved in skin development and gas transport.
- Codon optimization is stronger in structured protein regions than in disordered ones.
- Frequent codon use correlates with higher tRNA gene copy numbers, supporting translational selection.

## Abstract

Although the genetic code is degenerate, codon selection is nonrandom and reflects significant functional constraints. Codon-usage bias (CUB) acts as a layer of post–transcriptional regulation, influencing messenger RNA (mRNA) stability, translation kinetics, and co-translational protein folding. While CUB is well-characterized in unicellular organisms, its regulatory scope and functional consequences in humans remain complex and less defined. Our study offers a comprehensive evaluation of human codon usage. We report that genes exhibiting the strongest codon bias are enriched in high-stoichiometry biological processes, such as skin development and oxygen/carbon dioxide transport, and harbor significantly fewer synonymous variants than expected (ρ = −0.24, P < 2.2 × 10−16). Furthermore, we find that codon optimization is structurally distinct: it is significantly more pronounced in structured protein domains compared to intrinsically disordered regions (IDRs) (Cliff’s Δ= 0.26, P < 2.2 × 10−16). Consistent with translational selection, the most frequently used codons are supported by higher transfer RNA (tRNA) gene copy numbers (ρ = 0.49, P < 6.4 × 10−4). Finally, by correcting for GC3 content, we reveal that the apparent correlation between effective number of codon and adaptation indices (CAI/tAI) vanishes, allowing us to disentangle mutational pressure from translational selection. Collectively, our findings position CUB as a central, evolutionarily conserved regulator of translation and protein folding in humans. Our results provide a comprehensive and integrated view of intergenic and intragenic CUB in humans, reinforcing the biological relevance of synonymous codon choice in shaping translational dynamics and protein biogenesis. This provides a refined framework for interpreting synonymous variation and guiding functional genomics.

Graphical Abstract