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

Area of Science:

• Genomics
• Molecular Biology
• Evolutionary Biology

Background:

• The genetic code is degenerate, but codon selection is nonrandom due to functional constraints.
• Codon-usage bias (CUB) regulates mRNA stability, translation speed, and protein folding.
• CUB's role in humans is less understood than in unicellular organisms.

Purpose of the Study:

• To comprehensively evaluate human codon usage.
• To investigate the functional consequences and regulatory scope of CUB in humans.
• To disentangle mutational pressure from translational selection.

Main Methods:

• Analysis of human codon usage patterns.
• Correlation analysis between CUB and gene function, synonymous variants, and protein structure.
• Investigating the relationship between codon usage and transfer RNA (tRNA) gene copy numbers.
• Correcting for GC3 content to differentiate mutational pressure and translational selection.

Main Results:

• Genes with strong CUB are enriched in high-stoichiometry processes (e.g., skin development, gas transport).
• Highly biased genes have significantly fewer synonymous variants than expected.
• Codon optimization is more pronounced in structured protein domains than intrinsically disordered regions.
• High codon usage correlates with increased tRNA gene copy numbers.
• Correcting for GC3 content reveals translational selection, not just mutational pressure.

Conclusions:

• CUB is a conserved, central regulator of translation and protein folding in humans.
• Synonymous codon choice significantly impacts translational dynamics and protein biogenesis.
• Provides a framework for interpreting synonymous variation and guiding functional genomics.