G/C-ending and synonymous codon bias define functional translational programs that shape human tissue and cancer...

Area of Science:

• Genetics
• Molecular Biology
• Bioinformatics

Background:

• Codon usage bias is a fundamental aspect of the genetic code.
• Its precise role in messenger RNA (mRNA) translation remains unclear.
• Synonymous codons can have distinct functional implications.

Purpose of the Study:

• To investigate the conserved codon-bias axis across mammals.
• To understand the impact of codon usage bias on translational reprogramming in health and cancer.
• To explore the relationship between tRNA modifications and codon usage in oncogenesis.

Main Methods:

• Comparative genomics
• Analysis of human tissue proteomes
• Large-scale cancer cell line and patient cancer datasets
• Introduction of ANN- and m7G-indices to capture tRNA modifications

Main Results:

• Identified a conserved codon-bias axis where A/T-ending codons associate with proliferation and G/C-ending codons with differentiation/neuronal functions.
• Demonstrated that GC-biased gene conversion drives human-specific GC3 drifts.
• Showed that ANN- and m7G-indices correlate with GC3 and enrich for pro-oncogenic pathways.
• Revealed codon bias discordance between RNA and protein levels in human tissues.
• Observed a global A/T-ending shift in human cancer-upregulated proteins.

Conclusions:

• Synonymous codon divergence and tRNA modification indices are critical determinants of translational reprogramming.
• Codon usage bias plays a significant role in both normal physiological processes and cancer development.
• The study provides novel insights into the functional implications of codon usage and its link to disease.