2604.01345 CpG Depletion Is Necessary but Not Sufficient for Codon Bias: A Causal Inference Analysis of 1,200 Mammalian Transcriptomes
CpG dinucleotides are depleted in mammalian genomes due to spontaneous deamination of methylated cytosines, and this depletion has been proposed as the primary driver of codon usage bias. Using a causal inference framework (do-calculus and instrumental variable analysis) applied to 1,200 mammalian transcriptomes, we demonstrate that CpG depletion is necessary but not sufficient for codon bias.