Codon Optimality Confers GC-Rich-Induced Stability to mRNAs in Humans

Codon optimality has been implicated as a major factor contributing to mRNA stability in yeast. However, the presence of codon optimality mediated decay has been unclear in humans. Here we show that human cells possess a mechanism to modulate RNA stability via codon optimality with a unique codon bias different from that of yeast. We performed dimensionality reduction analysis of genome wide codon frequencies and found that codons could be clustered into two distinct groups, codons with A or T at the third base position (AT3) and codons with either G or C at the third base position (GC3). Quantifying codon bias and subsequently gene optimality showed that increased GC3 content entails proportionately higher GC content which in turn confers stability to mRNA transcripts. Agreement of our codon optimality derived metric and ribosome occupancies across mRNAs determined from ribosome profiling suggests that codon optimality affects ribosome occupancy. This system was verified by measuring the stabilities of codon optimized and deoptimized reporter transcripts. Employing an immunoprecipitation based strategy, we identified ILF2 as an RNA binding protein that regulates global mRNA abundances via AU content. Our results demonstrate that codon optimality mediated decay is a highly conserved system which in the course of evolution has seen changes in codon usage.