Although translational selection to favour codons that match the most abundant tRNAs is not readily observed in humans, there is nonetheless selection in humans on synonymous mutations. We hypothesize that much of this synonymous site selection can be explained in terms of protection against unwanted RNAs — spurious transcripts, mis-spliced forms or RNAs derived from transposable elements or viruses. We propose not only that selection on synonymous sites functions to reduce the rate of creation of unwanted transcripts (for example, through selection on exonic splice enhancers and cryptic splice sites) but also that high-GC content (but low-CpG content), together with intron presence and position, is both particular to functional native mRNAs and used to recognize transcripts as native. In support of this hypothesis, transcription, nuclear export, liquid phase condensation and RNA degradation have all recently been shown to promote GC-rich transcripts and suppress AU/CpG-rich ones. With such ‘traps’ being set against AU/CpG-rich transcripts, the codon usage of native genes has, in turn, evolved to avoid such suppression. That parallel filters against AU/CpG-rich transcripts also affect the endosomal import of RNAs further supports the unwanted transcript hypothesis of synonymous site selection and explains the similar design rules that have enabled the successful use of transgenes and RNA vaccines.

尽管在人类中不容易观察到有利于与最丰富的 tRNA 相匹配的密码子的翻译选择，但人类中仍然存在对同义突变的选择。我们假设，这种同义位点选择在很大程度上可以用针对不需要的 RNA 的保护来解释——虚假转录物、错误剪接形式或源自转座元件或病毒的 RNA。我们建议，不仅对同义位点的选择可以降低不需要的转录本的产生率（例如，通过对外显子剪接增强子和隐性剪接位点的选择），而且还可以提高高GC含量（但低CpG含量）。具有内含子的存在和位置，既是功能性天然 mRNA 所特有的，又用于将转录物识别为天然的。为了支持这一假设，转录、核输出、液相浓缩和 RNA 降解最近都被证明可以促进富含 GC 的转录物并抑制富含 AU/CpG 的转录物。由于针对富含 AU/CpG 的转录本设置了此类“陷阱”，天然基因的密码子使用反过来又进化为避免此类抑制。针对富含 AU/CpG 转录物的平行过滤也会影响 RNA 的内体输入，进一步支持同义位点选择的不需要的转录物假设，并解释了能够成功使用转基因和 RNA 疫苗的类似设计规则。