The inclusion of exons during the splicing process depends on the binding of splicing factors to short low-complexity regulatory sequences. The relationship between exonic splicing regulatory sequences and coding sequences is still poorly understood. We demonstrate that exons that are coregulated by any given splicing factor share a similar nucleotide composition bias and preferentially code for amino acids with similar physicochemical properties because of the nonrandomness of the genetic code. Indeed, amino acids sharing similar physicochemical properties correspond to codons that have the same nucleotide composition bias. In particular, we uncover that the TRA2A and TRA2B splicing factors that bind to adenine-rich motifs promote the inclusion of adenine-rich exons coding preferentially for hydrophilic amino acids that correspond to adenine-rich codons. SRSF2 that binds guanine/cytosine-rich motifs promotes the inclusion of GC-rich exons coding preferentially for small amino acids, whereas SRSF3 that binds cytosine-rich motifs promotes the inclusion of exons coding preferentially for uncharged amino acids, like serine and threonine that can be phosphorylated. Finally, coregulated exons encoding amino acids with similar physicochemical properties correspond to specific protein features. In conclusion, the regulation of an exon by a splicing factor that relies on the affinity of this factor for specific nucleotide(s) is tightly interconnected with the exon-encoded physicochemical properties. We therefore uncover an unanticipated bidirectional interplay between the splicing regulatory process and its biological functional outcome.

中文翻译：

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编码和外显子剪接调节序列之间的相互作用。

剪接过程中外显子的包含取决于剪接因子与短的低复杂度调节序列的结合。外显子剪接调节序列和编码序列之间的关系仍然知之甚少。我们证明，由任何给定的剪接因子核心调控的外显子均具有相似的核苷酸组成偏差，并且由于遗传密码的非随机性，优先编码具有相似物理化学性质的氨基酸。实际上，具有相似理化特性的氨基酸对应于具有相同核苷酸组成偏差的密码子。特别是，我们发现，与富含腺嘌呤的基序结合的TRA2A和TRA2B剪接因子促进包含富含腺嘌呤的外显子的编码，该外显子优先编码对应于富含腺嘌呤的密码子的亲水性氨基酸。结合鸟嘌呤/富含胞嘧啶的基序的SRSF2促进优先编码小氨基酸的富含GC的外显子的包容，而结合富含胞嘧啶的基序的SRSF3促进优先编码不带电荷的氨基酸的丝氨酸和苏氨酸的外显子的包被被磷酸化。最终，编码具有相似理化性质的氨基酸的有核外显子对应于特定的蛋白质特征。结论，依赖该因子对特定核苷酸亲和力的剪接因子对外显子的调节与外显子编码的理化特性紧密相关。因此，我们发现了剪接调控过程与其生物学功能结果之间无法预料的双向相互作用。