Alternative polyadenylation (APA) is a major layer of gene regulation. However, it has recently been argued that most APA represents molecular noise. To clarify their functional relevance and evolution, we quantified allele-specific APA patterns in multiple tissues from an F1 hybrid mouse. We found a clearly negative correlation between gene expression and APA diversity for the 2,866 genes (24.9%) with a dominant polyadenylation site (PAS) usage above or equal to 90%, suggesting that their other PASs represent molecular errors. Among the remaining genes with multiple PASs, 3,971 genes (34.5%) express two or more isoforms with potentially functional importance. Interestingly, the genes with potentially functional minor PASs specific to neuronal tissues often express two APA isoforms with distinct subcellular localizations. Furthermore, our analysis of cis-APA divergence shows its pattern across tissues is distinct from that of gene expression. Finally, we demonstrate that the relative usage of alternative PASs is not only affected by their cis-regulatory elements, but also by potential coupling between transcriptional and APA regulation as well as competition kinetics between alternative sites.

中文翻译：

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等位基因选择性多腺苷酸化的泛组织分析表明广泛的功能调节。

选择性多聚腺苷酸化 (APA) 是基因调控的主要层。然而，最近有人认为大多数 APA 代表了分子噪音。为了阐明它们的功能相关性和进化，我们量化了 F1 杂交小鼠多个组织中的等位基因特异性 APA 模式。我们发现 2,866 个基因 (24.9%) 的基因表达和 APA 多样性之间存在明显的负相关，其中显性多聚腺苷酸化位点 (PAS) 使用率高于或等于 90%，这表明它们的其他 PAS 代表分子错误。在具有多个 PAS 的其余基因中，3,971 个基因 (34.5%) 表达两种或多种具有潜在功能重要性的亚型。有趣的是，具有神经元组织特异性的潜在功能性次要 PAS 的基因通常表达两种具有不同亚细胞定位的 APA 亚型。此外，我们对 cis-APA 差异的分析表明，其跨组织的模式与基因表达的模式不同。最后，我们证明替代 PAS 的相对使用不仅受到其顺式调控元件的影响，而且还受到转录和 APA 调控之间的潜在耦合以及替代位点之间的竞争动力学的影响。