Cancer is a heterogeneous genetic disease that alters the proper functioning of proteins involved in key regulatory processes such as cell cycle, DNA repair, survival, or apoptosis. Mutations often accumulate in hot-spots regions, highlighting critical functional modules within these proteins that need to be altered, amplified, or abolished for tumor formation. Recent evidence suggests that these mutational hotspots can correspond not only to globular domains, but also to intrinsically disordered regions (IDRs), which play a significant role in a subset of cancer types. IDRs have distinct functional properties that originate from their inherent flexibility. Generally, they correspond to more recent evolutionary inventions and show larger sequence variations across species. In this work, we analyzed the evolutionary origin of disordered regions that are specifically targeted in cancer. Surprisingly, the majority of these disordered cancer risk regions showed remarkable conservation with ancient evolutionary origin, stemming from the earliest multicellular animals or even beyond. Nevertheless, we encountered several examples where the mutated region emerged at a later stage compared with the origin of the gene family. We also showed the cancer risk regions become quickly fixated after their emergence, but evolution continues to tinker with their genes with novel regulatory elements introduced even at the level of humans. Our concise analysis provides a much clearer picture of the emergence of key regulatory elements in proteins and highlights the importance of taking into account the modular organisation of proteins for the analyses of evolutionary origin.

中文翻译：

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固有疾病癌症风险区域的古代进化起源。

癌症是一种异质性遗传疾病，会改变参与关键调控过程（例如细胞周期，DNA修复，存活或凋亡）的蛋白质的正常功能。突变通常在热点区域积聚，突显了这些蛋白质内的关键功能模块，需要改变，扩增或废除这些蛋白才能形成肿瘤。最近的证据表明，这些突变热点不仅可以对应于球状结构域，而且还可以对应于固有杂乱区（IDR），这些杂散区在一部分癌症类型中起着重要作用。IDR具有独特的功能特性，这些特性源于其固有的灵活性。通常，它们对应于较新的进化发明，并显示出物种间较大的序列变异。在这项工作中 我们分析了专门针对癌症的无序区域的进化起源。出人意料的是，这些无序的癌症风险区域中的大多数显示出具有古老进化起源的显着保守性，其起源于最早的多细胞动物甚至更多。然而，我们遇到了几个例子，其中与基因家族的起源相比，突变区域出现在较晚的阶段。我们还显示出，癌症风险区域在出现后很快就被固定了下来，但进化过程却不断地改变着它们的基因，甚至在人类的水平上也引入了新的调控元件。