Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a central role in cholesterol homeostasis in humans as a major regulator of LDLR levels. PCSK9 is an intriguing protease in that it does not act by proteolysis but by preventing LDLR recirculation from endosomes to the plasma membrane. This, and the inexistence of any other proteolytic substrate but itself could suggest that PCSK9 is an exquisite example of evolutionary fine-tuning. However, the gene has been lost in several mammalian species, and null alleles are present (albeit at low frequencies) in some human populations without apparently deleterious health effects, raising the possibility that the PCSK9 may have become dispensable in the mammalian lineage. To address this issue, we systematically recovered, assembled, corrected, annotated and analysed publicly available PCSK9 sequences for 420 eutherian species to determine the distribution, frequencies, mechanisms and timing of PCSK9 pseudogenization events, as well as the evolutionary pressures underlying the preservation or loss of the gene. We found a dramatic difference in the patterns of PCSK9 retention and loss between Euarchontoglires—where there is strong pressure for gene preservation—and Laurasiatheria, where multiple independent events have led to PCSK9 loss in most species. These results suggest that there is a fundamental difference in the regulation of cholesterol metabolism between Euarchontoglires and Laurasiatheria, which in turn has important implications for the use of Laurasiatheria species (e.g. pigs) as animal models of human cholesterol-related diseases.

前蛋白转化酶枯草杆菌蛋白酶/ kexin型9（PCSK9）在人体内胆固醇稳态中起着重要作用，是LDLR水平的主要调节剂。PCSK9是一种有趣的蛋白酶，它不通过蛋白水解起作用，而是通过阻止LDLR从内体到质膜的再循环而起作用。这以及其他任何蛋白水解底物的不存在，但本身可能表明PCSK9是进化微调的精妙示例。但是，该基因已经在几个哺乳动物物种中丢失，并且在某些人群中存在无效等位基因（尽管频率很低），对健康没有明显有害影响，这增加了PCSK9的可能性。可能已经在哺乳动物血统中变得不可或缺了。为了解决这个问题，我们系统地恢复，组装，校正，注释和分析了420种真人生物的PCSK9序列，以确定PCSK9假基因化事件的分布，频率，机制和时间，以及潜在的保存或丢失的进化压力。基因的 我们发现，在Eukarchontoglires和Laurasiatheria之间，PCSK9保留和丢失的模式有很大的不同，在Eukarchongliglires中有很大的基因保存压力，而Laurasiatheria在多个独立事件中导致了PCSK9大多数物种的损失。这些结果表明，Euchartogliglires和Laurasiatheria之间在胆固醇代谢调节方面存在根本差异，这反过来对于将Laurasiatheria物种（例如猪）用作人类胆固醇相关疾病的动物模型具有重要意义。