Human-specific pseudogenization of the CMAH gene eliminated the mammalian sialic acid (Sia) Neu5Gc (generating an excess of its precursor Neu5Ac), thus changing ubiquitous cell surface “self-associated molecular patterns” (SAMPs) that modulate innate immunity via engagement of CD33-related-Siglec receptors. The Alu-fusion-mediated loss-of-function of CMAH fixed ∼2-3 million years ago (Mya), possibly contributing to the origins of the genus Homo. The mutation likely altered human SAMPs, triggering multiple events, including emergence of human-adapted pathogens with strong preference for Neu5Ac recognition and/or presenting Neu5Ac-containing molecular mimics of human glycans, which can suppress immune responses via CD33-related-Siglec engagement. Human-specific alterations reported in some genes encoding Sia-sensing proteins suggested a “hotspot” in hominin evolution. The availability of more hominid genomes including those of two extinct hominins now allows full reanalysis and evolutionary timing. Functional changes occur in 8/13 members of the human genomic cluster encoding CD33-related-Siglecs, all predating the human common ancestor. Comparisons with great ape genomes indicate that these changes are unique to hominins. We found no evidence for strong selection after the Human-Neanderthal/Denisovan common ancestor, and these extinct hominin genomes include almost all major changes found in humans, indicating that these changes in hominin sialobiology predate the Neanderthal-human divergence ∼0.6Mya. Multiple changes in this genomic cluster may also explain human-specific expression of CD33rSiglecs in unexpected locations such as amnion, placental trophoblast, pancreatic islets, ovarian fibroblasts, microglia, NK cells and epithelia. Taken together, our data suggest that innate immune interactions with pathogens markedly altered hominin Siglec biology between 0.6-2 Mya, potentially affecting human evolution.

中文翻译：

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改变人类基因的多种基因组事件SIGLEC生物学和先天免疫力早于人类和古老人类的共同祖先。

CMAH基因的人类特异性假基因消除消除了哺乳动物唾液酸（Sia）Neu5Gc（产生了过量的前体Neu5Ac），从而改变了无处不在的细胞表面“自缔合分子模式”（SAMPs），该模式通过CD33的参与调节先天免疫力。相关的Siglec受体。该铝-融合介导丧失功能的CMAH固定~2-3万年前（妙），可能有助于属的起源智人。该突变可能会改变人类SAMPs，引发多种事件，包括出现高度适应Neu5Ac识别的适应人类的病原体和/或呈现人类聚糖中含有Neu5Ac的分子模拟物，从而可以通过抑制免疫反应CD33相关的Siglec参与。在一些编码Sia感应蛋白的基因中报道的人类特异性变化表明，人胶蛋白进化是一个“热点”。现在可以使用更多的人类基因组，包括两个已灭绝的人类素的基因组，从而可以进行全面的重新分析和进化时机。功能改变发生在人类基因组簇中编码CD33-Siglecs的8/13成员中，所有这些都早于人类共同祖先。与大猿基因组的比较表明，这些变化是人类素所特有的。在人类-尼安德特人/丹尼索万共同祖先之后，我们没有发现进行强选择的证据，并且这些灭绝的人红素基因组几乎包括人类发现的所有主要变化，这表明人参唾液病的这些变化早于尼安德特人-人类的差异约0.6Mya。该基因组簇的多个变化也可能解释了CD33rSiglecs在人为异常位置（如羊膜，胎盘滋养细胞，胰岛，卵巢成纤维细胞，小胶质细胞，NK细胞和上皮细胞）的人类特异性表达。两者合计，我们的数据表明与病原体的先天性免疫相互作用显着改变了人类糖蛋白希格勒克生物学在0.6-2 Mya之间，可能影响人类进化。