Uniquely human evolution of sialic acid genetics and biology
Uniquely human evolution of sialic acid genetics and biology
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DOI：
10.1073/pnas.0914634107
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发表时间：
2010-05-11
影响因子：
11.1
通讯作者：
Varki, Ajit
中科院分区：
文献类型：
--
作者：
Varki, Ajit
达尔文进化论认为，人类从与非人类灵长类动物的共同祖先进化而来，涉及到种群水平上的许多基因-环境相互作用，由此产生的人类特有的基因变化必然有助于“人类状况”。“最近的数据表明，唾液酸的生物学（直接涉及不到60个基因）与我们最近的进化亲属相比，显示出10多个独特的人类遗传变化。已知的结果是丰富的细胞表面聚糖的组织特异性变化，识别这些聚糖的多种蛋白质的特异性和/或表达的变化，以及新的病原体状态。具体事件包括CMAH基因的ESTA介导的失活，导致Sia N-羟乙酰神经氨酸（Neu 5Gc）合成的损失和前体N-乙酰神经氨酸（Neu 5Ac）表达的增加; α 2-6-连接的Sias表达的增加（可能是由于ST 6 GALI表达的改变）;以及编码Sia识别Ig样凝集素（Siglecs）的SIGLEC基因的多种变化。最后一种包括结合特异性变化（Siglecs-5、-7、-9、-11和-12中）;表达模式变化（Siglecs-1、-5、-6和-11中）;基因转换（SIGLEC 11）;以及缺失或假基因化（SIGLEC 13、SIGLEC 14和SIGLEC 16）。CMAH突变的非遗传结果是面对循环的抗Neu 5Gc抗体，外来饮食Neu 5Gc的人代谢掺入，产生新的“异种自身抗原”情况。总之，这些数据表明，与Sia生物学相关的基因和环境的相关影响构成了人类进化中遗传和生理变化的相对“热点”，并对健康和疾病方面的独特人类特征产生了影响。
Darwinian evolution of humans from our common ancestors with nonhuman primates involved many gene-environment interactions at the population level, and the resulting human-specific genetic changes must contribute to the "Human Condition." Recent data indicate that the biology of sialic acids (which directly involves less than 60 genes) shows more than 10 uniquely human genetic changes in comparison with our closest evolutionary relatives. Known outcomes are tissue-specific changes in abundant cell-surface glycans, changes in specificity and/or expression of multiple proteins that recognize these glycans, and novel pathogen regimes. Specific events include Alu-mediated inactivation of the CMAH gene, resulting in loss of synthesis of the Sia N-glycolylneuraminic acid (Neu5Gc) and increase in expression of the precursor N-acetylneuraminic acid (Neu5Ac); increased expression of alpha 2-6-linked Sias (likely because of changed expression of ST6GALI); and multiple changes in SIGLEC genes encoding Sia-recognizing Ig-like lectins (Siglecs). The last includes binding specificity changes (in Siglecs -5, -7, -9, -11, and -12); expression pattern changes (in Siglecs -1, -5, -6, and -11); gene conversion (SIGLEC11); and deletion or pseudogenization (SIGLEC13, SIGLEC14, and SIGLEC16). A nongenetic outcome of the CMAH mutation is human metabolic incorporation of foreign dietary Neu5Gc, in the face of circulating anti-Neu5Gc antibodies, generating a novel "xeno-auto-antigen" situation. Taken together, these data suggest that both the genes associated with Sia biology and the related impacts of the environment comprise a relative "hot spot" of genetic and physiological changes in human evolution, with implications for uniquely human features both in health and disease.