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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Inactivation of CMP-N-acetylneuraminic acid hydroxylase occurred prior to brain expansion during human evolution
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Inactivation of CMP-N-acetylneuraminic acid hydroxylase occurred prior to brain expansion during human evolution

机译：CMP-N-乙酰神经氨酸羟化酶的失活发生在人类进化过程中的大脑扩张之前

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摘要

Humans are genetically deficient in the common mammalian sialic acid N-glycolylneuraminic acid (Neu5Gc) because of an Alu-medi-ated inactivating mutation of the gene encoding the enzyme CMP-N-acetylneuraminic acid (CMP-Neu5Ac) hydroxylase (CMAH). This mutation occurred after our last common ancestor with bonobos and chimpanzees, and before the origin of present-day humans. Here, we take multiple approaches to estimate the timing of this mutation in relationship to human evolutionary history. First, we have developed a method to extract and identify sialic acids from bones and bony fossils. Two Neandertal fossils studied had clearly detectable Neu5Ac but no Neu5Gc, indicating that the CMAH mutation predated the common ancestor of humans and Neandertals, ≈ 0.5-0.6 million years ago (mya). Second, we date the insertion event of the inactivating human-specific sahAluY element that replaced the ancestral AluSq element found adjacent to exon 6 of the CMAH gene in the chimpanzee genome. Assuming Alu source genes based on a phylogenetic tree of human-specific Alu elements, we estimate the sahAluY insertion time at ≈ 2.7 mya. Third, we apply molecular clock analysis to chimpanzee and other great ape CMAH genes and the corresponding human pseudogene to estimate an inactivation time of ≈ 2.8 mya. Taken together, these studies indicate that the CMAH gene was inactivated shortly before the time when brain expansion began in humankind's ancestry, ≈ 2.1-2.2 mya. In this regard, it is of interest that although Neu5Gc is the major sialic acid in most organs of the chimpanzee, its expression is selectively down-regulated in the brain, for as yet unknown reasons.
机译：人类是普通哺乳动物唾液酸N-羟乙酰神经氨酸（Neu5Gc）的遗传缺陷，因为编码CMP-N-乙酰神经氨酸（CMP-Neu5Ac）羟化酶（CMAH）的基因经过Alu介导的失活突变。这种突变发生在我们上一个common黑猩猩和黑猩猩的祖先之后，并且在当今人类起源之前。在这里，我们采用多种方法来估计这种突变与人类进化史的关系的时机。首先，我们开发了一种从骨骼和骨化石中提取和鉴定唾液酸的方法。研究的两个尼安德特人化石具有明显可检测到的Neu5Ac，但没有Neu5Gc，这表明CMAH突变早于人类和尼安德特人的共同祖先，大约在0.5-0.6百万年前（mya）。其次，我们确定了灭活人类特异性sahAluY元件的插入事件，该元件取代了在黑猩猩基因组中与CMAH基因外显子6相邻的祖先AluSq元件。假设Alu源基因基于人类特异性Alu元素的系统树，我们估计sahAluY的插入时间约为2.7 mya。第三，我们对黑猩猩和其他大猿CMAH基因以及相应的人类假基因进行分子钟分析，以估计≈2.8 mya的失活时间。综上所述，这些研究表明，CMAH基因在人类祖先的大脑扩张开始之前不久就失活了，≈2.1-2.2 mya。在这方面，令人感兴趣的是，尽管Neu5Gc是黑猩猩大多数器官中的主要唾液酸，但出于未知的原因，其表达在大脑中选择性下调。

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