Chou Hsun-Hua, Hayakawa Toshiyuki, Diaz Sandra, Krings Matthias, Indriati Etty, Leakey Meave, Paabo Svante, Satta Yoko, Takahata Naoyuki, Varki Ajit
Glycobiology Research and Training Center, Department of Medicine, University of California at San Diego, La Jolla, CA 92093-0687, USA.
Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11736-41. doi: 10.1073/pnas.182257399. Epub 2002 Aug 21.
Humans are genetically deficient in the common mammalian sialic acid N-glycolylneuraminic acid (Neu5Gc) because of an Alu-mediated 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 Neanderthal fossils studied had clearly detectable Neu5Ac but no Neu5Gc, indicating that the CMAH mutation predated the common ancestor of humans and the Neanderthal, approximately 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 approximately 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 approximately 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, approximately 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.
由于编码胞苷单磷酸 - N - 乙酰神经氨酸（CMP - Neu5Ac）羟化酶（CMAH）的基因发生了Alu介导的失活突变，人类在常见的哺乳动物唾液酸N - 羟乙酰神经氨酸（Neu5Gc）方面存在基因缺陷。这种突变发生在我们与倭黑猩猩和黑猩猩的最后一个共同祖先之后，以及现代人类起源之前。在这里，我们采用多种方法来估计这种突变与人类进化历史相关的时间。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。研究的两块尼安德特人化石明显可检测到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50 - 60万年前。其次，我们确定了失活的人类特异性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相邻发现的祖先AluSq元件。基于人类特异性Alu元件的系统发育树假设Alu源基因，我们估计sahAluY插入时间约为270万年前。第三，我们对黑猩猩和其他大型猿类的CMAH基因以及相应的人类假基因进行分子钟分析，以估计失活时间约为280万年前。综合这些研究表明，CMAH基因在人类祖先大脑开始扩张之前不久就失活了，大约在210 - 220万年前。在这方面，有趣的是，尽管Neu5Gc是黑猩猩大多数器官中的主要唾液酸，但其在大脑中的表达却出于未知原因被选择性下调。
