Molecular evolution and genetics of the Saitohin gene and tau haplotype in Alzheimer's disease and argyrophilic grain disease
Molecular evolution and genetics of the Saitohin gene and tau haplotype in Alzheimer's disease and argyrophilic grain disease
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DOI：
10.1046/j.1471-4159.2004.02320.x
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发表时间：
2004-04-01
影响因子：
4.7
通讯作者：
Davies, P
中科院分区：
文献类型：
--
作者：
Conrad, C;Vianna, C;Davies, P
在Saitohin(STH)基因中发现了一种导致氨基酸变化(Q7R)的单核苷酸多态性，最初发现在晚发性阿尔茨海默病(AD)患者中，该基因在纯合状态下过度表达。更广泛的研究对AD的关联提供了有限的支持，但证实了Q等位基因与进行性核上性麻痹和嗜银颗粒病的关联。在大鼠和小鼠tau基因的适当位置发现了一个同源序列，但没有允许STH在这些物种中表达的开放阅读框架，这表明该基因的进化相对较晚。在一些非人类灵长类动物中，发现了STH基因，并发现在128个氨基酸中有两个与人类基因不同。所有鉴定出STH基因的灵长类动物都是STH R等位基因纯合的，提示这是祖先的等位基因。这一观察结果令人惊讶，因为Q等位基因在人类群体中更常见，并增加了自然选择有利于携带该等位基因的个体的可能性。STH多态是tau基因单倍型的一部分，在人类群体中存在两个主要的变异，Q是H1单倍型的一部分，R是H2单倍型的一部分。更详细的研究证实，H2单倍型是祖先tau基因。这种情况让人想起载脂蛋白(ApoE)基因的进化，这是另一个对AD风险具有潜在重要性的基因座。
A single nucleotide polymorphism that results in an amino acid change (Q7R) has been identified in the Saitohin (STH) gene and was initially found to be over-represented in the homozygous state in subjects with late-onset Alzheimer's disease (AD). More extensive studies provide limited support for the association with AD, but confirm an association of the Q allele with progressive supranuclear palsy and argyrophilic grain disease. A homologous sequence was found in the appropriate location of the rat and mouse tau genes, but there was no open reading frame allowing STH expression in these species, suggesting relatively recent evolution of this gene. In some non-human primates, the STH gene was identified, and this was found to differ from the human gene at two of 128 amino acids. All primates in which the STH gene was identified were homozygous for the R allele of STH, suggesting this is the ancestral allele. This observation was surprising, in that the Q allele is more common in human populations, and raises the possibility that natural selection has operated to favor individuals carrying this allele. The STH polymorphism is part of the tau gene haplotype, of which two major variants exist in human populations, the Q being part of the H1 haplotype and the R part of the H2 haplotype. More detailed studies confirm the H2 haplotype to be the ancestral tau gene. This situation is reminiscent of the evolution of the apolipoprotein (ApoE) gene, another locus that is potentially important for the risk of development of AD.