Alu-Mediated Acquisition of Unstable ATTCT Pentanucleotide Repeats in the Human ATXN10 Gene
Alu-Mediated Acquisition of Unstable ATTCT Pentanucleotide Repeats in the Human ATXN10 Gene
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DOI：
10.1093/molbev/msp172
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发表时间：
2009-11-01
影响因子：
10.7
通讯作者：
Ueda, Shintaroh
中科院分区：
文献类型：
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作者：
Kurosaki, Tatsuaki;Matsuura, Tohru;Ueda, Shintaroh
10 型脊髓小脑性共济失调是由人类 ATXN10 基因中的 ATTCT 重复扩增引起的。我们研究了人类基因组的进化史，以确定基因组中获得不稳定 ATTCT 重复的时间和机制。我们发现长散布元件1（LINE-1）被插入到ATXN10内含子9中；然后将 Alu 插入 LINE-1 的中间；内源性retrovilcus K最后转位到Alu中部。 ATTCT 重复序列位于 Alu 元件的 3' 端与 LINE-1 产生的直接重复序列之间的边界上。我们确定了代表 33 种灵长类动物的 50 个个体的直系同源区域的核苷酸序列，并将其与人类序列进行了比较。分析表明，ATTCT 重复序列仅存在于人类和猿类中。旧大陆猴子也具有五核苷酸重复序列，但它们的基序是 TGTCT 和 GGTCT。新世界猴和原猴没有提供任何信息，因为它们缺乏 ATXN10 内含子 9 中的相应区域。我们的研究规定了两种简约的进化情景。首先，barT 基序下的 TT (C) 源于 Alu 和 LINE-1 连接处的 TTTTT 基序，随后引入 A，在类激素中形成 (A) bar 下的 TTCT 基序。其次，barT 基序下的 ATT (C) 直接从卡他尼共同祖先的祖先 ATM 基序产生。我们还证明，猩猩独特地引入了 G，在 TTCT 基序下形成了 (G)，后来又引入了 C，在条形基序下形成了 GTTC (C)，其中新引入的核苷酸带有下划线。我们的研究表明，旧大陆猴子和类人猿的谱系中发生了 Alu 元件的聚 (A) 尾部的核苷酸取代以及随后的五核苷酸扩增，并且不稳定的 ATTCT 五核苷酸重复起源于类人猿的共同祖先。这些发现还强调了逆转录转座子在人类疾病和进化中作用的一个新方面，这可能有助于研究人类独特性之谜。
Spinocerebellar ataxia type 10 is caused by ATTCT repeat expansion in the ATXN10 gene in humans. We studied the evolutionary history of the human genome to determine the time and mechanism of the acquisition of unstable ATTCT repeats in the genome. We found that long interspersed element-1 (LINE-1) was inserted into ATXN10 intron 9; Alu was then inserted in the middle of LINE-1; and endogenous retrovilcus K was lastly retrotransposed in the middle of Alu. The ATTCT repeat was located on the boundary between the 3'-end of the Alu element and the direct repeat arising from LINE-1. We determined nucleotide sequences of the orthologous region of 50 individuals representing 33 primate species and compared them with the human sequence. The analysis revealed that the ATTCT repeat is present only in human and apes. Old World monkeys also possess pentanucleotide repeats, but their motifs are TGTCT and GGTCT. New World monkeys and prosimians are not informative because they lack the corresponding region in ATXN10 intron 9. Our studies dictate two parsimonious scenarios of evolution. First, a TT (C) under barT motif arose from a TTTTT motif at the junction of Alu and LINE-1, which was followed by introduction of A to make an (A) under bar TTCT motif in horminoids. Second, an ATT (C) under barT motif wits directly generated from an ancestral ATM motif in the common ancestor of catarrhines. We also demonstrate that orangutan uniquely introduced G to make a (G) under bar TTCT motif and later C to make a GTTC (C) under bar motif, where newly introduced nucleotides are underlined. Our Studies reveal that nucleotide substitutions in a poly(A) tail of the Alu element and the following amplification of pentanucleotides occurred in the lineages of Old World monkeys and hominoids and that unstable ATTCT pentanucleotide repeats originated in the common ancestor of hominoids. These findings also highlight a new aspect of the role of retrotransposons in human disease and evolution, which might be useful in investigating the mystery of human uniqueness.