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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 TTTCT motif arose from a  motif at the junction of Alu and LINE-1, which was followed by introduction of A to make an ATTCT motif in hominoids. Second, an ATTCT motif was directly generated from an ancestral ATTTT motif in the common ancestor of catarrhines. We also demonstrate that orangutan uniquely introduced G to make a GTTCT motif and later C to make a GTTCC 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.

Alu-Mediated Acquisition of Unstable ATTCT Pentanucleotide Repeats in the Human ATXN10 Gene