Approximately 80 long interspersed element (LINE-1 or L1) copies are able to retrotranspose actively in the human genome, and these are termed retrotransposition-competent L1s. The 5′ untranslated region (UTR) of the human-specific L1 contains an internal promoter and several transcription factor binding sites. To better understand the effect of the L1 5′ UTR on the evolution of human-specific L1s, we examined this population of elements, focusing on the sequence diversity and accumulated substitutions within their 5′ UTRs. Using network analysis, we estimated the age of each L1 component (the 5′ UTR, ORF1, ORF2, and 3′ UTR). Through the comparison of the L1 components based on their estimated ages, we found that the 5′ UTR of human-specific L1s accumulates mutations at a faster rate than the other components. To further investigate the L1 5′ UTR, we examined the substitution frequency per nucleotide position among them. The results showed that the L1 5′ UTRs shared relatively conserved transcription factor binding sites, despite their high sequence diversity. Thus, we suggest that the high level of sequence diversity in the 5′ UTRs could be one of the factors controlling the number of retrotransposition-competent L1s in the human genome during the evolutionary battle between L1s and their host genomes. 1. Introduction Transposable elements are a considerable component of the human genome, responsible for approximately 45% of the human genome sequence [1]. These elements are associated with genomic instability via de novo insertions, insertion-mediated deletions, and recombination events [2–8] and are responsible for a number of genetic disorders [9]. Almost all of the transposable elements belong to one of four types: long interspersed elements (LINEs), short interspersed elements (SINEs), long terminal repeat (LTR) retrotransposons, and DNA transposons [1, 10–12]. Among them, LINE-1s or L1s are one of the most successful retrotransposon families in the human genome, with 516,000 copies comprising 17% of the human genomic sequence [1]. A full-length functional L1 element is about 6？kb in length and contains a 5′ untranslated region (UTR) bearing an internal RNA polymerase II promoter, two open reading frames (ORF1 and ORF2), and a 3′ UTR terminating in a poly(A) tail [13]; ORF1 encodes an RNA-binding protein that has demonstrated nucleic acid chaperone activity in vitro, and ORF2 encodes a protein with both endonuclease (EN) and reverse transcriptase (RT) activities, which are required for L1 retrotransposition [14–16]. The generally accepted model for
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