Genomic Rearrangements by TEs
The comparison of human and chimpanzee genomic sequences showed that the two genomes have a much higher sequence identity than we expected [3, 4]. In spite of the sequence similarity, TEs have remarkably generated genomic differences between the two species since their divergence [22]. Many studies have suggested that a number of TEs are still active to retrotranspose and have the potential to cause genomic variations as a major driver [12, 16-19, 28]. In reality, TEs have rearranged human and non-human primate genomes through various mechanisms, such as de novo TE insertion, TE insertion-mediated deletion, and homologous recombination between them (Fig. 2) [29]. These genomic changes caused by TEs have increased the genomic difference between human and non-human primates, and some of the human-specific genomic rearrangements caused human diseases [28, 34].
Advanced sequencing technology, including next-generation sequencing, and combined computational analyses have accelerated the studies on the dynamics of TE mobilization [35]. In reality, human-specific TEs have been continuously investigated, and the majority of them are Alu, L1, and SVA elements [8, 14]. The relationship between human brain evolution and Alu elements was studied. Since the divergence of the human and chimpanzee lineages, the human brain has rapidly changed in terms of mass [36]. It is not an exaggeration to say that Alu elements are in part responsible for the human brain mass. Interestingly, de novo Alu insertions have been identified in many human brain genes that are related to neuronal functions and neurological disorders [37]. The inserted Alu elements belong to AluYa5, AluYb8, and AluYc1, which are human-specific Alu subfamilies [37].
Approximately 1,800 human-specific L1s were identified in the human genome [15]. They belonged to two different subfamilies, pre-Ta and Ta; Ta is subdivided into Ta-0 and Ta-1 by diagnostic nucleotides [38]. Among hominid-specific SVA subfamilies, SVA_E and SVA_F are only detected in the human genome, but the other four subfamilies, SVA_A, SVA_B, SVA_C, and SVA_D, are shared in human and other apes, including chimpanzee and gorilla [26]. HERV appeared in the primate genome through germ-line infection [30]. There are approximately 98,000 HERVs in the human genome. Full-length HERVs are ~10 kb in length, but most of the HERVS existing in the human are defective due to truncation and accumulation of mutations during primate evolution [39]. Among various HERV subfamilies, HERV-K (HML2) is the youngest element in the human genome [8, 40]; 113 human-specific HERV-Ks were identified in the human genome, and among them, there were 15 and 98 full-length HERV-Ks and solitary LTRs, respectively [39]. These de novo TE insertions showed polymorphisms among human populations and even human individuals [31, 39, 41, 42]. Therefore, they have the potential to be used as a genetic marker for racial identification [31, 41, 42].
De novo TE insertions contribute to the genome expansion. Actually, some of them somewhat decreased their host genomes involving the insertion-mediated deletion of host genome sequences [32, 33]. Through comparative genomic analyses, 50 L1 insertion-mediated deletion events were found in the human and chimpanzee genomes [18]. The sizes of the deleted sequences were variable, and in sum, ~18 kb and ~15 kb of sequences were removed from the human and chimpanzee genomes, respectively. Based on the result, it was estimated that L1 insertions may have deleted up to 7.5 Mb of target genomic sequences during the primate radiation. Alu insertions were also involved in the genomic deletions at its insertion target regions through Alu retrotransposition-mediated deletion. A total of 33 deletion events responsible for a ~9,000-bp deletion in human and chimpanzee genomes were identified. It was suggested that Alu retrotransposition may have contributed to over 3,000 deletion events, leading to a ~900-kb deletion during primate evolution [17]. Additionally, 13 SVA insertion-mediated deletions (SIMDs) were also identified in the human genome, and they deleted 30,785 bp of the human genome compared with the chimpanzee genome (Table 1). Among the 13 SIMDs, 9 were associated with the SVA_D subfamily, occupying the largest portion of SVAs, which suggests that SIMD frequency is directly correlated to the copy number of SVA elements. Furthermore, one of the deletion events occurred in the tMDC II gene associated with sperm-egg binding prior to fertilization [43, 44].
After TE insertions into the host genome, they could generate genomic variations through unequal homologous recombination events between them [17, 19, 43]. The copy number of TEs is closely related to the frequency of the recombination between them. Thus, compared to other TEs, Alu and L1 elements have a high probability of generating genomic structural variations due to their ubiquity. In reality, 492 Alu recombination-mediated deletions (ARMDs) were identified in the human genome, and they deleted ~400 kb of human genomic sequences (Table 1). About 60% of the deletion events were related to known or predicted genes, including three that deleted functional exons. Thus, the ARMD process has produced a considerable portion of the genomic and phenotypic variations between humans and chimpanzees since the divergence of the two species [16]. The recombination between L1 elements has also deleted human genome sequences. Seventy-three L1 recombination-associated deletions (L1RADs) were identified in the human genome [45]. The sizes of the deletion events range from 56 to 64,113 bp, and ~450 kb of human genomic sequence was deleted through this L1RAD process (Table 1). Thus, the L1RAD event has deleted 25 times as much human genomic sequence as the L1 insertion-mediated deletion event [18, 45].