Mobile Interspersed Repeats Are Major Structural Variants in the Human Genome

Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Cell (Impact Factor: 32.24). 06/2010; 141(7):1171-82. DOI: 10.1016/j.cell.2010.05.026
Source: PubMed


Characterizing structural variants in the human genome is of great importance, but a genome wide analysis to detect interspersed repeats has not been done. Thus, the degree to which mobile DNAs contribute to genetic diversity, heritable disease, and oncogenesis remains speculative. We perform transposon insertion profiling by microarray (TIP-chip) to map human L1(Ta) retrotransposons (LINE-1 s) genome-wide. This identified numerous novel human L1(Ta) insertional polymorphisms with highly variant allelic frequencies. We also explored TIP-chip's usefulness to identify candidate alleles associated with different phenotypes in clinical cohorts. Our data suggest that the occurrence of new insertions is twice as high as previously estimated, and that these repeats are under-recognized as sources of human genomic and phenotypic diversity. We have just begun to probe the universe of human L1(Ta) polymorphisms, and as TIP-chip is applied to other insertions such as Alu SINEs, it will expand the catalog of genomic variants even further.

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    • "(Middle panel) Seven patients with pancreatic carcinomas and metastases. The following five patient samples were genotyped by both L1-seq and TIP-seq, a method derived from TIP-chip (Huang et al. 2010; Rodi´c et al. 2015): A43, A55, A57, A82, and A146. Sixteen insertions found by TIP-seq overlap potential insertion sites found via L1-seq (sites with " 1 " in the column " TIP-seq " in Supplemental Table 2c). "
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    ABSTRACT: Somatic L1 retrotransposition events have been shown to occur in epithelial cancers. Here, we attempted to determine how early somatic L1 insertions occurred during the development of gastrointestinal (GI) cancers. Using L1-targeted resequencing (L1-seq), we studied different stages of four colorectal cancers arising from colonic polyps, seven pancreatic carcinomas, as well as seven gastric cancers. Surprisingly, we found somatic L1 insertions not only in all cancer types and metastases, but also in colonic adenomas, well-known cancer precursors. Some insertions were also present in low quantities in normal GI tissues, occasionally caught in the act of being clonally fixed in the adjacent tumors. Insertions in adenomas and cancers numbered in the hundreds and many were present in multiple tumor sections implying clonal distribution. Our results demonstrate that extensive somatic insertional mutagenesis occurs very early during the development of GI tumors, probably before dysplastic growth. Published by Cold Spring Harbor Laboratory Press.
    Genome Research 08/2015; 25(10). DOI:10.1101/gr.196238.115 · 14.63 Impact Factor
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    • "For over 100 million years, Long Interspersed Nuclear Elements 1 (known as LINE-1 or L1), from the L1 clade, have sculpted Metatheria and Eutheria genomes, representing between 15 to 20% of the DNA, while being almost absent in Prototheria genomes (Smit 1996; Lander et al. 2001; Lindblad-Toh et al. 2005; Mandal and Kazazian 2008; Warren et al. 2008). In the human genome, L1 is believed to be the only autonomous mobile element remaining active, and it continues to have a mutagenic impact by various mechanisms including insertion, duplication, deletion and recombination (Deininger et al. 2003; Chen et al. 2005; Babushok and Kazazian 2007; Jurka et al. 2007; Muotri et al. 2007; Cordaux and Batzer 2009; Xing et al. 2009; Beck et al. 2010; Ewing and Kazazian 2010; Huang et al. 2010; Iskow et al. 2010; O'Donnell and Burns 2010; Baillie et al. 2011). Although never observed, HERV-K, an LTR retrotransposon, may theoretically be active since functional copies have the potential to exist in individual genomes (Dewannieux et al. 2006; Ruprecht et al. 2008; Hohn et al. 2013). "
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    ABSTRACT: Transposable elements comprise more than 45% of the human genome and LINE-1 (L1) is the only autonomous mobile element remaining active. Since its identification, it has been proposed that L1 contributes to the mobilization and amplification of other cellular RNAs and more recently, experimental demonstrations of this function has been described for many transcripts such as Alu, a non-autonomous mobile element, cellular mRNAs or small non-coding RNAs. Detailed examination of the mobilization of various cellular RNAs revealed distinct pathways by which they could be recruited during retrotransposition; template choice or template switching. Here, by analysing genomic structures and retrotransposition signatures associated to small nuclear RNA (snRNA) sequences, we identified distinct recruiting steps during the L1 retrotransposition cycle for the formation of snRNA-processed pseudogenes. Interestingly, some of the identified recruiting steps take place in the nucleus. Moreover, after comparison to other vertebrate genomes, we established that snRNA amplification by template switching is common to many LINE families from several LINE clades. Finally, we suggest that U6 snRNA copies can serve as markers of L1 retrotransposition dynamics in mammalian genomes. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.
    Molecular Biology and Evolution 03/2015; 32(7). DOI:10.1093/molbev/msv062 · 9.11 Impact Factor
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    • "Next-generation sequencing studies and specially modified sequencing protocols have investigated polymorphic insertions segregating in different populations [Beck et al., 2010; Ewing and Kazazian, 2010; Huang et al., 2010; Iskow et al., 2010; Stewart et al., 2011] "
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    ABSTRACT: Transposable Elements (TEs) or transposons are low-complexity elements (e.g., LINEs, SINEs, SVAs, and HERVs) that make up to two-thirds of the human genome. There is mounting evidence that TEs play an essential role in genomic architecture and regulation related to both normal function and disease states. Recently, the identification of active TEs in several different human brain regions suggests that TEs play a role in normal brain development and adult physiology and quite possibly in psychiatric disorders. TEs have been implicated in hemophilia, neurofibromatosis, and cancer. With the advent of next-generation whole-genome sequencing approaches, our understanding of the relationship between TEs and psychiatric disorders will greatly improve. We will review the biology of TEs and early evidence for TE involvement in psychiatric disorders. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 04/2014; 165(3). DOI:10.1002/ajmg.b.32225 · 3.42 Impact Factor
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