Retrotransposition of marked SVA elements by human L1s in cultured cells

Hancks, Dustin C.; Goodier, John; Mandal, Prabhat Kumar; Cheung, Ling E.; Kazazian, Haig H.

doi:10.1093/hmg/ddr245

Cited by 176 publications

(204 citation statements)

References 87 publications

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“…Polymorphic interspersed repeats include LINE-1 sequences that copy and insert into new genomic loci using LINE-1-encoded reverse transcriptase (12,13). LINE-1 also mediates the retrotransposition of other interspersed repeats, including Alu SINE (14) and SINE-variable number tandem repeat (VNTR)-Alu elements (15,16). These interspersed repeats variants reflect a major source of genetic diversity in humans.…”

Section: −8mentioning

confidence: 99%

Structural variants caused byAluinsertions are associated with risks for many human diseases

Payer

Steranka

Yang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

128

102

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Interspersed repeat sequences comprise much of our DNA, although their functional effects are poorly understood. The most commonly occurring repeat is the Alu short interspersed element. New Alu insertions occur in human populations, and have been responsible for several instances of genetic disease. In this study, we sought to determine if there are instances of polymorphic Alu insertion variants that function in a common variant, common disease paradigm. We cataloged 809 polymorphic Alu elements mapping to 1,159 loci implicated in disease risk by genome-wide association study (GWAS) (P < 10−8). We found that Alu insertion variants occur disproportionately at GWAS loci (P = 0.013). Moreover, we identified 44 of these Alu elements in linkage disequilibrium (r2 > 0.7) with the trait-associated SNP. This figure represents a >20-fold increase in the number of polymorphic Alu elements associated with human phenotypes. This work provides a broader perspective on how structural variants in repetitive DNAs may contribute to human disease.

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Section: −8mentioning

confidence: 99%

Structural variants caused byAluinsertions are associated with risks for many human diseases

Payer

Steranka

Yang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

128

102

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“…Retrotransposition-competent cell lines have greatly assisted in understanding the mechanism of non-LTR retrotransposition in vivo [6][7][8][9][10] . Here we report the first such system in a parasitic protist E. histolytica.…”

Section: Discussionmentioning

confidence: 99%

“…Although sequence analysis of human Alu subfamilies showed the existence of mosaic elements 29, these were not experimentally found [7][8][9] . Mosaics could have been missed in these studies because of the smaller number of retrotransposition events scored, and the selection pressure used.…”

Section: Mismatchesmentioning

confidence: 99%

Recombinant SINEs are formed at high frequency during induced retrotransposition in vivo

et al. 2012

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non-long terminal repeat Retrotransposons are referred to as long interspersed nuclear elements (LInEs) and their non-autonomous partners are short interspersed nuclear elements (sInEs). It is believed that an active sInE copy, upon retrotransposition, generates near identical copies of itself, which subsequently accumulate mutations resulting in sequence polymorphism. Here we show that when a retrotransposition-competent cell line of the parasitic protist Entamoeba histolytica, transfected with a marked sInE copy, is induced to retrotranspose, > 20% of the newly retrotransposed copies are neither identical to the marked sInE nor to the mobilized resident sInEs. Rather they are recombinants of resident sInEs and the marked sInE. They are a consequence of retrotransposition and not DnA recombination, as they are absent in cells not expressing the retrotransposition functions. This high-frequency recombination provides a new explanation for the existence of mosaic sInEs, which may impact on genetic analysis of sInE lineages, and measurement of phylogenetic distances.

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“…[14][15][16][17] Mouse SINE B2 is derived from transfer RNA sequences while human Alu and mouse SINE B1 are derived from 7SL RNA sequences of the ribosome signal recognition particle (Figure 1). 7 Sequences needed for association with the signal recognition particle are required for efficient Alu mobilization.…”

Section: Advances In Genomics Andmentioning

confidence: 99%

“…19,20 SINEs contain internal RNA polymerase III promoters, while SVA elements are likely transcribed by RNA polymerase II. 1,7 Retrotransposition of human Alu and SVA elements minimally requires L1 ORF2p, 15,17 but ORF1p increases Alu mobilization and is needed to mobilize some SVA elements. 17,21 L1 elements can also mobilize reporter gene transcripts, which requires both ORF1p and ORF2p, providing support for the role of L1 in generating retrocopies of cellular RNA that do not code for proteins (processed pseudogenes) or that do code for proteins and that are expressed from heterologous promoters at target sites (retrogenes).…”

Section: Advances In Genomics Andmentioning

confidence: 99%

Consequences of ongoing retrotransposition in mammalian genomes

Maxwell

2014

AGG

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Abstract:Retrotransposons can have significant influences on gene expression and genome stability through their ability to integrate reverse-transcript copies of their sequences at new genomic locations by retrotransposition. These elements have been long known to retrotranspose in mammalian germ cells to give rise to inherited insertion alleles, but more recent work has also shown that retrotransposition can occur in mammalian somatic cells, particularly in brain tissue and tumors. Retrotransposition makes appreciable contributions to spontaneous diseasecausing alleles in humans and a more significant contribution to spontaneous mutations in mice. Genome-wide studies have found high levels of polymorphic retrotransposon insertions in human populations that are consistent with ongoing retrotransposition. Many insertions do not disrupt exons, but insertions into introns or flanking genes can alter gene expression patterns, generate truncated or antisense gene transcripts, alter splicing patterns, or result in premature polyadenylation of gene transcripts. Furthermore, the very high genomic copy numbers of these elements can lead to nonallelic homologous recombination events that produce gene deletions/ duplications and genome rearrangements, and can also lead to evolution of particular insertions or types of elements to have cellular functions through exaptation. Mobility of these elements occurs despite multiple epigenetic mechanisms to restrict their expression. While the potential for retrotransposons to significantly influence mammalian health and cellular functions is clear, substantial research efforts will be needed to fully elucidate the actual contributions of natural levels of mobility of endogenous elements to the health and development of humans and other mammals.

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Retrotransposition of marked SVA elements by human L1s in cultured cells

Cited by 176 publications

References 87 publications

Structural variants caused byAluinsertions are associated with risks for many human diseases

Structural variants caused byAluinsertions are associated with risks for many human diseases

Recombinant SINEs are formed at high frequency during induced retrotransposition in vivo

Consequences of ongoing retrotransposition in mammalian genomes

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