Estimating genomic instability mediated by Alu retroelements in breast cancer

Fazza, Ana Cristina; Sabino, Flávia Cal; Setta, Nathalia de; Bordin, Newton Antonio; Silva, Eloiza Helena Tajara da; Carareto, Claudia M. A.

doi:10.1590/s1415-47572009005000018

Cited by 11 publications

(5 citation statements)

References 40 publications

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“…Furthermore, Alu-mediated unequal recombination has been reported, resulting in mutation or polymorphic substitution, implying contribution to structure variation and Alu evolution [56,57]. In addition, insertion of Alu elements might cause genetic disease and cancer through structural variation and genomic instability [58][59][60][61]. In fact, partial AluSz6 insertion in the ACAT1 gene has a negative effect downstream of exon inclusion, depending on the distance between the Alu element and the splice site acceptor site [62].…”

Section: Discussionmentioning

confidence: 99%

A single mutation in the ACTR8 gene associated with lineage-specific expression in primates

et al. 2020

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Background: Alternative splicing (AS) generates various transcripts from a single gene and thus plays a significant role in transcriptomic diversity and proteomic complexity. Alu elements are primate-specific transposable elements (TEs) and can provide a donor or acceptor site for AS. In a study on TE-mediated AS, we recently identified a novel AluSz6-exonized ACTR8 transcript of the crab-eating monkey (Macaca fascicularis). In the present study, we sought to determine the molecular mechanism of AluSz6 exonization of the ACTR8 gene and investigate its evolutionary and functional consequences in the crab-eating monkey. Results: We performed RT-PCR and genomic PCR to analyze AluSz6 exonization in the ACTR8 gene and the expression of the AluSz6-exonized transcript in nine primate samples, including prosimians, New world monkeys, Old world monkeys, and hominoids. AluSz6 integration was estimated to have occurred before the divergence of simians and prosimians. The Alu-exonized transcript obtained by AS was lineage-specific and expressed only in Old world monkeys and apes, and humans. This lineage-specific expression was caused by a single G duplication in AluSz6, which provides a new canonical 5′ splicing site. We further identified other alternative transcripts that were unaffected by the AluSz6 insertion. Finally, we observed that the alternative transcripts were transcribed into new isoforms with C-terminus deletion, and in silico analysis showed that these isoforms do not have a destructive function. Conclusions: The single G duplication in the TE sequence is the source of TE exonization and AS, and this mutation may suffer a different fate of ACTR8 gene expression during primate evolution.

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Section: Discussionmentioning

confidence: 99%

A single mutation in the ACTR8 gene associated with lineage-specific expression in primates

et al. 2020

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“…Furthermore, Alumediated unequal recombination has been reported, resulting in mutation or polymorphic substitution, implying contribution to structure variation and Alu evolution [56,57]. In addition, insertion of Alu elements might cause genetic disease and cancer through structural variation and genomic instability [58][59][60][61]. In fact, partial AluSz6 insertion in the ACAT1 gene has a negative effect downstream of exon inclusion, depending on the distance between the Alu element and the splice site acceptor site [62].…”

Section: Discussionmentioning

confidence: 99%

A single mutation in ACTR8 gene results in lineage-specific expression in primates

Choe

Park

Cho

et al. 2020

Preprint

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Background: Alternative splicing (AS) generate various transcripts from a single gene and thus plays a significant role in transcriptomic diversity and proteomic complexity. Alu elements are primate-specific transposable elements (TEs) and can provide a donor or acceptor site for AS. In a study on TE-mediated AS, we recently identified a novel AluSz6-exonized ACTR8 transcript of a crab-eating monkey (Macaca fascicularis). In the present study, we sought to analyse the molecular mechanism of AluSz6-derived exonization in ACTR8 gene. Results: We performed RT-PCR and genomic PCR using the tissue RNA and DNA samples from the crab-eating monkey and various other primates, including humans, to study AluSz6-derived exonization in ACTR8 gene and transcript variants expression. AluSz6 integration was estimated to have occurred before the divergence of simians and prosimians. The novel transcript was expressed only in Old world monkeys and apes, and humans. Lineage-specific expression of ACTR8 gene was due to a ‘G’ duplication in the AluSz6 sequences of Old world monkey and ape lineages. Six alternative transcripts (TV1-TV6) generated by various AS mechanisms were newly identified. Based on in-silico analysis, the alternative transcripts were transcribed into new isoforms with C-terminus deletion. Conclusion: ‘G’ duplication together with TE exonization and AS via various mechanisms resulted in a different fate of ACTR8 gene expression during primate evolution.

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“…Alu elements have been found at many SV breakpoints [25][26][27]. Alu elements have also been linked to cancer [28][29][30]. Hundreds of deletions generated by Alu-Alu recombination events have been shown to be present in humans [31,32].…”

Section: Introductionmentioning

confidence: 99%

“…The structural motif of inverted repetitive DNA has long been recognized as a source of human genomic instability [38,39]. Long inverted repeats have recently been correlated with SV in cancer [40,41] and fused inverted Alu element pairs have also been identified in cancer [29,41]. Alu elements are primate specific repeats which generate the most common form of inverted repetitive DNA in the human genome.…”

Section: Introductionmentioning

confidence: 99%

Structural variation and its potential impact on genome instability: Novel discoveries in the EGFR landscape by long-read sequencing

et al. 2020

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Structural variation (SV) is typically defined as variation within the human genome that exceeds 50 base pairs (bp). SV may be copy number neutral or it may involve duplications, deletions, and complex rearrangements. Recent studies have shown SV to be associated with many human diseases. However, studies of SV have been challenging due to technological constraints. With the advent of third generation (long-read) sequencing technology, exploration of longer stretches of DNA not easily examined previously has been made possible. In the present study, we utilized third generation (long-read) sequencing techniques to examine SV in the EGFR landscape of four haplotypes derived from two human samples. We analyzed the EGFR gene and its landscape (+/-500,000 base pairs) using this approach and were able to identify a region of non-coding DNA with over 90% similarity to the most common activating EGFR mutation in non-small cell lung cancer. Based on previously published Alu-element genome instability algorithms, we propose a molecular mechanism to explain how this non-coding region of DNA may be interacting with and impacting the stability of the EGFR gene and potentially generating this cancer-driver gene. By these techniques, we were also able to identify previously hidden structural variation in the four haplotypes and in the human reference genome (hg38). We applied previously published algorithms to compare the relative stabilities of these five different EGFR gene landscape haplotypes to estimate their relative potentials to generate the EGFR exon 19, 15 bp canonical deletion. To our knowledge, the present study is the first to use the differences in genomic architecture between targeted cancer-linked phased haplotypes to estimate their relative potentials to form a common cancer-linked driver mutation.

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Estimating genomic instability mediated by Alu retroelements in breast cancer

Cited by 11 publications

References 40 publications

A single mutation in the ACTR8 gene associated with lineage-specific expression in primates

A single mutation in the ACTR8 gene associated with lineage-specific expression in primates

A single mutation in ACTR8 gene results in lineage-specific expression in primates

Structural variation and its potential impact on genome instability: Novel discoveries in the EGFR landscape by long-read sequencing

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