Structural variants caused by<i>Alu</i>insertions are associated with risks for many human diseases

Payer, Lindsay M.; Steranka, Jared P.; Yang, Wan Rou; Kryatova, Maria S.; Medabalimi, Sibyl; Ardeljan, Daniel; Liu, Chunhong; Boeke, Jef D.; Avramopoulos, Dimitri; Burns, Kathleen H.

doi:10.1073/pnas.1704117114

Cited by 129 publications

(118 citation statements)

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“…Indeed, it is known that the RNA helicase Upf1 can sense 3'-UTR size and 490 promote nonsense mediated decay of abnormally long 3'-UTRs [62]. Also, because we 491 cloned the "presence" and "absence" 3'-UTR haplotypes from two different LCLs, we 492 cannot rule out that another polymorphism 'hitchhiking' with the Alu insertion, is causing 493 as well as the many other TE-QTLs identified in this study underscore a plausible 501 contribution of TE insertions commonly segregating in the population in human trait 502 variation, including disease susceptibility [16,19,63]. These findings confirm the 503 potential of unfixed TEs to make a non-trivial contribution to human gene expression [5-504 7].…”

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confidence: 93%

“…To date, whole genome sequencing studies have discovered 42 more than 19,000 TE loci segregating in the human population [11][12][13][14][15]. Despite their 43 potential role in shaping human phenotypic variation, including disease 44 susceptibility [16,17], very little is known about the impact of these polymorphic 45 insertions on genome function. Only a handful of recent studies have started to unravel 46 their contribution to gene expression variation [16][17][18][19].…”

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confidence: 99%

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Contribution of unfixed transposable element insertions to human regulatory variation

Goubert

Zevallos

Feschotte

2019

Preprint

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8Thousands of unfixed transposable element (TE) insertions segregate in the human 9 population, but little is known about their impact on genome function. Recently, a few 10 studies associated polymorphic TE insertions to mRNA levels of adjacent genes, but the 11 biological significance of these associations, their replicability across cell types, and the 12 mechanisms by which they may regulate genes remain largely unknown. Here we 13 performed a TE-expression QTL analysis of 444 lymphoblastoid cell lines and 294 14 induced pluripotent stem cells using a newly developed set of genotypes for 2,806 15 polymorphic TE insertions. We identified 211 and 324 TE-eQTL acting in cis in each 16 respective cell type. Approximately one fourth were shared across cell types with 17 strongly correlated effects. Furthermore, analysis of chromatin accessibility QTL in a 18 subset of the lymphoblastoid cell lines suggests that unfixed TEs often modulate the 19 activity of enhancers and other distal regulatory DNA elements, which tend to lose 20 accessibility when a TE inserts within them. We also document a case of an unfixed TE 21 likely influencing gene expression at the post-transcriptional level. Our study points to 22 broad and diverse cis-regulatory effects of unfixed TEs in the human population and 23 underscores their plausible contribution to phenotypic variation. 24 25 Keywords: unfixed transposable elements, gene expression, chromatin accessibility, 26 QTL, human, lymphoblastoid cell line, induced pluripotent stem cell 27 48 The regulation of gene expression is central to cellular function and differentiation in 49 development and physiology and changes in gene expression are important drivers of 50 phenotypic variation[20]. Steady state mRNA levels partially govern gene expression in 51 response to inputs integrated by various regulatory sequences acting in cis or 52trans [20,21]. Expression quantitative trait loci (eQTL) studies offer a systematic 53 approach to identify such cis-regulatory elements by correlating the genotypes of 54 genomic variants segregating in individuals with mRNA levels of specific genes, which 55 can be measured on a large scale by RNA-sequencing (RNA-seq) [22,23]. Previous 56 eQTL studies have established that virtually every gene in the human genome has its 57 expression affected by at least one genomic variant (typically a single nucleotide 58 polymorphism, SNP) located in cis (usually defined as within a maximum distance of 1 59Mb) and generally in non-coding regions [21,[24][25][26]. A recent analysis of 44 different 60 tissues by the GTEx consortium indicates that such cis-eQTL fall into two broad 61 categories: those shared across most tissues and those apparently acting in a single or 62 a restricted number of similar tissues [21]. Importantly, most eQTL studies thus far have 63 focused on SNPs, yet other type of genomic variants, such as unfixed TEs insertions, 64 are common in the human population and likely to have more drastic effects on gene 65 expression [27][28][29][30]. 66 67 I...

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confidence: 93%

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Contribution of unfixed transposable element insertions to human regulatory variation

Goubert

Zevallos

Feschotte

2019

Preprint

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“…Nevertheless, more than 70 de novo Alu insertions are known to cause genetic diseases (Hancks and Kazazian 2016), including neurological disorders (Larsen et al 2018; Hueso et al, n.d.). Furthermore, polymorphic Alu insertions have been identified as candidate causative variants in common polygenic diseases (Payer et al 2017), and a handful have been shown to alter mRNA splicing (Payer et al 2019). Finally, worldwide reference pMEI datasets such as those produced by 1000 GP (Sudmant et al 2015) can be used in conjunction with gene expression data (e.g.…”

Section: Introductionmentioning

confidence: 99%

TypeTE: a tool to genotype mobile element insertions from whole genome resequencing data

Goubert

Thomas

Payer

et al. 2019

Preprint

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Alu retrotransposons account for more than 10% of the human genome, and insertions of these elements create structural variants segregating in human populations. Such polymorphic Alu are powerful markers to understand population structure, and they represent variants that can greatly impact genome function, including gene expression. Accurate genotyping of Alu and other mobile elements has been challenging. Indeed, we found that Alu genotypes previously called for the 1000 Genomes Project are sometimes erroneous, which poses significant problems for phasing these insertions with other variants that comprise the haplotype. To ameliorate this issue, we introduce a new pipeline -- TypeTE -- which genotypes Alu insertions from whole-genome sequencing data. Starting from a list of polymorphic Alus, TypeTE identifies the hallmarks (poly-A tail and target site duplication) and orientation of Alu insertions using local re-assembly to reconstruct presence and absence alleles. Genotype likelihoods are then computed after re-mapping sequencing reads to the reconstructed alleles. Using a ‘gold standard’ set of PCR-based genotyping of >200 loci, we show that TypeTE improves genotype accuracy from 83% to 92% in the 1000 Genomes dataset. TypeTE can be readily adapted to other retrotransposon families and brings a valuable toolbox addition for population genomics.

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“…Primate specific Alu retrotransposons, which occupy ~11% of the human genome, are major players in this process (1,7). These provide non-canonical transcription factor binding sites and other regulatory sites that govern epigenetic modifications as well as provide cryptic splice sites that lead to alternative splicing or differential mRNA stability (5,(8)(9)(10)(11)(12)(13)(14). Alu-derived exons exhibit lineage specificity with high transcript inclusion levels and have much higher rates of evolution (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Origin of a novel CYP20A1 transcript isoform through multiple Alu exaptations creates a potential miRNA sponge

Bhattacharya

Jha

Singhal

et al. 2019

Preprint

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Background: Primate-specific Alus contribute to transcriptional novelties in conserved gene regulatory networks. Alu RNAs are present at elevated levels in stress conditions and consequently leads to transcript isoform specific functional role modulating the physiological outcome. One of the possible mechanisms could be Alu nucleated mRNA-miRNA interplay.Result: Using combination of bioinformatics and experiments, we report a transcript isoform of an orphan gene, CYP20A1 (CYP20A1_Alu-LT) through exaptation of 23 Alus in its 9kb 3'UTR. CYP20A1_Alu-LT, confirmed by 3'RACE, is an outlier in length and expressed in multiple cell lines. We demonstrate its presence in single nucleus RNA-seq of ~16000 human cortical neurons (including rosehip neurons). Its expression is restricted to the higher primates. Most strikingly, miRanda predicts ~4700 miRNA recognition elements (MREs; with threshold< -25kcal/mol) for ~1000 miRNAs, which have majorly originated within the 3'UTR-Alus post exaptation. We hypothesized that differential expression of this transcript could modulate mRNA-miRNA networks and tested it in primary human neurons where CYP20A1_Alu-LT is downregulated during heat shock response and upregulated upon HIV1-Tat treatment. CYP20A1_Alu-LT could possibly function as a miRNA sponge as it exhibits features of a sponge RNA such as cytosolic localization and ≥10 MREs for 140 miRNAs. Small RNA-seq revealed expression of nine miRNAs that can potentially be sponged by CYP20A1_Alu-LT in neurons. Additionally, CYP20A1_Alu-LT expression was positively correlated (low in heat shock and high in Tat) with 380 differentially expressed genes that contain cognate MREs for these nine miRNAs. This set is enriched in genes involved in neuronal development and hemostasis pathways. Conclusion:We demonstrate a potential role for CYP20A1_Alu-LT as miRNA sponge through preferential presence of MREs within Alus in a transcript isoform specific manner. This highlights a novel component of Alu-miRNA mediated transcriptional modulation leading to physiological homeostasis.Nearly 14% of the human transcriptome contain exonized Alus, predominantly in the principal isoforms of genes. Exonization is frequently reported in genes that have arisen de novo in primates, with most of the events in 3'UTRs (18,19). Such exonized Alus can increase the regulatory possibilities for a transcript, in a spatio-temporal manner, through antisense, miRNAs, A-to-I RNA editing, alternative splicing and enhancers. We have shown that transcript isoform dynamics i.e., the relative proportion of exonized versus non-exonized isoforms of a gene, could be modulated by these events in viral recovery and stress response (19,20). Besides, Alus provide substrates for other regulatory events such as gain of poly-A sites, AU-rich motifs and miRNA recognition elements (MREs) that can result in alternative polyadenylation, mRNA decay or translation stalling; and formation of specific secondary structures (9,(21)(22)(23)(24)(25). We have also reported that Alu-MREs can alter trans...

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

Cited by 129 publications

References 84 publications

Contribution of unfixed transposable element insertions to human regulatory variation

Contribution of unfixed transposable element insertions to human regulatory variation

TypeTE: a tool to genotype mobile element insertions from whole genome resequencing data

Origin of a novel CYP20A1 transcript isoform through multiple Alu exaptations creates a potential miRNA sponge

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