Human population-specific gene expression and transcriptional network modification with polymorphic transposable elements

Wang, Lu; Rishishwar, Lavanya; Mariño-Ramírez, Leonardo; Jordan, I. King

doi:10.1093/nar/gkw1286

Cited by 61 publications

(98 citation statements)

References 52 publications

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“…By leveraging newly predicted genotypes for 2,806 TE insertions, we were able to 400 identify 211 cis-TE-eQTL across 444 LCL and 314 cis-TE-eQTL across 294 iPSC. A 401 previous analysis of the same LCL dataset using a similar analytical framework reported 402 53 cis-TE-eQTL (outside the HLA and 17q21.31 loci) [18], including 20 loci that our 403 analysis also identified. The difference in the outcomes of the two studies, and notably 404 the considerably larger set of TE-eQTLs captured by our approach, can be attributed to 405 several important methodological differences.…”

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confidence: 59%

“…Unfixed TE insertions represent an important class of structural variants between 391 human genomes, but their impact on gene regulation remains poorly characterized [16-392 19]. To our knowledge, this study is only the second to broadly assess the regulatory 393 potential of unfixed TEs on human gene expression [18] and the first to consider their 394 effects across multiple cell types. We also present the first TE-chromatin accessibility 395 QTL (TE-caQTL) analysis, which sheds light on the impact of recent TE insertions on 396 chromatin state at or near their insertion sites and enables a more direct evaluation of 397 their contribution to cis-regulatory variation.…”

Section: Discussion 390mentioning

confidence: 99%

“…75 However, many questions remain unexplored, in particular (i) the size, direction and 76 strength of the discovered associations, (ii) their tissue-or cell type-specificity and (iii) a 77 better understanding of the molecular mechanisms by which unfixed TEs may modulate 78 gene expression. 79 80To begin filling these gaps, we use a newly assembled set of TE genotypes [31], 81including more than 800 TE insertions not considered in previous studies [17,18,32], in 82 conjunction with reprocessed RNA-seq quantifications to map TE-eQTL in the 83 aforementioned LCL from 444 individuals. We examined the cell type-specificity of 84 these associations by performing another TE-eQTL mapping in 294 induced human 85 pluripotent stem cells (iPSC) available through the HipSci consortium[24, 86 www.hipsci.org].…”

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confidence: 99%

“…including more than 800 TE insertions not considered in previous studies [17,18,32], in 82 conjunction with reprocessed RNA-seq quantifications to map TE-eQTL in the 83 aforementioned LCL from 444 individuals. We examined the cell type-specificity of 84 these associations by performing another TE-eQTL mapping in 294 induced human 85 pluripotent stem cells (iPSC) available through the HipSci consortium[24, 86 www.hipsci.org].…”

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confidence: 99%

“…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]. 47…”

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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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Section: Discussion 390mentioning

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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Transposable Elements: Classification, Identification, and Their Use As a Tool For Comparative Genomics

Makałowski

Gotea

Pande

et al. 2019

Methods in Molecular Biology

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Most genomes are populated by hundreds of thousands of sequences originated from mobile elements. On the one hand, these sequences present a real challenge in the process of genome analysis and annotation. On the other hand, they are very interesting biological subjects involved in many cellular processes. Here we present an overview of transposable elements biodiversity, and we discuss different approaches to transposable elements detection and analyses.

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Chromothripsis, a credible chromosomal mechanism in evolutionary process

Pellestor

Gatinois

2018

Chromosoma

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The recent discovery of a new class of massive chromosomal rearrangements, occurring during one unique cellular event and baptized "chromothripsis," deeply modifies our perception on the genesis of complex genomic rearrangements, but also, it raises the question of the potential driving role of chromothripsis in species evolution. Analyses of the etiology of chromothripsis have led to the identification of various cellular processes capable of generating chromothripsis, such as premature chromosome condensation, telomere dysfunction, abortive apoptosis, and micronucleus formation. All these causative mechanisms may occur in germlines or during early embryonic development, suggesting that chromothripsis could be an unexpected mechanism for profound genome modification. The occurrence of chromothripsis appears to be in good agreement with macroevolution models proposed as a complement to phyletic gradualism. Various cases of chromosomal speciation and short-term adaptation could be correlated to chromothripsis-mediated mechanism. The emergency of this unanticipated chaotic phenomenon may contribute to demonstrate the contribution of chromosome rearrangements to speciation process. New sequencing and bioinformatics methods can be expected to shed new light on the role of chromothripsis in evolutionary process.

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Human population-specific gene expression and transcriptional network modification with polymorphic transposable elements

Cited by 61 publications

References 52 publications

Contribution of unfixed transposable element insertions to human regulatory variation

Contribution of unfixed transposable element insertions to human regulatory variation

Transposable Elements: Classification, Identification, and Their Use As a Tool For Comparative Genomics

Chromothripsis, a credible chromosomal mechanism in evolutionary process

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