Telescope: Characterization of the retrotranscriptome by accurate estimation of transposable element expression

Bendall, Matthew L.; Mulder, Miguel de; Íñiguez, Luis P.; Lecanda, Aarón; Pérez‐Losada, Marcos; Ostrowski, Mario; Jones, R. Brad; Mulder, Lubbertus C. F.; Reyes‐Terán, Gustavo; Crandall, Keith A.; Ormsby, Christopher E.; Nixon, Douglas F.

doi:10.1101/398172

Cited by 16 publications

(40 citation statements)

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“…A recently developed annotation of putatively functional HERV elements describes 14,968 elements dispersed throughout the genome, which were defined based on the presence of LTRs and remnants of genetic elements which code for viral proteins like env , gag or pol 20 . We assessed the contribution of common genetic variants within HERVs to schizophrenia susceptibility using GARFIELD 27 .…”

Section: Resultsmentioning

confidence: 99%

“…Gene-level enrichment analysis of the schizophrenia GWAS summary statistics using the HERV annotation developed by Bendall and colleagues 20 , calculated using MAGMA 28 . Chromosomes 1-22 only, extended MHC region excluded (chromosome 6, from 26-34 Mb).…”

Section: Resultsmentioning

confidence: 99%

“…To explore the contribution of HERV families towards schizophrenia risk, we investigated whether any of the 60 families defined in the HERV annotation were overrepresented in the list of schizophrenia-associated HERVs using a gene-set enrichment analysis in MAGMA. Each HERV was assigned to a family based on the RepBase model that most closely matched the internal region sequences 20,29 . We observed a nominal association between schizophrenia and the HERVL40 family (P = 0.02, β = 0.14 ± 0.02, SE = 0.07), but this did not survive multiple testing correction (P corrected [for 60 families] > 0.05; Supplemental Figure 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…For example, Karlsson and colleagues 17 reported decreased ERV9 expression in the brain of schizophrenia patients, whereas Diem and collaborators 18 found the opposite. While the heterogeneity of schizophrenia is also likely to be a contributing factor for these contradictory findings, there are approximately 120 copies of ERV9 in the genome 19,20 that likely also confounded these reports.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, there have been significant advances in the annotation of HERVs in the genome 20–24 , and in the development of tools that are able to map repetitive sequences in RNA-sequencing data to their most likely source of origin in the genome 20,25,26 . These improvements allow for the identification and quantification of specific HERV copies associated with traits of interest.…”

Section: Introductionmentioning

confidence: 99%

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Schizophrenia risk from locus-specific human endogenous retroviruses

Duarte

et al. 2019

Preprint

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24Schizophrenia genome-wide association studies highlight the substantial contribution of risk 25 attributed to the non-coding genome where human endogenous retroviruses (HERVs) are encoded. 26These ancient viral elements have previously been overlooked in genetic and transcriptomic studies 27 due to their poor annotation and repetitive nature. Using a new, comprehensive HERV annotation, 28 we found that the fraction of the genome where HERVs are located (the 'retrogenome') is enriched 29 for schizophrenia risk variants, and that there are 148 disparate HERVs involved in susceptibility. 30Analysis of RNA-sequencing data from the dorsolateral prefrontal cortex of 259 schizophrenia cases 31 and 279 controls from the CommonMind Consortium showed that HERVs are actively expressed in 32 the brain (n = 3,979), regulated in cis by common genetic variants (n = 1,759), and differentially 33 expressed in patients (n = 81). Convergent analyses implicate LTR25_6q21 and ERVLE_8q24.3h 34 as HERVs of etiological relevance to schizophrenia, which are co-regulated with genes involved in 35 neuronal and mitochondrial function, respectively. Our findings provide a strong rationale for 36 exploring the retrogenome and the expression of these locus-specific HERVs as novel risk factors 37 for schizophrenia and potential diagnostic biomarkers and treatment targets. 39 42These viruses multiplied through a copy-and-paste mechanism and were eventually endogenized 43 (i.e., vertically transmitted), and now constitute approximately 8% of the genome 1,2 . These repetitive 44 sequences were generally assumed to be transcriptionally inactive in the modern genome, having a 45 purely regulatory function due to the retainment of the viral promoters (long-terminal repeats, LTRs). 46However, certain HERVs were co-opted to serve novel specialized roles, including in the regulation 47 of embryonic development 3,4 and neural progenitor cells 5,6 . They have also been implicated in 48 neuropsychiatric conditions such as amyotrophic lateral sclerosis 7-9 , major depressive disorder, 49 bipolar disorder, and schizophrenia 10-12 . Despite their abundance in the genome and relevance to 50 disease and fundamental aspects of human biology, the location and function of most HERVs remain 51 elusive to-date. 53Recent large genome-wide association studies (GWAS) comparing schizophrenia cases and non-54 affected individuals enabled the identification of polymorphisms mediating risk for this disorder [13][14][15] . 55These studies highlight the substantial contribution of risk attributed to the non-coding genome, 56where HERVs are encoded, which are often overlooked in both genomic and transcriptomic 57 studies 16 . Until recently, there was no comprehensively annotated map of HERVs in the genome, 58 and there were no computationally efficient tools to analyze the expression of these repetitive 59 sequences with single-locus resolution. Consequently, previous studies were unable to test whether 60 locus-specific HERVs were genetically associated with traits of int...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Schizophrenia risk from locus-specific human endogenous retroviruses

Duarte

et al. 2019

Preprint

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HERVs characterize normal and leukemia stem cells and represent a source of shared epitopes for cancer immunotherapy

et al. 2022

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Human endogenous retroviruses (HERVs) represent 8% of the human genome. The expression of HERVs and their immune impact have not been extensively studied in Acute Myeloid Leukemia (AML). In this study, we used a reference of 14 968 HERV functional units to provide a thorough analysis of HERV expression in normal and AML bone marrow cells. We show that the HERV retrotranscriptome accurately characterizes normal and leukemic cell subpopulations, including leukemia stem cells, in line with different epigenetic profiles. We then show that HERV expression delineates AML subtypes with different prognoses. We finally propose a method to select and prioritize CD8+ T cell epitopes derived from AML‐specific HERVs and we show that lymphocytes infiltrating patient bone marrow at diagnosis contain naturally occurring CD8+ T cells against these HERV epitopes. We also provide in vitro data supporting the functionality of HERV‐specific CD8+ T‐cells against AML cells. These results show that HERVs represent an important source of genetic information that can help enhancing disease stratification or biomarker identification and an important reservoir of alternative tumor‐specific T cell epitopes relevant for cancer immunotherapy.

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RepExpress: A Novel Pipeline for the Quantification and Characterization of Transposable Element Expression from RNA‐seq Data

et al. 2021

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Transposable elements (TEs) are key regulators of both development and disease; however, their repetitive nature presents substantial computational challenges to their analysis. Due to a lack of computational tools and suitable analysis frameworks, TE expression is often not quantified at the locus level. Therefore, we have developed RepExpress, a novel pipeline that enables locus‐level TE quantification and characterization. RepExpress enables the characterization of TE expression in a genomic context, and is the first tool focusing on the identification of tissue‐specific TE‐derived and TE‐regulated genes. RepExpress identifies expressed TEs overlapping with annotated genomic features and enables tissue‐specific profiles of TE‐derived genes. TEs that are expressed with no overlap with any known genomic features are characterized by the closest downstream genomic feature enabling identification of novel TE‐gene regulatory relationships. RepExpress takes standard RNA‐seq data as input and performs genomic alignment optimized for TEs. Our novel pipeline quantifies expression of both TEs and genes using featureCounts and Stringtie, respectively. RepExpress then filters expressed repeats and characterizes their genomic context, enabling the identification of TEs that overlap with genes, or that may be influencing gene expression. Here, we describe RepExpress, and provide a step‐by‐step protocol detailing its workflow. We also discuss other TE analysis tools and their applicability to addressing different biological questions. © 2021 Wiley Periodicals LLC. Basic Protocol: RepExpress workflow

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Telescope: Characterization of the retrotranscriptome by accurate estimation of transposable element expression

Cited by 16 publications

References 58 publications

Schizophrenia risk from locus-specific human endogenous retroviruses

Schizophrenia risk from locus-specific human endogenous retroviruses

HERVs characterize normal and leukemia stem cells and represent a source of shared epitopes for cancer immunotherapy

RepExpress: A Novel Pipeline for the Quantification and Characterization of Transposable Element Expression from RNA‐seq Data

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