Comprehensive identification of transposable element insertions using multiple sequencing technologies.
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ABSTRACT:
SUBMITTER: Chu C
PROVIDER: S-EPMC8219666 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Transposable element (TE) mobilization is a significant source of genomic variation and has been associated with various human diseases. The exponential growth of population-scale whole-genome sequencing and rapid innovations in long-read sequencing technologies provide unprecedented opportunities to study TE insertions and their functional impact in human health and disease. Identifying TE insertions, however, is challenging due to the repetitive nature of the TE sequences. Here, we review computational approaches to detecting and genotyping TE insertions using short- and long-read sequencing and discuss the strengths and weaknesses of different approaches. © 2020 Wiley Periodicals LLC.
| S-EPMC8906366 | biostudies-literature
Project description:The majority of rare diseases are genetic, and regardless of advanced high-throughput genomics-based investigations, 60% of patients remain undiagnosed. A major factor limiting our ability to identify disease-causing alterations is a poor understanding of the morbid and normal human genome. A major genomic contributor of which function and distribution remain largely unstudied are the transposable elements (TE), which constitute 50% of our genome. Here we aim to resolve this knowledge gap and increase the diagnostic yield of rare disease patients investigated with clinical genome sequencing. To this end we characterized TE insertions in 1000 Swedish individuals from the SweGen dataset and 2504 individuals from the 1000 Genomes Project (1KGP), creating seven population-specific TE insertion databases. Of note, 66% of TE insertions in SweGen were present at >1% in the 1KGP databases, proving that most insertions are common across populations. Focusing on the rare TE insertions, we show that even though ~0.7% of those insertions affect protein coding genes, they rarely affect known disease casing genes (<0.1%). Finally, we applied a TE insertion identification workflow on two clinical cases where disease causing TE insertions were suspected and could verify the presence of pathogenic TE insertions in both. Altogether we demonstrate the importance of TE insertion detection and highlight possible clinical implications in rare disease diagnostics.
| S-EPMC10381067 | biostudies-literature
Project description:Transposable element (TE) insertions are among the most challenging types of variants to detect in genomic data because of their repetitive nature and complex mechanisms of replication . Nevertheless, the recent availability of large resequencing data sets has spurred the development of many new methods to detect TE insertions in whole-genome shotgun sequences. Here we report an integrated bioinformatics pipeline for the detection of TE insertions in whole-genome shotgun data, called McClintock (https://github.com/bergmanlab/mcclintock), which automatically runs and standardizes output for multiple TE detection methods. We demonstrate the utility of McClintock by evaluating six TE detection methods using simulated and real genome data from the model microbial eukaryote, Saccharomyces cerevisiae We find substantial variation among McClintock component methods in their ability to detect nonreference TEs in the yeast genome, but show that nonreference TEs at nearly all biologically realistic locations can be detected in simulated data by combining multiple methods that use split-read and read-pair evidence. In general, our results reveal that split-read methods detect fewer nonreference TE insertions than read-pair methods, but generally have much higher positional accuracy. Analysis of a large sample of real yeast genomes reveals that most McClintock component methods can recover known aspects of TE biology in yeast such as the transpositional activity status of families, target preferences, and target site duplication structure, albeit with varying levels of accuracy. Our work provides a general framework for integrating and analyzing results from multiple TE detection methods, as well as useful guidance for researchers studying TEs in yeast resequencing data.
| S-EPMC5555480 | biostudies-literature
Project description:Thousands of unfixed transposable element (TE) insertions segregate in the human population, but little is known about their impact on genome function. Recently, a few studies associated unfixed TE insertions to mRNA levels of adjacent genes, but the biological significance of these associations, their replicability across cell types and the mechanisms by which they may regulate genes remain largely unknown. Here, we performed a TE-expression QTL analysis of 444 lymphoblastoid cell lines (LCL) and 289 induced pluripotent stem cells using a newly developed set of genotypes for 2743 polymorphic TE insertions. We identified 211 and 176 TE-eQTL acting in cis in each respective cell type. Approximately 18% were shared across cell types with strongly correlated effects. Furthermore, analysis of chromatin accessibility QTL in a subset of the LCL suggests that unfixed TEs often modulate the activity of enhancers and other distal regulatory DNA elements, which tend to lose accessibility when a TE inserts within them. We also document a case of an unfixed TE likely influencing gene expression at the post-transcriptional level. Our study points to broad and diverse cis-regulatory effects of unfixed TEs in the human population and underscores their plausible contribution to phenotypic variation. This article is part of a discussion meeting issue 'Crossroads between transposons and gene regulation'.
| S-EPMC7061991 | biostudies-literature
Project description:Transposable elements (TEs) are mobile genetic elements that parasitize genomes by semi-autonomously increasing their own copy number within the host genome. While TEs are important for genome evolution, appropriate methods for performing unbiased genome-wide surveys of TE variation in natural populations have been lacking. Here, we describe a novel and cost-effective approach for estimating population frequencies of TE insertions using paired-end Illumina reads from a pooled population sample. Importantly, the method treats insertions present in and absent from the reference genome identically, allowing unbiased TE population frequency estimates. We apply this method to data from a natural Drosophila melanogaster population from Portugal. Consistent with previous reports, we show that low recombining genomic regions harbor more TE insertions and maintain insertions at higher frequencies than do high recombining regions. We conservatively estimate that there are almost twice as many "novel" TE insertion sites as sites known from the reference sequence in our population sample (6,824 novel versus 3,639 reference sites, with on average a 31-fold coverage per insertion site). Different families of transposable elements show large differences in their insertion densities and population frequencies. Our analyses suggest that the history of TE activity significantly contributes to this pattern, with recently active families segregating at lower frequencies than those active in the more distant past. Finally, using our high-resolution TE abundance measurements, we identified 13 candidate positively selected TE insertions based on their high population frequencies and on low Tajima's D values in their neighborhoods.
| S-EPMC3266889 | biostudies-literature
Project description:How natural selection acts to limit the proliferation of transposable elements (TEs) in genomes has been of interest to evolutionary biologists for many years. To describe TE dynamics in populations, previous studies have used models of transposition-selection equilibrium that assume a constant rate of transposition. However, since TE invasions are known to happen in bursts through time, this assumption may not be reasonable. Here we propose a test of neutrality for TE insertions that does not rely on the assumption of a constant transposition rate. We consider the case of TE insertions that have been ascertained from a single haploid reference genome sequence. By conditioning on the age of an individual TE insertion allele (inferred by the number of unique substitutions that have occurred within the particular TE sequence since insertion), we determine the probability distribution of the insertion allele frequency in a population sample under neutrality. Taking models of varying population size into account, we then evaluate predictions of our model against allele frequency data from 190 retrotransposon insertions sampled from North American and African populations of Drosophila melanogaster. Using this nonequilibrium neutral model, we are able to explain ? 80% of the variance in TE insertion allele frequencies based on age alone. Controlling for both nonequilibrium dynamics of transposition and host demography, we provide evidence for negative selection acting against most TEs as well as for positive selection acting on a small subset of TEs. Our work establishes a new framework for the analysis of the evolutionary forces governing large insertion mutations like TEs, gene duplications, or other copy number variants.
| S-EPMC3914624 | biostudies-literature
Project description:Cells are regularly exposed to a range of naturally occurring stress that can restrict growth or cause lethality. In response, cells activate expression networks with hundreds of genes that together increase resistance to common environmental insults. However, stress response networks can be insufficient to ensure survival, which raises the question of whether cells possess genetic programs that can promote adaptation to novel forms of stress. We found transposable element (TE) mobility in Schizosaccharomyces pombe was greatly increased when cells were exposed to unusual forms of stress such as heavy metals, caffeine, and the plasticizer phthalate. By subjecting TE-tagged cells to CoCl2, we found the TE integration provided the major path to resistance. Groups of insertions that provided resistance were linked to TOR regulation and metal response genes. We extended our study of adaptation by analyzing TE positions in 57 genetically distinct wild strains. The genomic positions of 1048 polymorphic LTRs were strongly associated with a range of stress response genes, indicating TE integration promotes adaptation in natural conditions. These data provide strong support for the idea, first proposed by Barbara McClintock, that TEs provide a system to modify the genome in response to stress.
| S-EPMC6314160 | biostudies-literature
Project description:The proximal promoter regions of heat-shock genes harbor a remarkable number of P transposable element (TE) insertions relative to both positive and negative control proximal promoter regions in natural populations of Drosophila melanogaster. We have screened the sequenced genomes of 12 species of Drosophila to test whether this pattern is unique to these populations. In the 12 species' genomes, transposable element insertions are no more abundant in promoter regions of single-copy heat-shock genes than in promoters with similar or dissimilar architecture. Also, insertions appear randomly distributed across the promoter region, whereas insertions clustered near the transcription start site in promoters of single-copy heat-shock genes in D. melanogaster natural populations. Hsp70 promoters exhibit more TE insertions per promoter than all other genesets in the 12 species, similarly to in natural populations of D. melanogaster. Insertions in the Hsp70 promoter region, however, cluster away from the transcription start site in the 12 species, but near it in natural populations of D. melanogaster. These results suggest that D. melanogaster heat-shock promoters are unique in terms of their interaction with transposable elements, and confirm that Hsp70 promoters are distinctive in TE insertions across Drosophila.
| S-EPMC2793543 | biostudies-literature
Project description:BackgroundMany genomes contain a substantial number of transposable elements (TEs), a few of which are known to be involved in regulating gene expression. However, recent observations suggest that TEs may have played a very important role in the evolution of gene expression because many conserved non-genic sequences, some of which are know to be involved in gene regulation, resemble TEs.ResultsHere we investigate whether new TE insertions affect gene expression profiles by testing whether gene expression divergence between mouse and rat is correlated to the numbers of new transposable elements inserted near genes. We show that expression divergence is significantly correlated to the number of new LTR and SINE elements, but not to the numbers of LINEs. We also show that expression divergence is not significantly correlated to the numbers of ancestral TEs in most cases, which suggests that the correlations between expression divergence and the numbers of new TEs are causal in nature. We quantify the effect and estimate that TE insertion has accounted for approximately 20% (95% confidence interval: 12% to 26%) of all expression profile divergence in rodents.ConclusionsWe conclude that TE insertions may have had a major impact on the evolution of gene expression levels in rodents.
| S-EPMC2629548 | biostudies-literature
Project description:Transposable elements (TEs) are abundant in mammalian genomes and appear to have contributed to the evolution of their hosts by providing novel regulatory or coding sequences. We analyzed different regions of long intergenic non-coding RNA (lincRNA) genes in human and mouse genomes to systematically assess the potential contribution of TEs to the evolution of the structure and regulation of expression of lincRNA genes. Introns of lincRNA genes contain the highest percentage of TE-derived sequences (TES), followed by exons and then promoter regions although the density of TEs is not significantly different between exons and promoters. Higher frequencies of ancient TEs in promoters and exons compared to introns implies that many lincRNA genes emerged before the split of primates and rodents. The content of TES in lincRNA genes is substantially higher than that in protein-coding genes, especially in exons and promoter regions. A significant positive correlation was detected between the content of TEs and evolutionary rate of lincRNAs indicating that inserted TEs are preferentially fixed in fast-evolving lincRNA genes. These results are consistent with the repeat insertion domains of LncRNAs hypothesis under which TEs have substantially contributed to the origin, evolution, and, in particular, fast functional diversification, of lincRNA genes.
| S-EPMC4460805 | biostudies-other