Endogenous retroviruses (ERVs) arise from retroviruses chromosomally integrated in the host germline. ERVs are common in vertebrate genomes and provide a valuable fossil record of past retroviral ...infections to investigate the biology and evolution of retroviruses over a deep time scale, including cross-species transmission events. Here we took advantage of a catalog of ERVs we recently produced for the bat Myotis lucifugus to seek evidence for infiltration of these retroviruses in other mammalian species (>100) currently represented in the genome sequence database. We provide multiple lines of evidence for the cross-ordinal transmission of a gammaretrovirus endogenized independently in the lineages of vespertilionid bats, felid cats and pangolin ~13-25 million years ago. Following its initial introduction, the ERV amplified extensively in parallel in both bat and cat lineages, generating hundreds of species-specific insertions throughout evolution. However, despite being derived from the same viral species, phylogenetic and selection analyses suggest that the ERV experienced different amplification dynamics in the two mammalian lineages. In the cat lineage, the ERV appears to have expanded primarily by retrotransposition of a single proviral progenitor that lost infectious capacity shortly after endogenization. In the bat lineage, the ERV followed a more complex path of germline invasion characterized by both retrotransposition and multiple infection events. The results also suggest that some of the bat ERVs have maintained infectious capacity for extended period of time and may be still infectious today. This study provides one of the most rigorously documented cases of cross-ordinal transmission of a mammalian retrovirus. It also illustrates how the same retrovirus species has transitioned multiple times from an infectious pathogen to a genomic parasite (i.e. retrotransposon), yet experiencing different invasion dynamics in different mammalian hosts.
Advances in vertebrate genomics have uncovered thousands of loci encoding long noncoding RNAs (lncRNAs). While progress has been made in elucidating the regulatory functions of lncRNAs, little is ...known about their origins and evolution. Here we explore the contribution of transposable elements (TEs) to the makeup and regulation of lncRNAs in human, mouse, and zebrafish. Surprisingly, TEs occur in more than two thirds of mature lncRNA transcripts and account for a substantial portion of total lncRNA sequence (~30% in human), whereas they seldom occur in protein-coding transcripts. While TEs contribute less to lncRNA exons than expected, several TE families are strongly enriched in lncRNAs. There is also substantial interspecific variation in the coverage and types of TEs embedded in lncRNAs, partially reflecting differences in the TE landscapes of the genomes surveyed. In human, TE sequences in lncRNAs evolve under greater evolutionary constraint than their non-TE sequences, than their intronic TEs, or than random DNA. Consistent with functional constraint, we found that TEs contribute signals essential for the biogenesis of many lncRNAs, including ~30,000 unique sites for transcription initiation, splicing, or polyadenylation in human. In addition, we identified ~35,000 TEs marked as open chromatin located within 10 kb upstream of lncRNA genes. The density of these marks in one cell type correlate with elevated expression of the downstream lncRNA in the same cell type, suggesting that these TEs contribute to cis-regulation. These global trends are recapitulated in several lncRNAs with established functions. Finally a subset of TEs embedded in lncRNAs are subject to RNA editing and predicted to form secondary structures likely important for function. In conclusion, TEs are nearly ubiquitous in lncRNAs and have played an important role in the lineage-specific diversification of vertebrate lncRNA repertoires.
Abstract
WashU Epigenome Browser (https://epigenomegateway.wustl.edu/browser/) is a web-based genomic data exploration tool that provides visualization, integration, and analysis of epigenomic ...datasets. The newly renovated user interface and functions have enabled researchers to engage with the browser and genomic data more efficiently and effectively since 2018. Here, we introduce a new integrated panel design in the browser that allows users to interact with 1D (genomic features), 2D (such as Hi-C), 3D (genome structure), and 4D (time series) data in a single web page. The browser can display three-dimensional chromatin structures with the 3D viewer module. The 4D tracks, called ‘Dynamic’ tracks, animatedly display time-series data, allowing for a more striking visual impact to identify the gene or genomic region candidates as a function of time. Genomic data, such as annotation features, numerical values, and chromatin interaction data can all be viewed in the dynamic track mode. Imaging data from microscopy experiments can also be displayed in the browser. In addition to software development, we continue to service and expand the data hubs we host for large consortia including 4DN, Roadmap Epigenomics, TaRGET and ENCODE, among others. Our growing user/developer community developed additional track types as plugins, such as qBed and dynseq tracks, which extend the utility of the browser. The browser serves as a foundation for additional genomics platforms including the WashU Virus Genome Browser (for COVID-19 research) and the Comparative Genome Browser. The WashU Epigenome Browser can also be accessed freely through Amazon Web Services at https://epigenomegateway.org/.
Graphical Abstract
Graphical Abstract
New components of WashU Epigenome Browser: 3D chromatin viewer, imaging data viewer and dynamic tracks.
Transposable elements (TEs) make up half of mammalian genomes and shape genome regulation by harboring binding sites for regulatory factors. These include binding sites for architectural proteins, ...such as CTCF, RAD21, and SMC3, that are involved in tethering chromatin loops and marking domain boundaries. The 3D organization of the mammalian genome is intimately linked to its function and is remarkably conserved. However, the mechanisms by which these structural intricacies emerge and evolve have not been thoroughly probed.
Here, we show that TEs contribute extensively to both the formation of species-specific loops in humans and mice through deposition of novel anchoring motifs, as well as to the maintenance of conserved loops across both species through CTCF binding site turnover. The latter function demonstrates the ability of TEs to contribute to genome plasticity and reinforce conserved genome architecture as redundant loop anchors. Deleting such candidate TEs in human cells leads to the collapse of conserved loop and domain structures. These TEs are also marked by reduced DNA methylation and bear mutational signatures of hypomethylation through evolutionary time.
TEs have long been considered a source of genetic innovation. By examining their contribution to genome topology, we show that TEs can contribute to regulatory plasticity by inducing redundancy and potentiating genetic drift locally while conserving genome architecture globally, revealing a paradigm for defining regulatory conservation in the noncoding genome beyond classic sequence-level conservation.
Transposable elements (TEs) comprise ~50% of our genome, but knowledge of how TEs affect genome evolution remains incomplete. Leveraging ENCODE4 data, we provide the most comprehensive study to date ...of TE contributions to the regulatory genome. We find 236,181 (~25%) human candidate cis-regulatory elements (cCREs) are TE-derived, with over 90% lineage-specific since the human-mouse split, accounting for 8–36% of lineage-specific cCREs. Except for SINEs, cCRE-associated transcription factor (TF) motifs in TEs are derived from ancestral TE sequence more than expected by chance. We show that TEs may adopt similar regulatory activities of elements near their integration site. Since human-mouse divergence, TEs have contributed 3–56% of TF binding site turnover events across 30 examined TFs. Finally, TE-derived cCREs are similar to non-TE cCREs in terms of MPRA activity and GWAS variant enrichment. Overall, our results substantiate the notion that TEs have played an important role in shaping the human regulatory genome.Half of our genome is transposable elements (TEs), often called junk DNA. Using the latest ENCODE data, the authors find TEs to contribute ~25% of human regulatory elements (REs). TEs can be adopted into new REs or replace old ones during evolution.
PIWI-interacting RNAs (piRNAs) protect the germ line by targeting transposable elements (TEs) through the base-pair complementarity. We do not know how piRNAs co-evolve with TEs in chickens. Here we ...reported that all active TEs in the chicken germ line are targeted by piRNAs, and as TEs lose their activity, the corresponding piRNAs erode away. We observed de novo piRNA birth as host responds to a recent retroviral invasion. Avian leukosis virus (ALV) has endogenized prior to chicken domestication, remains infectious, and threatens poultry industry. Domestic fowl produce piRNAs targeting ALV from one ALV provirus that was known to render its host ALV resistant. This proviral locus does not produce piRNAs in undomesticated wild chickens. Our findings uncover rapid piRNA evolution reflecting contemporary TE activity, identify a new piRNA acquisition modality by activating a pre-existing genomic locus, and extend piRNA defense roles to include the period when endogenous retroviruses are still infectious.
Many transposable elements (TEs) contain transcription factor binding sites and are implicated as potential regulatory elements. However, TEs are rarely functionally tested for regulatory activity, ...which in turn limits our understanding of how TE regulatory activity has evolved. We systematically tested the human LTR18A subfamily for regulatory activity using massively parallel reporter assay (MPRA) and found AP-1- and CEBP-related binding motifs as drivers of enhancer activity. Functional analysis of evolutionarily reconstructed ancestral sequences revealed that LTR18A elements have generally lost regulatory activity over time through sequence changes, with the largest effects occurring owing to mutations in the AP-1 and CEBP motifs. We observed that the two motifs are conserved at higher rates than expected based on neutral evolution. Finally, we identified LTR18A elements as potential enhancers in the human genome, primarily in epithelial cells. Together, our results provide a model for the origin, evolution, and co-option of TE-derived regulatory elements.
Unlike PIWI-interacting RNA (piRNA) in other species that mostly target transposable elements (TEs), >80% of piRNAs in adult mammalian testes lack obvious targets. However, mammalian piRNA sequences ...and piRNA-producing loci evolve more rapidly than the rest of the genome for unknown reasons. Here, through comparative studies of chickens, ducks, mice, and humans, as well as long-read nanopore sequencing on diverse chicken breeds, we find that piRNA loci across amniotes experience: (1) a high local mutation rate of structural variations (SVs, mutations ≥ 50 bp in size); (2) positive selection to suppress young and actively mobilizing TEs commencing at the pachytene stage of meiosis during germ cell development; and (3) negative selection to purge deleterious SV hotspots. Our results indicate that genetic instability at pachytene piRNA loci, while producing certain pathogenic SVs, also protects genome integrity against TE mobilization by driving the formation of rapid-evolving piRNA sequences.
Following publication of the original paper 1, an error was reported in the processing of Fig. 2. The correct Fig. 2 is supplied below and the original article 1 has been corrected. The publishers ...apologize for the error.
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