Functional characterization of enhancer evolution in the primate lineage
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA454716 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7095720_1.fastq.gz | Fastqsanger.gz | |||
| SRR7095720_2.fastq.gz | Fastqsanger.gz | |||
| SRR7095721_1.fastq.gz | Fastqsanger.gz | |||
| SRR7095721_2.fastq.gz | Fastqsanger.gz | |||
| SRR7095722_1.fastq.gz | Fastqsanger.gz |
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Project description:BackgroundEnhancers play an important role in morphological evolution and speciation by controlling the spatiotemporal expression of genes. Previous efforts to understand the evolution of enhancers in primates have typically studied many enhancers at low resolution, or single enhancers at high resolution. Although comparative genomic studies reveal large-scale turnover of enhancers, a specific understanding of the molecular steps by which mammalian or primate enhancers evolve remains elusive.ResultsWe identified candidate hominoid-specific liver enhancers from H3K27ac ChIP-seq data. After locating orthologs in 11 primates spanning around 40 million years, we synthesized all orthologs as well as computational reconstructions of 9 ancestral sequences for 348 active tiles of 233 putative enhancers. We concurrently tested all sequences for regulatory activity with STARR-seq in HepG2 cells. We observe groups of enhancer tiles with coherent trajectories, most of which can be potentially explained by a single gain or loss-of-activity event per tile. We quantify the correlation between the number of mutations along a branch and the magnitude of change in functional activity. Finally, we identify 84 mutations that correlate with functional changes; these are enriched for cytosine deamination events within CpGs.ConclusionsWe characterized the evolutionary-functional trajectories of hundreds of liver enhancers throughout the primate phylogeny. We observe subsets of regulatory sequences that appear to have gained or lost activity. We use these data to quantify the relationship between sequence and functional divergence, and to identify CpG deamination as a potentially important force in driving changes in enhancer activity during primate evolution.
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Project description:STARR-seq assay tiling across putative hominoid-specific enhancers and for orthologs from 11 primates and 9 ancestral reconstructions of each active tile
2018-05-03 | GSE113978 | GEO
Project description:Long noncoding RNA sequences evolve relatively rapidly, but it is unclear whether this is due to relaxed constraint or accelerated evolution. Here, we trace the recent evolutionary history of human lncRNAs, using genomes of multiple individuals from all great ape species to map fixed lineage-specific nucleotide variants. We find that the lower conservation of lncRNAs compared to protein coding genes partially arises from lncRNA’s more recent evolutionary origin. We identify more than one hundred lncRNAs that show some evidence of accelerated evolution in at least one primate species, including 17 in human. Several of these display transcriptional regulatory activity in an RNA-specific reporter assay. By experimentally reconstructing the ancestral lncRNA sequence, we find that this activity has been altered by human-specific nucleotide substitutions. Functional analysis of accelerated lncRNAs with specific expression in blood suggests lncRNAs have participated in adaptive regulatory changes in the immune system during recent human evolution. Together our results provide evidence that accelerated evolution of lncRNAs may have contributed, through regulatory changes, to human-specific phenotypes.
2018-11-30 | GSE80554 | GEO
Project description: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 C/EBP-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 due to mutations in the AP-1 and C/EBP 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.
2022-08-12 | GSE201068 | GEO
Project description:Many endogenous retroviruses (ERVs) in the human genome are primate-specific and contribute novel cis-regulatory elements and transcripts. Classification and annotation of ERVs, which are flanked by long terminal repeats (LTRs) containing sequences that control their transcriptional activity, is important to better understand their evolution and potential roles in the host. Here, we observed that many of the currently annotated LTR subfamilies spreading in the primate lineage have subsets of instances that appear to be misclassified. Focusing on the evolutionary young MER11A/B/C subfamilies, we performed a phylogenetic analysis and relied on cross-species conservation to reveal the presence of 4 phyletic groups, suggesting a new annotation for 412 (19.8%) of the MER11 instances. Next, we showed that the epigenetic heterogeneity observed within the MER11A/B/C subfamilies was better explained in the context of these new phyletic groups. Using a massively parallel reporter assay (MPRA), we also demonstrated the regulatory potential of the four phyletic groups and identified motifs that were associated with their differential activities. The MPRA combined with the use of phyletic groups across primates revealed an apes-specific gain of SOX related motifs through a single-nucleotide deletion. Finally, we applied a similar approach across all 53 simian-specific LTR subfamilies and determined the presence of 75 phyletic groups. We found that 3,807 (30.0%) instances from 26 of these LTR subfamilies changed annotation and could be characterized into one of these novel phyletic groups, many of which with a distinct epigenetic profile. This refined annotation of simian-specific LTRs could improve our understanding of the evolution of ERVs in primate genomes and reveal functional signals that would have been missed otherwise.
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Project description:Functional characterization of enhancer activity during a long terminal repeat's evolution
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Project description:While genome sequencing has identified numerous non-coding alterations between primate species, which of these are regulatory and potentially relevant to the evolution of the human brain is unclear. Here, we annotate cis-regulatory elements (CREs) in the human, rhesus macaque and chimpanzee genome using ChIP-sequencing in different anatomical parts of the adult brain. We find high similarity in the genomic positioning of CREs between rhesus macaque and humans, suggesting that the majority of these elements were already present in a common ancestor 25 million years ago. Most of the observed regulatory changes between humans and rhesus macaque occurred prior to the ancestral separation of humans and chimpanzee, leaving a modest set of regulatory elements with predicted human-specificity. Our data refine previous predictions and hypotheses on the consequences of genomic changes between primate species, and allow the identification of regulatory alterations relevant to the evolution of the brain. ChIP-Sequencing for H3K27ac on 8 distinct brain regions from human (three biological replicates per brain region), chimpanzee (two biological replicates per brain region) and rhesus macaque (three biological replicates per brain region).
2016-01-13 | E-GEOD-67978 | biostudies-arrayexpress
Project description:Phenotypic differences between closely related species are thought to arise primarily from changes in gene expression due to mutations in cis-regulatory sequences (enhancers). However, it has remained unclear, how frequently mutations alter enhancer activity or create functional enhancers de novo. Here, we use STARR-seq, a recently developed quantitative enhancer assay, to determine genome-wide enhancer activity profiles for five Drosophila species in the constant trans-regulatory environment of D. melanogaster S2 cells. We find that the function of a large fraction of D. melanogaster enhancers is conserved in their orthologous sequences due to selection and stabilizing turnover of transcription factor motifs. Moreover, hundreds of enhancers have been gained since the D. melanogaster M-bM-^@M-^S D. yakuba split about 11 million years ago without apparent adaptive selection and can contribute to gene expression changes in vivo. Our finding that enhancer activity is often deeply conserved and frequently gained provides important functional insights into regulatory evolution. STARR-seq was performed in S2 cells with paired-end sequencing in two replicates and respective inputs using genomic DNA from different Drosophila species. RNA-seq was performed in a non-stranded manner without replicates for two Drosophila species.
2014-04-28 | E-GEOD-48251 | biostudies-arrayexpress
Project description:Cryptic endogenous retrovirus subfamilies in the primate lineage
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Project description:In mammals, fine motor control is essential for skilled behavior, and is subserved by specialized subdivisions of the primary motor cortex (M1) and other components of the brain’s motor circuitry. We profiled the epigenomic state of several components of the Rhesus macaque motor system, including subdivisions of M1 corresponding to hand and orofacial control. We compared this to open chromatin data from M1 in rat, mouse, and human. We found broad similarities as well as unique specializations in open chromatin regions (OCRs) between M1 subdivisions and other brain regions, as well as species- and lineage-specific differences reflecting their evolutionary histories. By distinguishing shared mammalian M1 OCRs from primate- and human-specific specializations, we highlight gene regulatory programs that could subserve the evolution of skilled motor behaviors such as speech and tool use. Further, in order to predict candidate enhancers in additional species for which primary data was not available, we developed machine learning models trained on genome sequence across species.
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