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Functional characterization of enhancer evolution in the primate lineage

ABSTRACT: Functional characterization of enhancer evolution in the primate lineage

PROVIDER: PRJNA454716 | ENA |

REPOSITORIES: ENA

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			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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Functional characterization of enhancer evolution in the primate lineage.

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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Functional characterization of enhancer evolution in the primate lineage

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

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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.

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