Massively parallel dissection of human accelerated regions in human and chimpanzee neural progenitors
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PROVIDER: PRJNA434468 | ENA |
REPOSITORIES: ENA
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Project description:Human accelerated regions (HARs) are evolutionarily conserved sequences that acquired human-specific nucleotide changes and reside in genomic regions associated with unique human traits and disease. The majority of HARs (96%) are noncoding, a few of which have been shown to be functional enhancers. Here, we comprehensively tested human and chimpanzee sequences of HARs (N=714) for enhancer activity using a lentivirus-based massively parallel reporter assay (lentiMPRA) in human and chimpanzee iPSC derived neural progenitors at two differentiation time points. We found that 43% (306/714) function as enhancers and over two-thirds (204/306) showed consistent differences in activity between human and chimpanzee sequences across conditions. We also tested all possible permutations of substitutions in seven HARs and found significant positive and negative interactions. Our study provides a comprehensive resource of functional neurodevelopmental HAR enhancers and shows that multiple interacting sites drive evolutionary activity differences.
2018-02-17 | GSE110759 | GEO
Project description:Human accelerated regions (HARs) are evolutionarily conserved sequences that acquired human-specific nucleotide changes and reside in genomic regions associated with unique human traits and disease. The majority of HARs (96%) are noncoding, a few of which have been shown to be functional enhancers. Here, we comprehensively tested human and chimpanzee sequences of HARs (N=714) for enhancer activity using a lentivirus-based massively parallel reporter assay (lentiMPRA) in human and chimpanzee iPSC derived neural progenitors at two differentiation time points. We found that 43% (306/714) function as enhancers and over two-thirds (204/306) showed consistent differences in activity between human and chimpanzee sequences across conditions. We also tested all possible permutations of substitutions in seven HARs and found significant positive and negative interactions. Our study provides a comprehensive resource of functional neurodevelopmental HAR enhancers and shows that multiple interacting sites drive evolutionary activity differences.
2018-02-17 | GSE110758 | GEO
Project description:We performed a Massively Parallel Reporter Assay (MPRA) to screen >30,000 human-specific substitutions in ChIP-seq-identified Human Gain Enhancers (HGEs) and Human Accelerated Regions (HARs), highly conserved non-coding regions that show accelerated sequence evolution in humans. After comparing human and chimpanzee reference alleles, we used a second MPRA to deconvolute individual substitutions within differentially active enhancers from substitutions in the same fragment and from other variants (human segregating variants or chimpanzee-specific variants) to isolate their specific effects on enhancer activity.
2019-11-26 | GSE140983 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-02-17 | GSE110760 | GEO
Project description:Every element of the human skeleton exhibits some differences in comparison to our closest living relatives. Many of these skeletal modifications underpin key events in human evolution, enabling our species to walk upright, manipulate tools with precision, and support enlarged brains. Accordingly, many derived human features related to changes in the brain, locomotion, diet, and life history have been under natural selection since our last common ancestor with chimpanzees. Other changes result from random processes such as genetic drift. Identifying the genomic changes that underlie human-specific features of the skeleton (and other tissues) remains an outstanding challenge due to the substantial number of differences between the human and chimpanzee genomes. Approximately 3,000 of these changes are human accelerated regions (HARs) or regions that have accumulated more nucleotide changes than expected by chance, while others are single base-pair substitutions or other genomic signals. For the most part, a comprehensive functional analysis of all such changes as they pertain to the skeleton, let alone any tissue, remains lacking. Therefore, to identify human-chimp sequence differences that modulate gene expression in the developing postcranial skeleton, we used a massively parallel reporter assay (MPRA) to screen the human and chimp versions of 70,000 regulatory elements present in the prenatal cartilage template for differential activity. After testing our library in two cartilage and one bone marrow-derived lymphoblast line, we identify 30,736 regions (45.2%) with activity in our assay. Of the active regions, we find that 11,542 (37.6%; or 17% of the entire pool) regions exhibited differential activity between the human and chimpanzee. We find that human ancestor quickly evolved regions (HAQERs) were predictive of differential activity while HARs were not and both sets failed to predict the magnitude of effect, unlike the total number of base pair differences between species, which was weakly correlated with effect size. These findings reveal that human skeletal evolution involves widespread regulatory changes distributed across thousands of elements rather than concentrated effects at a few key loci, supporting a polygenic model for the evolution of complex morphological traits. This comprehensive dataset provides a large resource for understanding the regulatory basis of human skeletal adaptations and demonstrates the necessity of large-scale functional validation for interpreting evolutionary genomic comparisons.
2025-10-21 | GSE298093 | GEO
Project description:Human Accelerated Regions (HARs) are highly conserved across species but exhibit a significant excess of human-specific sequence changes, suggesting they may have gained novel functions in human evolution. HARs include gene regulatory elements with human-specific activity and have been implicated in the evolution of the human brain. However, our understanding of how HARs contributed to uniquely human features of the brain is hindered by a lack of insight into the genes and pathways that HARs regulate. It is unknown whether HARs acted by altering the expression of gene targets conserved between HARs and their chimpanzee orthologs or by gaining new gene targets in human, a mechanism termed enhancer hijacking. We generated a high-resolution map of chromatin interactions for 1,590 HARs and their orthologs in human and chimpanzee neural stem cells (NSCs) to comprehensively identify gene targets in both species. HARs and their chimpanzee orthologs targeted a conserved set of 2,963 genes enriched for neurodevelopmental processes including neurogenesis and synaptic transmission. Changes in HAR enhancer activity were correlated with changes in conserved gene target expression. Conserved targets were enriched among genes differentially expressed between human and chimpanzee NSCs or between human and non-human primate developing and adult brain. Species-specific HAR gene targets did not converge on known biological functions and were not significantly enriched among differentially expressed genes, suggesting that most HARs did not alter gene expression via enhancer hijacking. HAR gene targets, including differentially expressed targets, also showed cell type-specific expression patterns in the developing human brain, notably in outer radial glia, which are hypothesized to contribute to human cortical expansion. Our findings support that HARs influenced human brain evolution by altering the expression of a conserved set of gene targets and provide the means to functionally link HARs with novel human brain features.
2024-06-25 | GSE270272 | GEO
Project description:Resolving the three-dimensional interactome of Human Accelerated Regions during human and chimpanzee neurodevelopment
| PRJNA1126107 | ENA
Project description:Massively parallel functional screen identifies thousands of regulatory differences in human versus chimpanzee postcranial skeletal development
| PRJNA1268339 | ENA
Project description:Human Accelerated Regions (HARs) are conserved genomic loci that evolved at an accelerated rate in the human lineage and may underlie human-specific traits. We generated HARs and chimpanzee accelerated regions with an automated pipeline and an alignment of 251 mammalian genomes. Combining deep-learning with chromatin capture experiments in human and chimpanzee neural progenitor cells, we discovered a significant enrichment of HARs in topologically associating domains (TADs) containing human-specific genomic variants that change three-dimensional (3D) genome organization. Differential gene expression between humans and chimpanzees at these loci suggests rewiring of regulatory interactions between HARs and neurodevelopmental genes. Thus, comparative genomics together with models of 3D genome folding revealed enhancer hijacking as an explanation for the rapid evolution of HARs.
2022-12-21 | GSE183137 | GEO
Project description:We employ a massively parallel reporter assay (MPRA) to measure the ex vivo activities of hundreds of K562 and HepG2 enhancers with known transcription factor motif instances. For seven selected motifs that correspond to known or predicted activators and repressors in the two cell types, we make directed modifications of the bases corresponding to these motifs and observe the changes in enhancer activity. Reporter mRNA-seq from HepG2 and K562 cells transfected with a ~55,000-plex MPRA plasmid pool containing 5,418 mutated human enhancer sequences, each linked to 10 distinct 10-nt tags. The reporter mRNA tags facilitate quantitation of their abundances. The same tags were also sequenced from the transfected MPRA plasmid pool to facilitate normalization to plasmid copy numbers.
2013-03-15 | E-GEOD-33367 | biostudies-arrayexpress