ArticleProceedings of the National Academy of Sciences of the United States of America2021
Massively parallel discovery of human-specific substitutions that alter enhancer activity.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 75 papers, 1 of them a synthesis that pooled it.
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Who cites it
75 citing papers in PubMed, 1 synthesis or guideline pooled it, 116 citations in OpenAlex.
- A Systematic Review of the Human Accelerated Regions in Schizophrenia and Related Disorders: Where the Evolutionary and Neurodevelopmental Hypotheses Converge.International journal of molecular sciences · 2023Pooled it
- A Human Accelerated Region Drives Opposing Heterochronic Changes in Craniofacial and Limb Development.bioRxiv : the preprint server for biology · 2026Article
- CNEwrap: a scalable toolkit with a novel algorithm for large-scale genome-wide accelerated conserved non-coding elements detection.Nucleic acids research · 2026Article
- Influence ofGenome research · 2026Article
- Genomic approaches for understanding the evolution of the human brain.Nature neuroscience · 2026Review
- In Vitro Massively Parallel Screening of Human Regulatory Elements Involved in Postcranial Skeletal Development for Differential Activity Compared to Chimpanzee.Genome biology and evolution · 2026Article
- Retracing and rewriting the evolutionary trajectories of mammalian developmental enhancers.bioRxiv : the preprint server for biology · 2026Article
- Species-specific chromatin architecture and neurogenesis mediated by a human enhancer.Cell stem cell · 2026Article
- 3D genetic architecture of schizophrenia risk across three neuronal subtypes.Molecular psychiatry · 2026Article
- So Fragile, So Human: Noncoding DNA Regions Orchestrating Gene Expression Involved in Neurodevelopmental Disorders and in Human Brain Evolution.International journal of molecular sciences · 2026Review
- Mapping the gene regulatory landscape of archaic hominin introgression in modern Papuans.PLoS genetics · 2026Article
- Influence ofbioRxiv : the preprint server for biology · 2025Article
- Comparative genomics sheds light on mammalian and avian gene regulation and phenotypic evolution.Nature communications · 2025Article
- Lineage-specific regulatory evolution: insights from massively parallel reporter assays.Current opinion in genetics & development · 2025Review
- Decoding DNA sequence-driven evolution of the human brain epigenome at cellular resolution.Nature communications · 2025Article
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- Massively parallel reporter assays and mouse transgenic assays provide correlated and complementary information about neuronal enhancer activity.Nature communications · 2025Article
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- Regulatory Plasticity of the Human Genome.Molecular biology and evolution · 2025Article
15 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
Genetic changes that altered the function of gene regulatory elements have been implicated in the evolution of human traits such as the expansion of the cerebral cortex. However, identifying the particular changes that modified regulatory activity during human evolution remain challenging. Here we used massively parallel enhancer assays in neural stem cells to quantify the functional impact of >32,000 human-specific substitutions in >4,300 human accelerated regions (HARs) and human gain enhancers (HGEs), which include enhancers with novel activities in humans. We found that >30% of active HARs and HGEs exhibited differential activity between human and chimpanzee. We isolated the effects of human-specific substitutions from background genetic variation to identify the effects of genetic changes most relevant to human evolution. We found that substitutions interacted in both additive and nonadditive ways to modify enhancer function. Substitutions within HARs, which are highly constrained compared to HGEs, showed smaller effects on enhancer activity, suggesting that the impact of human-specific substitutions is buffered in enhancers with constrained ancestral functions. Our findings yield insight into how human-specific genetic changes altered enhancer function and provide a rich set of candidates for studies of regulatory evolution in humans.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.