Decoding DNA sequence-driven evolution of the human brain epigenome at cellular resolution
Abstract DNA-based evolutionary comparisons of regulatory genomic elements enable insight into functional changes driven in cis, partially overcoming tissue inaccessibility. Here, we harnessed adult and fetal cortex single-cell ATAC-seq datasets to uncover DNA substitutions specific to the human and...
Saved in:
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-07-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60665-w |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849769133496860672 |
|---|---|
| author | Emre Caglayan Genevieve Konopka |
| author_facet | Emre Caglayan Genevieve Konopka |
| author_sort | Emre Caglayan |
| collection | DOAJ |
| description | Abstract DNA-based evolutionary comparisons of regulatory genomic elements enable insight into functional changes driven in cis, partially overcoming tissue inaccessibility. Here, we harnessed adult and fetal cortex single-cell ATAC-seq datasets to uncover DNA substitutions specific to the human and human-ancestral lineages within apes. We found that fetal microglia identity is evolutionarily divergent in all lineages, whereas other cell types are conserved. Using multiomic datasets, we further identified genes linked to multiple lineage-divergent gene regulatory elements and implicated biological pathways associated with these divergent features. We also uncovered patterns of transcription factor binding site evolution across lineages and identified expansion of bHLH-PAS transcription factor targets in human-hominin lineages, and MEF2 transcription factor targets in the ape lineage. Finally, conserved features were more enriched in brain disease variants, whereas there was no distinct enrichment of brain disease variants on the human lineage compared to its ancestral lineages. Our study identifies ancestral evolutionary patterns of the human brain epigenome at cellular resolution. |
| format | Article |
| id | doaj-art-bddf087e619148259f01b14840c68eaa |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-bddf087e619148259f01b14840c68eaa2025-08-20T03:03:33ZengNature PortfolioNature Communications2041-17232025-07-0116111210.1038/s41467-025-60665-wDecoding DNA sequence-driven evolution of the human brain epigenome at cellular resolutionEmre Caglayan0Genevieve Konopka1Department of Neuroscience, UT Southwestern Medical CenterDepartment of Neuroscience, UT Southwestern Medical CenterAbstract DNA-based evolutionary comparisons of regulatory genomic elements enable insight into functional changes driven in cis, partially overcoming tissue inaccessibility. Here, we harnessed adult and fetal cortex single-cell ATAC-seq datasets to uncover DNA substitutions specific to the human and human-ancestral lineages within apes. We found that fetal microglia identity is evolutionarily divergent in all lineages, whereas other cell types are conserved. Using multiomic datasets, we further identified genes linked to multiple lineage-divergent gene regulatory elements and implicated biological pathways associated with these divergent features. We also uncovered patterns of transcription factor binding site evolution across lineages and identified expansion of bHLH-PAS transcription factor targets in human-hominin lineages, and MEF2 transcription factor targets in the ape lineage. Finally, conserved features were more enriched in brain disease variants, whereas there was no distinct enrichment of brain disease variants on the human lineage compared to its ancestral lineages. Our study identifies ancestral evolutionary patterns of the human brain epigenome at cellular resolution.https://doi.org/10.1038/s41467-025-60665-w |
| spellingShingle | Emre Caglayan Genevieve Konopka Decoding DNA sequence-driven evolution of the human brain epigenome at cellular resolution Nature Communications |
| title | Decoding DNA sequence-driven evolution of the human brain epigenome at cellular resolution |
| title_full | Decoding DNA sequence-driven evolution of the human brain epigenome at cellular resolution |
| title_fullStr | Decoding DNA sequence-driven evolution of the human brain epigenome at cellular resolution |
| title_full_unstemmed | Decoding DNA sequence-driven evolution of the human brain epigenome at cellular resolution |
| title_short | Decoding DNA sequence-driven evolution of the human brain epigenome at cellular resolution |
| title_sort | decoding dna sequence driven evolution of the human brain epigenome at cellular resolution |
| url | https://doi.org/10.1038/s41467-025-60665-w |
| work_keys_str_mv | AT emrecaglayan decodingdnasequencedrivenevolutionofthehumanbrainepigenomeatcellularresolution AT genevievekonopka decodingdnasequencedrivenevolutionofthehumanbrainepigenomeatcellularresolution |