Evolutionary relevance of single nucleotide variants within the forebrain exclusive human accelerated enhancer regions
Abstract Background Human accelerated regions (HARs) are short conserved genomic sequences that have acquired significantly more nucleotide substitutions than expected in the human lineage after divergence from chimpanzees. The fast evolution of HARs may reflect their roles in the origin of human-sp...
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| Format: | Article |
| Language: | English |
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BMC
2023-03-01
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| Series: | BMC Molecular and Cell Biology |
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| Online Access: | https://doi.org/10.1186/s12860-023-00474-5 |
| _version_ | 1797836245347336192 |
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| author | Hizran Khatoon Rabail Zehra Raza Shoaib Saleem Fatima Batool Saba Arshad Muhammad Abrar Shahid Ali Irfan Hussain Neil H. Shubin Amir Ali Abbasi |
| author_facet | Hizran Khatoon Rabail Zehra Raza Shoaib Saleem Fatima Batool Saba Arshad Muhammad Abrar Shahid Ali Irfan Hussain Neil H. Shubin Amir Ali Abbasi |
| author_sort | Hizran Khatoon |
| collection | DOAJ |
| description | Abstract Background Human accelerated regions (HARs) are short conserved genomic sequences that have acquired significantly more nucleotide substitutions than expected in the human lineage after divergence from chimpanzees. The fast evolution of HARs may reflect their roles in the origin of human-specific traits. A recent study has reported positively-selected single nucleotide variants (SNVs) within brain-exclusive human accelerated enhancers (BE-HAEs) hs1210 (forebrain), hs563 (hindbrain) and hs304 (midbrain/forebrain). By including data from archaic hominins, these SNVs were shown to be Homo sapiens-specific, residing within transcriptional factors binding sites (TFBSs) for SOX2 (hs1210), RUNX1/3 (hs563), and FOS/JUND (hs304). Although these findings suggest that the predicted modifications in TFBSs may have some role in present-day brain structure, work is required to verify the extent to which these changes translate into functional variation. Results To start to fill this gap, we investigate the SOX2 SNV, with both forebrain expression and strong signal of positive selection in humans. We demonstrate that the HMG box of SOX2 binds in vitro with Homo sapiens-specific derived A-allele and ancestral T-allele carrying DNA sites in BE-HAE hs1210. Molecular docking and simulation analysis indicated highly favourable binding of HMG box with derived A-allele containing DNA site when compared to site carrying ancestral T-allele. Conclusion These results suggest that adoptive changes in TF affinity within BE-HAE hs1210 and other HAR enhancers in the evolutionary history of Homo sapiens might have brought about changes in gene expression patterns and have functional consequences on forebrain formation and evolution. Methods The present study employ electrophoretic mobility shift assays (EMSA) and molecular docking and molecular dynamics simulations approaches. |
| first_indexed | 2024-04-09T15:05:35Z |
| format | Article |
| id | doaj.art-d505f9f7b2bd4954a5240f23461ba72f |
| institution | Directory Open Access Journal |
| issn | 2661-8850 |
| language | English |
| last_indexed | 2024-04-09T15:05:35Z |
| publishDate | 2023-03-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Molecular and Cell Biology |
| spelling | doaj.art-d505f9f7b2bd4954a5240f23461ba72f2023-04-30T11:31:30ZengBMCBMC Molecular and Cell Biology2661-88502023-03-0124111610.1186/s12860-023-00474-5Evolutionary relevance of single nucleotide variants within the forebrain exclusive human accelerated enhancer regionsHizran Khatoon0Rabail Zehra Raza1Shoaib Saleem2Fatima Batool3Saba Arshad4Muhammad Abrar5Shahid Ali6Irfan Hussain7Neil H. Shubin8Amir Ali Abbasi9National Center for Bioinformatics, Program of Comparative and Evolutionary Genomics, Faculty of Biological Sciences, Quaid-I-Azam UniversityDepartment of Biological Sciences, National University of Medical SciencesNational Center for Bioinformatics, Program of Comparative and Evolutionary Genomics, Faculty of Biological Sciences, Quaid-I-Azam UniversityNational Center for Bioinformatics, Program of Comparative and Evolutionary Genomics, Faculty of Biological Sciences, Quaid-I-Azam UniversityNational Center for Bioinformatics, Program of Comparative and Evolutionary Genomics, Faculty of Biological Sciences, Quaid-I-Azam UniversityNational Center for Bioinformatics, Program of Comparative and Evolutionary Genomics, Faculty of Biological Sciences, Quaid-I-Azam UniversityDepartment of Organismal Biology and Anatomy, The University of ChicagoNational Center for Bioinformatics, Program of Comparative and Evolutionary Genomics, Faculty of Biological Sciences, Quaid-I-Azam UniversityDepartment of Organismal Biology and Anatomy, The University of ChicagoNational Center for Bioinformatics, Program of Comparative and Evolutionary Genomics, Faculty of Biological Sciences, Quaid-I-Azam UniversityAbstract Background Human accelerated regions (HARs) are short conserved genomic sequences that have acquired significantly more nucleotide substitutions than expected in the human lineage after divergence from chimpanzees. The fast evolution of HARs may reflect their roles in the origin of human-specific traits. A recent study has reported positively-selected single nucleotide variants (SNVs) within brain-exclusive human accelerated enhancers (BE-HAEs) hs1210 (forebrain), hs563 (hindbrain) and hs304 (midbrain/forebrain). By including data from archaic hominins, these SNVs were shown to be Homo sapiens-specific, residing within transcriptional factors binding sites (TFBSs) for SOX2 (hs1210), RUNX1/3 (hs563), and FOS/JUND (hs304). Although these findings suggest that the predicted modifications in TFBSs may have some role in present-day brain structure, work is required to verify the extent to which these changes translate into functional variation. Results To start to fill this gap, we investigate the SOX2 SNV, with both forebrain expression and strong signal of positive selection in humans. We demonstrate that the HMG box of SOX2 binds in vitro with Homo sapiens-specific derived A-allele and ancestral T-allele carrying DNA sites in BE-HAE hs1210. Molecular docking and simulation analysis indicated highly favourable binding of HMG box with derived A-allele containing DNA site when compared to site carrying ancestral T-allele. Conclusion These results suggest that adoptive changes in TF affinity within BE-HAE hs1210 and other HAR enhancers in the evolutionary history of Homo sapiens might have brought about changes in gene expression patterns and have functional consequences on forebrain formation and evolution. Methods The present study employ electrophoretic mobility shift assays (EMSA) and molecular docking and molecular dynamics simulations approaches.https://doi.org/10.1186/s12860-023-00474-5EvolutionEnhancersHuman accelerated regionsForebrainArchaic homininsTFBS |
| spellingShingle | Hizran Khatoon Rabail Zehra Raza Shoaib Saleem Fatima Batool Saba Arshad Muhammad Abrar Shahid Ali Irfan Hussain Neil H. Shubin Amir Ali Abbasi Evolutionary relevance of single nucleotide variants within the forebrain exclusive human accelerated enhancer regions BMC Molecular and Cell Biology Evolution Enhancers Human accelerated regions Forebrain Archaic hominins TFBS |
| title | Evolutionary relevance of single nucleotide variants within the forebrain exclusive human accelerated enhancer regions |
| title_full | Evolutionary relevance of single nucleotide variants within the forebrain exclusive human accelerated enhancer regions |
| title_fullStr | Evolutionary relevance of single nucleotide variants within the forebrain exclusive human accelerated enhancer regions |
| title_full_unstemmed | Evolutionary relevance of single nucleotide variants within the forebrain exclusive human accelerated enhancer regions |
| title_short | Evolutionary relevance of single nucleotide variants within the forebrain exclusive human accelerated enhancer regions |
| title_sort | evolutionary relevance of single nucleotide variants within the forebrain exclusive human accelerated enhancer regions |
| topic | Evolution Enhancers Human accelerated regions Forebrain Archaic hominins TFBS |
| url | https://doi.org/10.1186/s12860-023-00474-5 |
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