Abstract:
SINE-VNTR-Alu (SVA) retrotransposons arose and expanded in the genome of hominoid primates concurrent with the slowing of brain maturation. We report genes with intronic SVA transposons are enriched for neurodevelopmental disease and transcribed into long non-coding SVA-lncRNAs. Human-specific SVAs in microcephaly CDK5RAP2 and epilepsy SCN8A gene introns repress their expression via transcription factor ZNF91 to delay neuronal maturation. Deleting the SVA in CDK5RAP2 initiates multi-dimensional and in SCN8A selective sodium current neuronal maturation by upregulating these genes. SVA-lncRNA AK057321 forms RNA:DNA heteroduplexes with the genomic SVAs and upregulates these genes to initiate neuronal maturation. SVA-lncRNA AK057321 also promotes species-specific cortex and cerebellum-enriched expression upregulating human genes with intronic SVAs (e.g., HTT, CHAF1B and KCNJ6) but not mouse orthologs. The diversity of neuronal genes with intronic SVAs suggest this hominoid-specific SVA transposon-based gene regulatory mechanism may act at multiple steps to specialize and achieve neoteny of the human brain.
Notes:
Nadler, Monica J S Chang, Weipang Ozkaynak, Ekim Huo, Yuda Nong, Yi Boillot, Morgane Johnson, Mark Moreno, Antonio Matthew P Anderson eng R01 MH112714/MH/NIMH NIH HHS/ R01 MH114858/MH/NIMH NIH HHS/ R21 MH100868/MH/NIMH NIH HHS/ R21 HD079249/HD/NICHD NIH HHS/ U54 HD090255/HD/NICHD NIH HHS/ P30 HD018655/HD/NICHD NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England 2023/03/31 Commun Biol. 2023 Mar 30;6(1):347. doi: 10.1038/s42003-023-04683-8.
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