Human brain evolution: Role of SINE-VNTR-Alu retrotransposons and SINE-VNTR-Alu long noncoding RNA AK057321.

Humans differ remarkably from great apes, with advanced cognitive abilities correlated to enlarged brains resulting from prolonged neurodevelopment. The SINE-VNTR-Alu (SVA) retrotransposons are candidate genetic drivers of these differences. Human genes with intronic SVAs are enriched for neurodevelopmental diseases; the microcephaly gene CDK5 regulatory subunit associated protein 2 (CDK5RAP2) and epilepsy/intellectual disability gene SCN8A coding for sodium channel subunit contain human-specific, intronic SVAs. Deleting gene ZNF91 coding for the SVA-binding zinc finger protein 91 or the intronic SVAs upregulate gene expression to accelerate functional and structural neuron maturation. We also discovered the function of AK057321, duplicated in ultrarare autism, founding a new gene family of long noncoding RNAs containing SVA sequences. AK057321 increases 10-fold as progenitors mature into glutamatergic neurons, and its premature increase upregulates CDK5RAP2 and SCN8A to accelerate neuron maturation. As anticipated by its sequence complementarity, AK057321 forms RNA:DNA heteroduplexes with genomic SVAs and decoy-binds the ZNF91 repressive complex. SVA-mediated block of CDK5RAP2-induced neuron maturation could prolong progenitor proliferation to increase neuron numbers and cerebral cortex size. SVA-lncRNA AK057321 also acts in adulthood to promote threefold enriched expression of Huntington (containing an SVA) in the frontal cortex relative to the brain stem. The large number of neurologic genes regulated by SVA-lncRNA AK057321 suggests the retrotransposon-based gene regulatory mechanism shaped human brain development and functions to advance cognitive abilities.