Abstract:

Over the past 5 to 7 million years, humans and chimpanzees have diverged in brain size, structure, and cognition despite high conservation of protein-coding genes. However, retroviral infections within host genomes have introduced numerous species-specific regulatory elements. Chimpanzees harbor lineage-specific PTERV1 endogenous retroviruses that are absent in humans, but their role in brain evolution has remained unclear. We performed an epigenomic analysis of PTERV1 insertions in chimpanzee neural organoids and found they are heavily DNA methylated, forming over 150 species-specific heterochromatin domains with the potential to influence gene regulation. We identified a chimpanzee-specific insertion on chromosome 19 that silences the long noncoding RNA LINC00662 through DNA methylation spreading. CRISPR-mediated deletion of this PTERV1 restored LINC00662 expression in chimpanzee induced pluripotent stem cells. We show that LINC00662, a human-specific transcript expressed during brain development, plays a role in neuronal maturation, axon outgrowth, and neural organoid development. These findings reveal a mechanism by which endogenous retroviral insertions contributed to human-chimpanzee brain divergence.

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