Retroviral insertions contributed to the divergence of human and chimpanzee brains

Abstract

Over the past 5-7 million years, humans and chimpanzees have diverged in brain size, structural complexity, and cognitive abilities despite high conservation of protein-coding genes. Notably, the endogenization and proliferation of retroviral infections within host genomes has introduced numerous species-specific regulatory elements that have the potential to influence gene regulation. However, the role of these endogenous retroviruses in hominoid brain evolution remains unclear. A burst of lineage-specific PTERV1 retroviruses recently invaded the chimpanzee genome but are absent in humans. We conducted an epigenomic analysis of PTERV1 insertions in chimpanzee neural organoids and found that they are heavily covered by DNA methylation, representing more than 150 species-specific heterochromatin domains with the capacity to influence gene regulatory networks. We identified one such chimpanzee-specific PTERV1 insertion on chromosome 19 that blocks the expression of the long noncoding RNA LINC00662, via DNA methylation spread to the adjacent genomic region. The expression of LINC00662 was restored in chimpanzee induced pluripotent stem cells when we deleted the PTERV1 insertion using CRISPR editing. We found that LINC00662, a human-specific RNA, is highly expressed in the developing brain and plays an important role in the posttranscriptional control of neuronal maturation, axon outgrowth, and neural organoid development. In summary, our findings describe how endogenous retroviral insertions contributed to the functional divergence of the human and chimpanzee brains. This provides a new mechanism by which retroviral pandemics influenced primate brain speciation.