A LINE-1 insertion upstream of FOXP2 promotes neuronal differentiation during primate evolution

BACKGROUND: The evolutionary trajectory of FOXP2, a key regulator of language acquisition and higher-order cognitive function, remains incompletely understood. Retrotransposons such as long interspersed element-1 (LINE-1) are recognized as important contributors to genome regulation, influencing embryonic and neuronal developmental programs. However, the potential contribution of LINE-1 to shaping the cis-regulatory landscape of FOXP2 remains unclear. RESULTS: Through comparative evolutionary genomic analyses, we identify a locus positioned 342 kb upstream of the FOXP2 transcription start site that has experienced multiple, successive LINE-1 retrotransposition events during primate evolution. This process produces a 10.6 kb composite LINE-1 element present in both human and chimpanzee genomes, which we designate FOXP2-342L1. This element exhibits moderate signals of recent positive selection in modern human populations and resides near a topologically associating domain boundary within the FOXP2 regulatory landscape. Integrative 3D genome mapping in human and marmoset neural stem cell models demonstrates that FOXP2-342L1 mediates long range chromatin interactions across the FOXP2 cis regulatory domain. Notably, FOXP2-342L1 functions as an evolutionary "hub" that accumulates successive LINE-1 insertions during primate evolution, thereby regulating FOXP2 activity and promoting cortical neuron differentiation. CONCLUSION: Our findings uncover a LINE-1 driven reconfiguration of 3D chromatin architecture within the FOXP2 regulatory landscape and reveal a primate specific model of neuronal development shaped by retrotransposon activity during primate evolution.