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

作者：Jinhao Liu, Zihang Yin, Yonglin Peng, Shuang Cui, Bo Shi, X W Jiang, Ziyi Yang, Sijie Gu, Yude Lin, Lingfeng Xu, Zhen Xu, Xuankai Wang, Tienan Chen, Wei Zhang, Shaojiao Wang, Zhiwei Xiao, Zhibo Huang, Rujiang Zhou, Zhengju Yao, Xiaodong Zhao, Ya Guo, Shuhua Xu, Weidong Li, Xizhi Guo · 发表于：Genome biology · 年份：2026 · DOI：10.1186/s13059-026-04098-8 · 研究领域：Chromosomal and Genetic Variations、Genomics and Chromatin Dynamics、Congenital heart defects research

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 3...