Interrogating the Regulatory Function of HAQERs during Human Cortical Development

Fifty HAQERs with accessible chromatin were identified in developing human cortex, largely from previously unconstrained ancestral sequences, marking where human-specific regulatory evolution occurs.

• Why it matters: Sequence divergence in regulatory elements is linked to human cortical expansion, but the mutational origins and which target genes HAQERs regulate during development remain unclear.
• What they did: Using an all-in-one CRISPRi lentiviral vector, 26 HAQERs were linked to nearby target genes across cell types and Wnt activation contexts, revealing rapid CpG gains and 107 HAQER CpG Beacons with at least 17 human-specific CpG gains per kb.
• The result: HAQER CpG Beacons emerged via GC-biased gene conversion with selection preferentially fixing CpG sites, and CHL1 and DPP10 each contained two gene-linked beacons, supporting regulatory innovation in human cortical development.

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