Segmentally duplicated regulatory elements undergo human-specific rewiring.

Area of Science:

• Genomics
• Evolutionary Biology
• Gene Regulation

Background:

• Gene regulatory innovation drives phenotypic evolution.
• Transposable elements are known drivers of cis-regulatory element families.
• Understanding novel mechanisms for co-regulatory network formation is crucial.

Purpose of the Study:

• To identify mechanisms forming co-regulatory networks beyond transposable elements.
• To analyze regulatory element families based on sequence similarity and cell type-specific activity.
• To investigate the role of segmental duplications in creating and modifying regulatory networks.

Main Methods:

• Applied sequence similarity and chromatin accessibility analysis to the human T2T genome assembly and ESC data.
• Utilized STARR-seq for functional validation of regulatory element networks.
• Employed CRISPRi for identifying target genes of validated regulatory elements in ESCs.

Main Results:

• Segmental duplications are a major mechanism creating over a thousand regulatory element networks in ESCs.
• Functional validation confirmed these networks as regulatory element families.
• Post-duplication, regulatory elements exhibit both maintenance and rewiring of target gene relationships, including novel distal and inter-locus regulation.
• Many rewiring events are human-specific.
• Segmental duplications disproportionately expanded regulatory elements in immune cells and specific brain regions.

Conclusions:

• Segmental duplications are a significant source of gene regulatory innovation.
• Regulatory rewiring following duplication contributes to gene regulatory evolution.
• Neofunctionalization of regulatory elements may be facilitated by new genomic contexts after duplication.