Genome-wide comparative analysis reveals human-mouse regulatory landscape and evolution

Area of Science:

• Comparative genomics
• Regulatory element evolution
• Species divergence

Background:

• Understanding species-specific gene regulation is key to explaining species differences.
• Relationships between regulatory DNA sequence, conservation, and function remain unclear.

Purpose of the Study:

• To map and compare transcription factor occupied segments (TFos) between human and mouse.
• To investigate the evolutionary conservation and functional repurposing of regulatory sequences.

Main Methods:

• Utilized whole genome alignments (WGA) and a cross-species mapper (bnMapper) to compare human and mouse TFos.
• Analyzed TFos across numerous cell types and tissues from the ENCODE projects.
• Compared sequence homology, binding activity, and target gene associations.

Main Results:

• TFos are evolutionarily constrained, but significant portions lack homology or are repurposed in the other species.
• A large percentage of homologous TFos show binding activity, with extensive repurposing for new functions or TFs.
• Repurposed TFos often become preferred sites for novel TF binding, suggesting exaptation.
• Despite repurposing, predicted target genes remained largely unchanged, indicating regulatory network stability.

Conclusions:

• Mapped human and mouse regulatory sequences, revealing substantial shared, yet repurposed, sequences.
• Evidence suggests exaptation of regulatory elements driven by sequence turnover.
• Regulatory sequence repurposing is a significant factor in species-specific gene regulation.