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

Olgert Denas1, Richard Sandstrom2, Yong Cheng3

  • 1Department of Mathematics and Computer Science, Emory University, Atlanta, GA, 30322, USA. denas@adobe.com.

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Summary
This summary is machine-generated.

Species-specific gene regulation differences arise from repurposed regulatory sequences, not just conserved ones. This study reveals extensive sequence repurposing and exaptation in human and mouse regulatory elements.

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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.