REforge Associates Transcription Factor Binding Site Divergence in Regulatory Elements with Phenotypic Differences...

Area of Science:

• Evolutionary Biology
• Genomics

Background:

• Identifying the genetic basis of morphological differences between species is crucial for understanding evolution.
• Cis-regulatory element differences are a known driver of morphological evolution, but pinpointing specific elements is difficult.

Purpose of the Study:

• To develop and validate a computational method for identifying regulatory elements associated with phenotypic divergence between species.
• To investigate the role of regulatory element divergence in the eye degeneration of subterranean mammals.

Main Methods:

• Developed Regulatory Element forward genomics (REforge), a computational approach to associate transcription factor binding site divergence with phenotypic differences.
• Simulated regulatory element evolution in silico to assess REforge's detection power.
• Applied REforge to known binding motifs of eye-related transcription factors in subterranean mammals.

Main Results:

• REforge demonstrated substantial power in simulated data.
• Identified significant binding site divergence in 1% of conserved noncoding elements in subterranean mammals.
• These regions were enriched for eye-specific regulatory elements and located near genes crucial for eye development and function, implicated in human eye disorders.

Conclusions:

• REforge effectively detects regulatory elements contributing to phenotypic differences.
• The study highlights widespread divergence in eye-regulatory elements, likely driving eye degeneration in subterranean mammals.
• REforge offers a broadly applicable tool for uncovering the genomic basis of morphological diversity.