Repeats mimic pathogen-associated patterns across a vast evolutionary landscape

Area of Science:

• Genomics and Molecular Biology
• Immunology
• Evolutionary Biology
• Statistical Physics

Background:

• Many human diseases involve the transcription of repetitive DNA elements that are usually silenced.
• These transcribed elements contain pathogen-associated molecular patterns (PAMPs) that activate the innate immune system through pattern recognition receptors (PRRs), a process termed viral mimicry.
• Understanding the evolutionary forces driving the emergence and retention of these PAMPs is crucial.

Purpose of the Study:

• To develop a statistical physics framework for quantifying viral mimicry.
• To identify specific repetitive DNA elements that act as potential viral mimics across eukaryotic genomes.
• To propose evolutionary hypotheses explaining the enrichment and maintenance of PAMPs within repetitive DNA.

Main Methods:

• Developed a statistical physics framework to measure 'selective forces' enriching PAMPs.
• Compared PAMP enrichment against genome-wide reference distributions.
• Validated predictions by identifying specific repeats binding to different PRRs in eukaryotic genomes.

Main Results:

• Identified potential viral mimics within various repeat families across eukaryotic genomes.
• Demonstrated that shared evolutionary mechanisms likely drive the emergence and retention of these PAMPs.
• Showed that PAMPs can be enriched due to selection acting on repetitive DNA.

Conclusions:

• Viral mimicry is an emerging hallmark of disease, driven by transcribed repetitive DNA.
• Two evolutionary hypotheses, 'repeat-centric' and 'organism-centric', are proposed to explain PAMP maintenance.
• The findings suggest PAMPs are integral to repeat expansion or serve as a cell-intrinsic regulatory mechanism against transcriptional dysregulation.