Genomics in Equine MEED: Whole-Genome Sequencing and Target Mutation Identification.

Genomic analysis of a horse affected by multisystemic eosinophilic epitheliotropic disease (MEED) identified multiple genetic mutations that likely contribute to the disease, highlighting disruptions in epithelial and immune system pathways.

Study Objective and Background

• MEED is a rare and severe disease in horses involving chronic inflammation characterized by eosinophil infiltration, damage to epithelial tissues, and multiple organ involvement.
• The genetic causes underlying MEED were previously unknown.
• The study aimed to investigate the genetic basis of MEED through whole-genome sequencing of an affected horse compared to healthy controls.

Methodology

• Performed whole-genome sequencing at approximately 40× coverage on one horse diagnosed with MEED.
• Sequenced and compared the genome data against 40 control horse genomes without MEED.
• Identified and cataloged genetic variants, focusing on those with moderate and high predicted impact on protein function.
• Employed gene prioritization, pathway, and network analyses to interpret the functional relevance of the variants.

Key Findings

• Over 6.3 million genetic variants were detected in the affected horse’s genome.
• Variants with moderate and high impacts were significantly enriched among low-frequency categories, including rare and private mutations absent from control genomes.
• The affected horse’s genome showed a predominance of missense mutations, which change amino acids in proteins, but lacked single high-impact mutations likely causing the disease alone.
• This suggests the disease results from the cumulative effect of multiple protein-altering mutations rather than one mutation with large effect.

Biological Implications of Genetic Variants

• Gene and pathway analyses revealed variants affecting cytoskeletal organization and microtubule dynamics, important for cellular structure and transport.
• Disruptions in epithelial integrity were indicated, which is consistent with the epithelial tissue damage seen in MEED.
• Variants also affected immune regulatory pathways, providing insight into the chronic eosinophilic inflammation characteristic of the disease.
• Network analysis highlighted the interconnectedness between structural cellular pathways and inflammatory/immune pathways, suggesting impaired epithelial barriers lead to altered immune homeostasis.

Conclusions and Significance

• The study is the first to provide population-level genomic insight into MEED in horses.
• Results support a disease model where multiple, cumulative mutations collectively disrupt epithelial stability and trigger persistent inflammation.
• Understanding these genetic underpinnings could guide future diagnostic, therapeutic, and breeding strategies to manage or prevent MEED.
• Overall, this work advances knowledge of a complex equine disease by linking genomics with pathological features of epithelial barrier dysfunction and immune dysregulation.