To ERV Is Human: A Phenotype-Wide Scan Linking Polymorphic Human Endogenous Retrovirus-K Insertions to Complex...

Area of Science:

• Genomics
• Human Genetics
• Retrovirology

Background:

• Endogenous retroviral insertions (ERVs) constitute a significant portion of the human genome and are known gene expression regulators.
• The role of ERV insertional polymorphisms in complex trait heritability remains underexplored.
• Human Endogenous Retrovirus-K (HERV-K), the most recent ERV, is implicated in various human diseases, including cancer and neurological disorders.

Purpose of the Study:

• To identify polymorphic HERV-K insertions within the human genome.
• To investigate the association of these insertions with gene expression and complex disease phenotypes.
• To establish a foundation for studying the heritability of complex diseases influenced by HERV-K.

Main Methods:

• Utilized whole-genome sequencing data from the 1,000 Genomes Phase 3 population (n=2,504).
• Developed a computational pipeline to identify 46 polymorphic HERV-K insertions tagged by single nucleotide polymorphisms (SNPs).
• Queried existing databases to assess enrichment of HERV-K insertion-associated SNPs (hiSNPs) with gene expression quantitative trait loci (eQTLs) and disease phenotypes.

Main Results:

• Identified 46 polymorphic HERV-K insertions associated with adjacent SNPs.
• Demonstrated statistically significant enrichment of hiSNPs for eQTLs across 44 human tissues (p < 1.0E-16).
• Found that 15 HERV-K insertions had hiSNPs linked to over 100 phenotypes in the EMBL-EBI GWAS Catalog, particularly in neurological and immunological domains.

Conclusions:

• Polymorphic HERV-K insertions are strongly associated with gene expression regulation and complex disease phenotypes.
• Specific HERV-K insertions are implicated in neurological conditions like Parkinson's disease and intracranial volume, as well as autoimmune diseases.
• These findings offer a roadmap for future research into the role of polymorphic HERV-K in disease heritability.