Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage

Area of Science:

• Genomics
• Neuroscience
• Evolutionary Biology

Background:

• Understanding human-specific genomic features is crucial for insights into brain-related diseases.
• Genetic variation and cross-species conservation patterns can highlight regions under unique evolutionary pressures.

Purpose of the Study:

• To identify and characterize human-specific genomic regions under purifying selection.
• To investigate the enrichment of brain-specific elements and disease associations within these regions.

Main Methods:

• Utilized high-depth whole genome sequencing data for combined annotation.
• Identified constrained, non-conserved regions (CNCRs) depleted for genetic variation and poorly conserved across primates.
• Analyzed per-SNP heritability for brain-relevant phenotypes and gene density in neurological diseases.

Main Results:

• CNCRs are depleted in protein-coding genes but enriched in long non-coding RNAs (lncRNAs).
• CNCRs show enrichment for the heritability of brain-relevant phenotypes.
• Genes implicated in neurological diseases, such as APOE, exhibit high CNCR density, including an unannotated intron-3 retention event.
• This intron-3-retaining transcript is more abundant in Alzheimer's disease patients with higher pathological burden.

Conclusions:

• CNCRs represent human-lineage-specific sequences potentially involved in brain development.
• These regions are significantly associated with neurological disease risk and progression.
• Findings highlight the role of human-specific genomic elements in brain function and disease.