Intronic CNVs and gene expression variation in human populations

Area of Science:

• Genomics
• Human Genetics
• Population Genetics

Background:

• Introns constitute the majority of human gene DNA but their structural variation patterns and functional roles remain largely unexplored.
• Understanding intronic structural variation is crucial for comprehending human genetic diversity and gene regulation.

Purpose of the Study:

• To investigate the population patterns of structural variation within introns of human protein-coding genes.
• To determine the functional implications of intronic structural variation on gene expression and splicing.

Main Methods:

• Utilized extensive human population maps of copy number variants (CNVs).
• Integrated CNV data with RNA-sequencing (RNA-seq) data.
• Analyzed intronic structural variations in relation to gene conservation, evolutionary age, and gene expression quantitative trait loci (eQTLs).

Main Results:

• Intronic deletions are the most frequent CNVs in human protein-coding genes, affecting thousands of genes, including essential and disease-related ones.
• Significant intronic length variation was observed, with some genes exhibiting extreme allelic diversity.
• Intronic losses were common in conserved, ancient genes, contrasting with exon losses predominantly found in primate-specific genes.
• Intronic CNVs were associated with population-level differences in gene expression (CNV-eQTLs), often linked to intronic enhancers and long-range regulatory interactions.

Conclusions:

• Intronic structural variation, particularly deletions, is a major source of genetic diversity in human protein-coding genes.
• Intronic CNVs contribute significantly to the variability of gene expression and splicing in human populations.
• These findings highlight the functional importance of intronic regions beyond their role as non-coding sequences.