The impact of structural variation on human gene expression

Area of Science:

• Human genetics
• Genomics
• Molecular biology

Background:

• Structural variants (SVs) contribute to human genetic diversity.
• The role of SVs in traits, disease, and gene regulation requires further elucidation.

Purpose of the Study:

• To investigate the contribution of SVs to gene expression regulation.
• To compare the impact of SVs with single-nucleotide variants (SNVs) and indels on expression quantitative trait loci (eQTLs).

Main Methods:

• Joint analysis of SVs, SNVs, and indels from whole-genome sequencing (WGS) data.
• Mapping of cis-acting eQTLs across 13 human tissues.
• Identification of putative causal SVs affecting gene expression.

Main Results:

• SVs were estimated to be causal in 3.5-6.8% of eQTLs, a higher fraction than previously reported.
• Expression-altering SVs demonstrated larger effect sizes compared to SNVs and indels.
• Identified 789 causal SVs, predominantly noncoding and enriched in regulatory elements; 52 linked to GWAS loci.
• Observed a high prevalence of rare, high-impact SVs associated with altered gene expression.

Conclusions:

• Comprehensive SV analysis using WGS enhances the power of genetic association studies for both common and rare variants.
• SVs play a more significant role in gene regulation and human traits than previously appreciated.
• The findings highlight the importance of integrating SVs into genomic analyses for a deeper understanding of genetic diversity and disease.