What are the Origins and Implications of Intron Retention Quantitative Trait Loci in Human Tissues?

The Findings

Researchers in the Center for Computational and Genomic Medicine at Children’s Hospital of Philadelphia systematically mapped genetic variants that affect intron retention — called intron retention quantitative trait loci (irQTLs). By analyzing RNA from 49 tissues and over 800 people, they found more than 8,600 irQTLs, many of which overlap with known disease-associated regions in the human genome.

While some genetic variants directly alter splicing, a process that removes intron from the precursor messenger RNA, the team also found strong evidence of genetic variants being able to indirectly give rise to irQTLs. Variants that change gene expression (eQTLs) — by altering transcription rate or RNA degradation rate — can shift the balance between spliced and unspliced RNAs, creating the appearance of an irQTL.

Scientists often think of splicing changes as leading to changes in steady state gene expression levels, but this study shows the two processes are intertwined to regulate phenotypic traits. Gene expression changes can indirectly reshape splicing balance, not because expression “controls splicing,” but because transcription rate and RNA degradation rate affect how many RNAs are available to be spliced and how long RNAs persist in the cell.

This feedback loop deepens researchers’ understanding of how DNA variants shape disease risk.

Why It Matters

An important area of biomedical research is discovering how differences in our DNA manifest as differences in our physical characteristics and disease susceptibility.

“The results of this study help identify the causes and consequences of molecular changes in RNA that arise from genetic differences between individuals,” said senior study author Yi Xing, PhD.

When our cells turn DNA into RNA, the initial precursor RNA molecules contain both exons (the protein-coding segments) and introns (extra non-coding segments usually removed). Cutting out introns and ligating exons — a process called splicing — creates the final instructions for building proteins. However, sometimes introns are retained. This “intron retention” can reduce the amount of usable RNA or even mark the RNA for destruction.

Intron retention has been shown to be involved in a wide range of biological processes such as development, rare disease, and cancer. Intron retention also has been suggested to be a source of tumor antigens for immunotherapy.

Who Conducted the Study

The study was led by Dr. Xing, Associate Chief Scientific Officer for Omics, Technology and Engineering and Director of the Center for Computational and Genomic Medicine. First author was Eddie Park, PhD, a Bioinformatics Scientist in the Xing Lab.

How They Did It

The team combined large-scale RNA and genetic data from the GTEx project with mathematical modeling of transcription, splicing, and degradation. Their novel model predicts how altering transcription or RNA degradation rates shifts the ratio of spliced versus unspliced RNAs. The researchers confirmed these predictions with experiments that stimulated transcription (inflammatory signaling) or slowed RNA degradation (by disrupting a microRNA-processing enzyme).

Quick Thoughts

“We usually think of splicing as contributing to expression differences,” Dr. Xing said. “The surprising insight here is that changes in transcription or degradation — which change expression — can also tip the balance between spliced and unspliced RNAs.”

What’s Next

The researchers aim to expand this work to single-cell data and disease tissues to clarify how these feedback loops operate in cancer, neurodevelopmental disorders, and immune diseases.

Where the Study Was Published

The findings were published in the American Journal of Human Genetics.