Allele-specific alternative splicing and its functional genetic variants in human tissues

Area of Science:

• Molecular Biology
• Genetics
• Bioinformatics

Background:

• Alternative splicing, a key RNA processing mechanism, influences human gene expression, disease, and phenotypic diversity.
• Splicing regulation involves complex interactions between cis-regulatory elements and trans-acting factors.
• Genetic variants can alter cis-regulation of splicing, impacting splicing outcomes and disease mechanisms.

Purpose of the Study:

• To identify and characterize genetically modulated alternative splicing (GMAS) events using large-scale datasets.
• To develop a novel method for predicting functional splicing-altering genetic variants.
• To investigate the link between GMAS, genetic variants, and human traits/diseases.

Main Methods:

• Utilized the Genotype-Tissue Expression (GTEx) project data to identify allele-specific splicing events.
• Developed a genotype-phenotype concordance model to predict functional splicing-altering variants.
• Performed experimental validations to confirm predicted functional variants.

Main Results:

• GMAS events exhibit significant sharing across human tissues and individuals, underscoring their genetic basis.
• Genetic background influences GMAS patterns comparably to tissue-specific splicing mechanisms.
• The developed method predicted over 1000 functional variants, many potentially affecting RNA-protein interactions, with enrichment in disease-relevant tissues.

Conclusions:

• Genetically driven alternative splicing is a widespread phenomenon in human tissues.
• The developed prediction method effectively identifies functional splicing variants.
• GMAS provides insights into the genetic architecture of human traits and diseases.