Predicting nonsense-mediated mRNA decay from splicing events in sepsis using RNA-sequencing data

Area of Science:

• Molecular Biology
• Genetics
• Computational Biology

Background:

• Alternative splicing (AS) and nonsense-mediated mRNA decay (NMD) are crucial conserved mechanisms regulating gene expression.
• Understanding the interplay between AS and NMD is vital for comprehending cellular responses to disease states.

Purpose of the Study:

• To introduce and validate a novel computational pipeline (NMD pipeline) for analyzing AS events and predicting NMD rates.
• To investigate the role of AS and NMD in sepsis using whole-blood RNA-sequencing data from critically ill patients.

Main Methods:

• Development of the NMD pipeline based on AS data from Whippet.
• Analysis of deep RNA-sequencing data from sepsis patients, control groups, and survival groups.
• Statistical analysis for differential gene expression (adjusted P < 0.05, |log2 fold change| > 2) and AS (probability ≥0.9, |DeltaPsi| > 0.1).

Main Results:

• The NMD pipeline demonstrated a higher rate of NMD in sepsis and deceased patient groups compared to control and survived groups.
• Aberrant splicing, particularly a predominance of non-exon skipping events, was associated with disease severity and mortality in sepsis.
• The pipeline identified proteins potentially associated with sepsis.

Conclusions:

• The NMD pipeline is a valuable tool for studying AS-NMD interactions and differential gene expression.
• Aberrant splicing and elevated NMD rates may be significant indicators of altered physiology in critical illness like sepsis.
• This approach aids in uncovering disease-associated proteins and understanding disease mechanisms.