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Beta-Binomial Model for the Detection of Rare Mutations in Pooled Next-Generation Sequencing Experiments
Audrone Jakaitiene1, Mariano Avino2, Mario Rosario Guarracino2
11 Bioinformatics and Biostatistics Center, Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University , Vilnius, Lithuania .
Summary
Next-generation sequencing (NGS) cost savings are achieved by pooling samples. A novel beta-binomial model accurately detects rare mutations in pooled data, identifying seven novel SNPs linked to neuromuscular disorders.
Area of Science:
- Genomics and Bioinformatics
- Genetic Mutation Detection
- Next-Generation Sequencing (NGS)
Background:
- Next-generation sequencing (NGS) remains costly for large-scale human studies.
- Pooled sequencing offers a cost-saving strategy by analyzing multiple samples simultaneously.
- Existing single-nucleotide polymorphism (SNP) detection software varies in sensitivity and specificity.
Purpose of the Study:
- To develop and validate a cost-effective method for rare mutation detection in pooled NGS data.
- To propose a multireference framework utilizing a beta-binomial model for pooled samples.
- To assess the model's accuracy in identifying rare variants, particularly in the context of neuromuscular disorders (NMD).
Main Methods:
- Application of a beta-binomial model for analyzing untagged pooled NGS data.
- Development of a multireference framework capable of specific variant detection in pooled samples.
- Comparative analysis against established SNP callers: GATK, CRISP, SNVer, and FreeBayes.
Main Results:
- The multireference approach with the beta-binomial model demonstrated high accuracy in predicting rare mutations at a 0.01 fraction.
- The model showed strong concordance with existing software for mutation detection.
- Seven novel SNPs were identified, with functional analysis revealing enrichment in terms related to locomotion and musculature, suggesting NMD relevance.
Conclusions:
- The beta-binomial based multireference framework is an accurate and cost-effective tool for rare mutation discovery in pooled NGS experiments.
- This approach holds significant potential for genetic studies of complex diseases like NMD where large cohorts are required.
- The identified novel SNPs provide a basis for further investigation into the genetic underpinnings of neuromuscular disorders.
