indelinside

Reanalyzing Somatic Indels on Locally Personalized Genomes for Indel Signature Analysis

indelinside is a command-line tool that resolves mapping ambiguities for indel signature analysis by realigning variants against a locally personalized germline background.

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Core Workflow

1. Harmonization Unifies inconsistent indel representations across different variant callers.

2. Local Haplotype Assembly Constructs local diploid germline haplotypes (hap1 & hap2) from the normal BAM file, alongside the somatic indel haplotype (hap0) from the tumor BAM file.

3. Origin Inference Determines which germline haplotype (hap1 or hap2) the somatic indel was derived from.

4. Personalized Realignment Realigns the somatic haplotype (hap0) to its inferred parent germline background. Depending on the context, the indel may be personalized to a substitute, a different indel class, or a complex indel—delivering a polished input for downstream signature analysis.

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Installation

indelinside is distributed as a command-line utility within the variantPost package:

pip install variantpost

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Usage

The pipeline consists of two steps: local personalization of somatic indels followed by feature extraction into an indel signature matrix.

Step 1: Personalize Alignments

Input BAM files and arbitrary numbers of VCFs from different variant callers into personalize. Variants are automatically consolidated, harmonized, and realigned against inferred germline haplotypes.

indelinside personalize \
  -t tumor.wgs.bam \
  -n normal.wgs.bam \
  -r reference.fa \
  -v caller_a.vcf caller_b.vcf caller_c.vcf \
  -o indelinside.out.txt \
  -p 12 # for faster analysis

Step 2: Generate Indel Signature Matrix

Generate a COSMIC-compatible indel signature matrix from the personalized output. Filter consensus calls across callers using -c / --consensus_level. -c N selects indels called by N or more callers (-c 1 is the union of all callers).

indelinside matrix \
  -i indelinside.out.txt \
  -c 2 \
  --sample_name my_sample

The output matrix can be used as input for external signature analysis tools such as SigProfilerAssignment.

from SigProfilerAssignment import Analyzer

Analyzer.cosmic_fit(
    samples="my_sample.indel_83_matrix.txt",  # COSMIC-compatible 83-indel channel matrix  
    output="/path/to/output_dir",
    input_type="matrix", 
    context_type="ID",  
    collapse_to_SBS96=False,
    signature_database="/path/to/COSMIC_signature_database" # restrict IDs as needed
)

Acknowledgements

variantPost internally uses the following packages. I thank the developers for making them freely available.

• SSW Library
• fastahack