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<p>Accurate detection of low-frequency mutations is crucial for understanding viral evolution and tumorigenesis in humans, but is often confounded by technical artifacts introduced during library preparation and sequencing. We present GENOMICON-Seq, an end-to-end simulation tool that models both amplicon and whole exome sequencing (WES) workflows with realistic biological mutations and technical noise. GENOMICON-Seq inserts ground truth mutations, ranging from APOBEC3-like edits to COSMIC single base substitution signatures, before subjecting samples to simulated PCR errors, probe-capture enrichment, and Illumina-specific sequencing biases. By tracking each mutation’s origin (true or error-derived), researchers can pinpoint detection limits and optimize variant-calling thresholds. We illustrate GENOMICON-Seq’s versatility through study cases involving human papillomavirus (HPV) amplicon sequencing, highlighting the impacts of polymerase fidelity, viral copy number, and read depth on detecting low-frequency mutations. In parallel, WES simulations demonstrate how capture biases and varying allele frequencies affect somatic mutation calls. GENOMICON-Seq is thus a flexible, reproducible framework for assessing new protocols, benchmarking variant callers, and refining data analysis pipelines, ultimately reducing costly trial-and-error in the laboratory. The Docker-based package is freely available at <a href="https://github.com/Rounge-lab/GENOMICON-Seq">https://github.com/Rounge-lab/GENOMICON-Seq</a>.</p>

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GENOMICON-Seq enables realistic simulation of amplicon and exome sequencing for low-frequency mutation detection

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月2日

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  • Milan S. Stosic,
  • Jean-Marc Costanzi,
  • Ole Herman Ambur,
  • Trine B. Rounge

摘要

Accurate detection of low-frequency mutations is crucial for understanding viral evolution and tumorigenesis in humans, but is often confounded by technical artifacts introduced during library preparation and sequencing. We present GENOMICON-Seq, an end-to-end simulation tool that models both amplicon and whole exome sequencing (WES) workflows with realistic biological mutations and technical noise. GENOMICON-Seq inserts ground truth mutations, ranging from APOBEC3-like edits to COSMIC single base substitution signatures, before subjecting samples to simulated PCR errors, probe-capture enrichment, and Illumina-specific sequencing biases. By tracking each mutation’s origin (true or error-derived), researchers can pinpoint detection limits and optimize variant-calling thresholds. We illustrate GENOMICON-Seq’s versatility through study cases involving human papillomavirus (HPV) amplicon sequencing, highlighting the impacts of polymerase fidelity, viral copy number, and read depth on detecting low-frequency mutations. In parallel, WES simulations demonstrate how capture biases and varying allele frequencies affect somatic mutation calls. GENOMICON-Seq is thus a flexible, reproducible framework for assessing new protocols, benchmarking variant callers, and refining data analysis pipelines, ultimately reducing costly trial-and-error in the laboratory. The Docker-based package is freely available at https://github.com/Rounge-lab/GENOMICON-Seq.