Somatic mutations from pathogenesis to forensic medicine: opportunities, challenges, and future directions

Somatic mutations, post-zygotic genetic alterations that accumulate throughout development and aging, generate intra-individual mosaicism that has traditionally been examined within oncology and developmental biology, but rarely contextualized for forensic practice. This review provides a critical forensic-centered synthesis of current biological evidence and sequencing technologies to evaluate whether, when, and how somatic variation may offer actionable value beyond conventional short tandem repeat (STR) profiling. Drawing on comparative analysis of international research, we examine how somatic mutations differ fundamentally from germline markers in terms of allele fraction, tissue specificity, and inheritance assumptions, and assess the implications of these properties for evidence interpretation, statistical evaluation, and courtroom robustness. We critically evaluate emerging ultra-deep and error-corrected sequencing strategies, highlighting where methodological advances genuinely overcome technical barriers, and where limitations such as sequencing artefacts, clonal heterogeneity, and interpretive ambiguity remain prohibitive for routine use. Rather than proposing somatic mutations as replacements for STRs, this review defines specific forensic scenarios, severely degraded samples, radiotherapy-damaged DNA, tissue-of-origin inference, and complex mixtures, where somatic variants may function as complementary, high-resolution markers. By integrating biological mechanisms, analytical constraints, and forensic validation standards, this work advances a practical framework for future research and responsible translation of somatic mutation analysis into forensic science.