REVIEW article
Front. Genet.
Sec. Human and Medical Genomics
Volume 16 - 2025 | doi: 10.3389/fgene.2025.1679660
This article is part of the Research TopicInsights in Human and Medical Genomics 2024View all 8 articles
Beyond single references: pangenome graphs and the future of genomic medicine
Provisionally accepted
- 1The Liggins Institute, The University of Auckland, Auckland, Auckland, New Zealand
- 2Department of Biochemistry, University of Otago, Dunedin, New Zealand
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Genomic medicine relies on single reference genomes that miss crucial genetic diversity, creating diagnostic gaps that disproportionately affect underrepresented populations. Pangenome graphs, collections of diverse genomes represented as interconnected genetic paths, offer a powerful alternative to the standard reference genome approach. Pangenome-based approaches capture the spectrum of human variation, dramatically improving how we detect complex structural variants, reconstruct haplotypes, and reduce bias in genetic studies. Projects like the Human Pangenome Reference Consortium have identified hundreds of megabases of missing genetic diversity, leading to remarkable improvements in variant detection across different populations. Yet, as pangenomes grow larger and computationally complex, they become more challenging to interpret clinically, creating a trade-off between comprehensiveness and usability. This review discusses the technical and conceptual advances enabling clinical applications of pangenomes in rare disease diagnosis. Realizing the future potential of pangenome graphs in genomic medicine will require innovative implementation strategies, thorough clinical testing, and user-friendly approaches.
Keywords: clinical diagnosis, genetic diversity, genome assembly, Haplotypes, long-readsequencing, Pangenome graphs, reference genomes
Received: 04 Aug 2025; Accepted: 08 Sep 2025.
Copyright: © 2025 Nyaga, Zaied, Silander, Black and O'Sullivan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Denis M Nyaga, The Liggins Institute, The University of Auckland, Auckland, Auckland, New Zealand
Justin Martin O'Sullivan, The Liggins Institute, The University of Auckland, Auckland, Auckland, New Zealand
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