A comprehensive assessment of tandem repeat genotyping methods for Nanopore long-read genomes

@article{aliyev2026comprehensive,
  title = {{A comprehensive assessment of tandem repeat genotyping methods for Nanopore long-read genomes}},
  author = {Elbay Aliyev and Akshay Avvaru and Wouter De Coster and Garrison M. Arner and Denis M. Nyaga and Sophia B. Gibson and Ben Weisburd and Bida Gu and Claudia Gonzaga-Jauregui and Elbay Aliyev and Elbay Aliyev and Akshay Avvaru and Wouter De Coster and Sophia B. Gibson and Claudia Gonzaga-Jauregui and Jonas A. Gustafson and Joy Goffena and Wayne E. Clarke and Evan E. Eichler and Theodore M. Nelson and Anthony A. Snead and Xinxia Peng and Marcelo Ayllon and Nikhita Damaraju and Miranda PG Zalusky and Kendra Hoekzema and David Twesigomwe and Lei Yang and Phillip A. Richmond and Nathan D. Olson and Andrea Guarracino and Qiuhui Li and Angela L. Miller and Zachary B. Anderson and Sophie HR Storz and Anna O. Basile and André Corvelo and Catherine E. Reeves and Adrienne Helland and Rajeeva Lochan Musunuri and Mahler Revsine and Karynne E. Patterson and Cate R. Paschal and Christina Zakarian and Sara Goodwin and Tanner D. Jensen and Esther Robb and W. Richard McCombie and Fritz J. Sedlazeck and Justin M. Zook and Stephen B. Montgomery and Erik Garrison and Mikhail Kolmogorov and Michael C. Schatz and Richard N. McLaughlin and Michael C. Zody and Matthew Loose and Miten Jain and Rob Patro and Caitlin N. Jacques},
  journal = {Genome Biology},
  year = {2026},
  month = aug,
  doi = {10.1186/s13059-026-04210-y},
  url = {https://doi.org/10.1186/s13059-026-04210-y},
  note = {CC BY-NC-ND 4.0},
}

TY  - JOUR
TI  - A comprehensive assessment of tandem repeat genotyping methods for Nanopore long-read genomes
AU  - Elbay Aliyev
AU  - Akshay Avvaru
AU  - Wouter De Coster
AU  - Garrison M. Arner
AU  - Denis M. Nyaga
AU  - Sophia B. Gibson
AU  - Ben Weisburd
AU  - Bida Gu
AU  - Claudia Gonzaga-Jauregui
AU  - Elbay Aliyev
AU  - Elbay Aliyev
AU  - Akshay Avvaru
AU  - Wouter De Coster
AU  - Sophia B. Gibson
AU  - Claudia Gonzaga-Jauregui
AU  - Jonas A. Gustafson
AU  - Joy Goffena
AU  - Wayne E. Clarke
AU  - Evan E. Eichler
AU  - Theodore M. Nelson
AU  - Anthony A. Snead
AU  - Xinxia Peng
AU  - Marcelo Ayllon
AU  - Nikhita Damaraju
AU  - Miranda PG Zalusky
AU  - Kendra Hoekzema
AU  - David Twesigomwe
AU  - Lei Yang
AU  - Phillip A. Richmond
AU  - Nathan D. Olson
AU  - Andrea Guarracino
AU  - Qiuhui Li
AU  - Angela L. Miller
AU  - Zachary B. Anderson
AU  - Sophie HR Storz
AU  - Anna O. Basile
AU  - André Corvelo
AU  - Catherine E. Reeves
AU  - Adrienne Helland
AU  - Rajeeva Lochan Musunuri
AU  - Mahler Revsine
AU  - Karynne E. Patterson
AU  - Cate R. Paschal
AU  - Christina Zakarian
AU  - Sara Goodwin
AU  - Tanner D. Jensen
AU  - Esther Robb
AU  - W. Richard McCombie
AU  - Fritz J. Sedlazeck
AU  - Justin M. Zook
AU  - Stephen B. Montgomery
AU  - Erik Garrison
AU  - Mikhail Kolmogorov
AU  - Michael C. Schatz
AU  - Richard N. McLaughlin
AU  - Michael C. Zody
AU  - Matthew Loose
AU  - Miten Jain
AU  - Rob Patro
AU  - Caitlin N. Jacques
PY  - 2026
DA  - 2026/08/04
JO  - Genome Biology
DO  - 10.1186/s13059-026-04210-y
UR  - https://doi.org/10.1186/s13059-026-04210-y
AB  - Background: Tandem repeats play critical roles in human disease and phenotypic diversity but are among the most challenging classes of genomic variation to measure accurately. Long-read sequencing has the potential to accurately characterize long and complex tandem repeats. While an increasing number of genotyping methods are available, no systematic effort has been undertaken to evaluate their usability, accuracy, and performance across motifs and allele lengths.  Results: We reviewed 25 bioinformatic tools and selected seven actively maintained methods for benchmarking using publicly available Oxford Nanopore genome sequencing data from more than 100 individuals. We assessed performance across 43,009 genome-wide tandem repeat loci using four complementary strategies: concordance with haplotype-resolved Human Pangenome Reference Consortium assemblies, Mendelian consistency, cross-tool consistency, and sensitivity to molecularly confirmed pathogenic expansions. Most methods achieved high concordance with assemblies, with higher accuracy using R10 Oxford Nanopore pore chemistry than older R9 chemistry. Accuracy declined with increasing allele length, and most tools performed worse on homopolymers, heterozygous loci, and alleles differing from the reference genome. Assembly concordance and Mendelian consistency did not predict sensitivity to pathogenic expansions, suggesting that these metrics captured distinct aspects of performance.  Conclusions: No single genotyper performs consistently best across all assessments, but strong contenders emerge in each. Our results demonstrate that length accuracy overestimates tandem repeat genotyping performance. Sequence-level benchmarking is essential for selecting tools best-suited for population studies and clinical diagnostics. This work provides practical guidance for tool selection and highlights key priorities for future long-read tandem repeat genotyping method development.  Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13059-026-04210-y.
SN  - 1474-7596
SN  - 1474-760X
ER  -