Straglr: Discovering and Genotyping Tandem Repeat Expansions Using Whole Genome Long-read Sequences

Overview

Journal Genome Biol

Specialties Biology
Genetics

Date 2021 Aug 14

PMID 34389037

Citations 31

Authors

Readman Chiu

Indhu-Shree Rajan-Babu

Jan M Friedman

Inanc Birol

Affiliations

Soon will be listed here.

Abstract

Tandem repeat (TR) expansion is the underlying cause of over 40 neurological disorders. Long-read sequencing offers an exciting avenue over conventional technologies for detecting TR expansions. Here, we present Straglr, a robust software tool for both targeted genotyping and novel expansion detection from long-read alignments. We benchmark Straglr using various simulations, targeted genotyping data of cell lines carrying expansions of known diseases, and whole genome sequencing data with chromosome-scale assembly. Our results suggest that Straglr may be useful for investigating disease-associated TR expansions using long-read sequencing.

Citing Articles

A detailed analysis of second and third-generation sequencing approaches for accurate length determination of short tandem repeats and homopolymers.

Jeanjean S, Shen Y, Hardy L, Daunay A, Delepine M, Gerber Z Nucleic Acids Res. 2025; 53(5).

PMID: 40036507 PMC: 11878640. DOI: 10.1093/nar/gkaf131.

Mosaicism in Short Tandem Repeat Disorders: A Clinical Perspective.

Doss R, Lopez-Ignacio S, Dischler A, Hiatt L, Dashnow H, Breuss M Genes (Basel). 2025; 16(2).

PMID: 40004546 PMC: 11855715. DOI: 10.3390/genes16020216.

The implementation of genome sequencing in rare genetic diseases diagnosis: a pilot study from the Hong Kong genome project.

Lam W, Lau C, Luk H, Au L, Chan G, Chan W Lancet Reg Health West Pac. 2025; 55:101473.

PMID: 39944418 PMC: 11814671. DOI: 10.1016/j.lanwpc.2025.101473.

SUMMER: an integrated nanopore sequencing pipeline for variants detection and clinical annotation on the human genome.

Li R, Chu H, Gao K, Luo H, Jiang Y Funct Integr Genomics. 2025; 25(1):21.

PMID: 39836277 PMC: 11750885. DOI: 10.1007/s10142-025-01534-z.

Nanopore sequencing as a novel method of characterising anorexia nervosa risk loci.

Berthold N, Gaudieri S, Hood S, Tschochner M, Miller A, Jordan J BMC Genomics. 2024; 25(1):1262.

PMID: 39741260 PMC: 11687000. DOI: 10.1186/s12864-024-11172-7.

References

Paulson H . Repeat expansion diseases. Handb Clin Neurol. 2018; 147:105-123. PMC: 6485936. DOI: 10.1016/B978-0-444-63233-3.00009-9. View

McFarland K, Liu J, Landrian I, Gao R, Sarkar P, Raskin S . Paradoxical effects of repeat interruptions on spinocerebellar ataxia type 10 expansions and repeat instability. Eur J Hum Genet. 2013; 21(11):1272-6. PMC: 3798839. DOI: 10.1038/ejhg.2013.32. View

Benson G . Tandem repeats finder: a program to analyze DNA sequences. Nucleic Acids Res. 1998; 27(2):573-80. PMC: 148217. DOI: 10.1093/nar/27.2.573. View

Yang C, Chu J, Warren R, Birol I . NanoSim: nanopore sequence read simulator based on statistical characterization. Gigascience. 2017; 6(4):1-6. PMC: 5530317. DOI: 10.1093/gigascience/gix010. View

Corbett M, Kroes T, Veneziano L, Bennett M, Florian R, Schneider A . Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2. Nat Commun. 2019; 10(1):4920. PMC: 6820779. DOI: 10.1038/s41467-019-12671-y. View

Trost B, Engchuan W, Nguyen C, Thiruvahindrapuram B, Dolzhenko E, Backstrom I . Genome-wide detection of tandem DNA repeats that are expanded in autism. Nature. 2020; 586(7827):80-86. PMC: 9348607. DOI: 10.1038/s41586-020-2579-z. View

Kobayashi H, Abe K, Matsuura T, Ikeda Y, Hitomi T, Akechi Y . Expansion of intronic GGCCTG hexanucleotide repeat in NOP56 causes SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement. Am J Hum Genet. 2011; 89(1):121-30. PMC: 3135815. DOI: 10.1016/j.ajhg.2011.05.015. View

Teng J, Yeung M, Chan E, Jia L, Lin C, Huang Y . PacBio But Not Illumina Technology Can Achieve Fast, Accurate and Complete Closure of the High GC, Complex Two-Chromosome Genome. Front Microbiol. 2017; 8:1448. PMC: 5539568. DOI: 10.3389/fmicb.2017.01448. View

Lalioti M, Scott H, Antonarakis S . Altered spacing of promoter elements due to the dodecamer repeat expansion contributes to reduced expression of the cystatin B gene in EPM1. Hum Mol Genet. 1999; 8(9):1791-8. DOI: 10.1093/hmg/8.9.1791. View

10.

Mitsuhashi S, Frith M, Mizuguchi T, Miyatake S, Toyota T, Adachi H . Tandem-genotypes: robust detection of tandem repeat expansions from long DNA reads. Genome Biol. 2019; 20(1):58. PMC: 6425644. DOI: 10.1186/s13059-019-1667-6. View

11.

Logsdon G, Vollger M, Eichler E . Long-read human genome sequencing and its applications. Nat Rev Genet. 2020; 21(10):597-614. PMC: 7877196. DOI: 10.1038/s41576-020-0236-x. View

12.

Pesovic J, Peric S, Brkusanin M, Brajuskovic G, Rakocevic-Stojanovic V, Savic-Pavicevic D . Repeat Interruptions Modify Age at Onset in Myotonic Dystrophy Type 1 by Stabilizing Expansions in Somatic Cells. Front Genet. 2018; 9:601. PMC: 6278776. DOI: 10.3389/fgene.2018.00601. View

13.

Mantere T, Kersten S, Hoischen A . Long-Read Sequencing Emerging in Medical Genetics. Front Genet. 2019; 10:426. PMC: 6514244. DOI: 10.3389/fgene.2019.00426. View

14.

Duitama J, Zablotskaya A, Gemayel R, Jansen A, Belet S, Vermeesch J . Large-scale analysis of tandem repeat variability in the human genome. Nucleic Acids Res. 2014; 42(9):5728-41. PMC: 4027155. DOI: 10.1093/nar/gku212. View

15.

Hoijer I, Johansson J, Gudmundsson S, Chin C, Bunikis I, Haggqvist S . Amplification-free long-read sequencing reveals unforeseen CRISPR-Cas9 off-target activity. Genome Biol. 2020; 21(1):290. PMC: 7706270. DOI: 10.1186/s13059-020-02206-w. View

16.

Ebler J, Haukness M, Pesout T, Marschall T, Paten B . Haplotype-aware diplotyping from noisy long reads. Genome Biol. 2019; 20(1):116. PMC: 6547545. DOI: 10.1186/s13059-019-1709-0. View

17.

Dobkin C, Nolin S, Cohen I, Sudhalter V, Bialer M, Ding X . Tissue differences in fragile X mosaics: mosaicism in blood cells may differ greatly from skin. Am J Med Genet. 1996; 64(2):296-301. DOI: 10.1002/(SICI)1096-8628(19960809)64:2<296::AID-AJMG13>3.0.CO;2-A. View

18.

Liu Q, Zhang P, Wang D, Gu W, Wang K . Interrogating the "unsequenceable" genomic trinucleotide repeat disorders by long-read sequencing. Genome Med. 2017; 9(1):65. PMC: 5514472. DOI: 10.1186/s13073-017-0456-7. View

19.

Harper P, Harley H, Reardon W, Shaw D . Anticipation in myotonic dystrophy: new light on an old problem. Am J Hum Genet. 1992; 51(1):10-6. PMC: 1682874. View

20.

Mitsuhashi S, Matsumoto N . Long-read sequencing for rare human genetic diseases. J Hum Genet. 2019; 65(1):11-19. DOI: 10.1038/s10038-019-0671-8. View