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Sequencing and characterizing short tandem repeats in the human genome

Nature Reviews Genetics (2024)Cite this article

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Abstract

Short tandem repeats (STRs) are highly polymorphic sequences throughout the human genome that are composed of repeated copies of a 1–6-bp motif. Over 1 million variable STR loci are known, some of which regulate gene expression and influence complex traits, such as height. Moreover, variants in at least 60 STR loci cause genetic disorders, including Huntington disease and fragile X syndrome. Accurately identifying and genotyping STR variants is challenging, in particular mapping short reads to repetitive regions and inferring expanded repeat lengths. Recent advances in sequencing technology and computational tools for STR genotyping from sequencing data promise to help overcome this challenge and solve genetically unresolved cases and the ‘missing heritability’ of polygenic traits. Here, we compare STR genotyping methods, analytical tools and their applications to understand the effect of STR variation on health and disease. We identify emergent opportunities to refine genotyping and quality-control approaches as well as to integrate STRs into variant-calling workflows and large cohort analyses.

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Fig. 1: Causes and consequences of short tandem repeat variation.
Fig. 2: Timeline of developments in short tandem repeat genotyping tools and applications.
Fig. 3: Methods overview of short-read short tandem repeat callers.
Fig. 4: Short tandem repeat association analysis.

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Acknowledgements

The authors thank H. Nicholas for substantial contributions to editing the manuscript and E. Dolzhenko, L. Hiatt, M.Goldberg, A. Quinlan and B. Weisburd for valuable discussions.

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Authors and Affiliations

  1. Centre for Population Genomics, Garvan Institute of Medical Research, Sydney, New South Wales, Australia

    Hope A. Tanudisastro & Daniel G. MacArthur

  2. Centre for Population Genomics, Murdoch Children’s Research Institute, Melbourne, Victoria, Australia

    Hope A. Tanudisastro & Daniel G. MacArthur

  3. Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia

    Hope A. Tanudisastro, Ira W. Deveson & Daniel G. MacArthur

  4. Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia

    Hope A. Tanudisastro

  5. Genomics and Inherited Disease Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia

    Ira W. Deveson

  6. Department of Human Genetics, University of Utah, Salt Lake City, UT, USA

    Harriet Dashnow

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Contributions

H.A.T. and H.D. researched the literature. All authors contributed substantially to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Harriet Dashnow or Daniel G. MacArthur.

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Competing interests

D.G.M. is a paid adviser to GlaxoSmithKline, Insitro, Variant Bio and Overtone Therapeutics and has received research support from AbbVie, Astellas, Biogen, BioMarin, Eisai, Merck, Pfizer and Sanofi-Genzyme; none of these activities are related to the work presented here. I.W.D. has previously received travel and accommodation expenses from ONT to speak at conferences. I.W.D. has a paid consultant role with Sequin Pty Ltd. H.A.T and H.D. declare no competing interests.

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Nature Reviews Genetics thanks Melissa Gymrek, who co-reviewed with Helyaneh Ziaei Jam; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Glossary

Abandonware

Software that is no longer maintained by its developer.

Allelic dropout

One of the two alleles at a locus is undetected, leading to a false homozygous genotype.

Graph genome

Representation of the genome involving graph structures, including nodes and branches.

Mate pairs

Paired reads obtained from opposite ends of a DNA fragment.

Mismatch error rate

Rate of insertion, deletion or substitution errors.

Motif structure

Repetitive sequence pattern that characterizes an STR locus.

Novel STR

An STR locus that is absent from the reference genome or has a motif or coordinates that differ from those in the reference genome.

PCR stutter artefacts

A distribution of erroneous STR allele sizes generated during PCR amplification owing to DNA polymerase slippage.

Regular expressions

Character sequence pattern convention used for efficient sequence matching.

Variable number tandem repeat

A repetitive sequence in the genome consisting of a repeating motif greater than 6 bp.

Variant-calling pipelines

Computational workflows used to identify genetic variants from sequencing data.

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Tanudisastro, H.A., Deveson, I.W., Dashnow, H. et al. Sequencing and characterizing short tandem repeats in the human genome. Nat Rev Genet (2024). https://doi.org/10.1038/s41576-024-00692-3

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