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Sequence composition changes in short tandem repeats: heterogeneity, detection, mechanisms and clinical implications

Nature Reviews Genetics (2024)Cite this article

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Abstract

Short tandem repeats (STRs) are a class of repetitive elements, composed of tandem arrays of 1–6 base pair sequence motifs, that comprise a substantial fraction of the human genome. STR expansions can cause a wide range of neurological and neuromuscular conditions, known as repeat expansion disorders, whose age of onset, severity, penetrance and/or clinical phenotype are influenced by the length of the repeats and their sequence composition. The presence of non-canonical motifs, depending on the type, frequency and position within the repeat tract, can alter clinical outcomes by modifying somatic and intergenerational repeat stability, gene expression and mutant transcript-mediated and/or protein-mediated toxicities. Here, we review the diverse structural conformations of repeat expansions, technological advances for the characterization of changes in sequence composition, their clinical correlations and the impact on disease mechanisms.

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Fig. 1: STR alleles and representative sequence configurations.
Fig. 2: Structural heterogeneity of representative FMR1, ATXN1, ATXN8OS/ATXN8, SAMD12 and RFC1 repeats.
Fig. 3: Detecting STR sequence composition changes with RP-PCR, optical genome mapping, short-read sequencing and long-read sequencing.
Fig. 4: Effect of sequence composition changes on repeat DNA structure, methylation, stability and gene expression.
Fig. 5: Effect of sequence composition changes on repeat mRNA-mediated and protein-mediated toxicities.

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Acknowledgements

The authors’ work is supported by the Canadian Institutes of Health Research (CIHR) Project Grant (PJT-169074) to J.M.F. and I.-S.R.-B. I.-S.R.-B. is funded by the CIHR Research Excellence, Diversity, and Independence (REDI) Early Career Transition Award (DI2-190730). The authors thank the reviewers, S. Vij, G. L. Sequiera, C. Guimond, and S. Adam for helpful comments on the manuscript.

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Authors and Affiliations

  1. Department of Medical Genetics, The University of British Columbia, and Children’s & Women’s Hospital, Vancouver, British Columbia, Canada

    Indhu-Shree Rajan-Babu & Jan M. Friedman

  2. Pacific Biosciences, Menlo Park, CA, USA

    Egor Dolzhenko & Michael A. Eberle

  3. BC Children’s Hospital Research Institute, Vancouver, British Columbia, Canada

    Jan M. Friedman

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I.-S.R.-B. and E.D. researched the literature and wrote the article. I.-S.R.-B. and J.M.F. provided substantial contributions to discussions of the content. I.-S.R.-B., M.A.E. and J.M.F. reviewed and/or edited the manuscript before submission.

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Glossary

Dominant-negative

Interference of mutant protein with the cellular functions of wild-type protein.

Gain-of-function

Repeat expansions lead to the production of expanded mRNA and/or protein with toxic properties.

Genetic anticipation

Earlier onset and more severe presentation of repeat expansion disorders with each passing generation.

Loss-of-function

Repeat expansions lead to the generation of non-functional gene product.

Non-reference expansions

Expansion of a previously unknown or unannotated repeat motif.

Paired-end reads

Reads (each 150–250 base pairs in length) generated from both ends of the DNA fragments (approximately 350–650 base pairs) in next-generation sequencing.

Repeat-associated non-AUG (RAN) translation

Translation initiated outside of the canonical AUG start codon that produces proteins corresponding to the different STR reading frames.

Soft-clipped

5′ and/or 3′ ends of reads that do not map to the reference sequence.

Somatic instability

Cell-specific or tissue-specific repeat length variations that are driven by age.

STR expansions

Repeat length at a disease-associated STR locus exceeds the known pathogenicity threshold.

STR genotyping

Determination of the number of repeat motifs in the STR locus.

Trans-acting genetic modifiers

Genetic variants that occur outside the implicated STR sequence and modify repeat expansion disorders.

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Rajan-Babu, IS., Dolzhenko, E., Eberle, M.A. et al. Sequence composition changes in short tandem repeats: heterogeneity, detection, mechanisms and clinical implications. Nat Rev Genet (2024). https://doi.org/10.1038/s41576-024-00696-z

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