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Analysis and benchmarking of small and large genomic variants across tandem repeats

Nature Biotechnology (2024)Cite this article

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Abstract

Tandem repeats (TRs) are highly polymorphic in the human genome, have thousands of associated molecular traits and are linked to over 60 disease phenotypes. However, they are often excluded from at-scale studies because of challenges with variant calling and representation, as well as a lack of a genome-wide standard. Here, to promote the development of TR methods, we created a catalog of TR regions and explored TR properties across 86 haplotype-resolved long-read human assemblies. We curated variants from the Genome in a Bottle (GIAB) HG002 individual to create a TR dataset to benchmark existing and future TR analysis methods. We also present an improved variant comparison method that handles variants greater than 4 bp in length and varying allelic representation. The 8.1% of the genome covered by the TR catalog holds ~24.9% of variants per individual, including 124,728 small and 17,988 large variants for the GIAB HG002 ‘truth-set’ TR benchmark. We demonstrate the utility of this pipeline across short-read and long-read technologies.

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Fig. 1: Sequence contexts of TR catalog.
Fig. 2: Location, sequence and length properties of the benchmark’s TR regions.
Fig. 3: Benchmarking pipeline performance.
Fig. 4: Diversity of TRs over 156 haplotypes at CODIS and known pathogenic loci.

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Data availability

The TR catalog (version 1.2) can be found at https://zenodo.org/records/8387564 (ref. 74). Supplementary Table 4 holds the paths to the input assemblies used to create the pVCF. The pVCF can be found at https://zenodo.org/records/6975244 (ref. 76). The TandemRepeat benchmark is hosted at https://ftp-trace.ncbi.nlm.nih.gov/ReferenceSamples/giab/release/AshkenazimTrio/HG002_NA24385_son/TandemRepeats_v1.0 (ref. 83). Comparison VCFs from TR callers HipSTR, GangSTR, Medaka and TRGT and whole-genome VCFs from DeepVariant, BioGraph and Sniffles are available at https://zenodo.org/records/10724503 (ref. 84).

Code availability

All code created for this project is available under an open-source license. Analysis scripts for this project are hosted at https://github.com/ACEnglish/adotto/ (ref. 85). Truvari can be found at https://github.com/ACEnglish/truvari/ (ref. 86). Laytr can be found at https://github.com/ACEnglish/laytr/ (ref. 87). A lightweight version of the TR catalog creation process is available as a snakemake pipeline at https://github.com/nate-d-olson/adotto-smk (ref. 88). The overlap permutation tool regioners can be downloaded from https://github.com/ACEnglish/regioners (ref. 89).

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Acknowledgements

We would like to thank the GIAB community for constant support. We thank J. McDaniel for very helpful comments on the paper, M. Wykes and S. Nurk for assistance in processing Medaka results and V. Bafna for contributions to the TR catalog. A.C.E. and F.J.S. were supported by HHSN268201800002I, U01AG058589, 1U01HG011758-01 and 1UG3NS132105-01. H.Z.J. was supported by NIH/NHGRI R01HG010149. M.J.P.C. and B.G. were supported by R01HG011649 and 5U24HG007497, respectively. J.P. was supported in part by HG010149. Certain commercial equipment, instruments or materials are identified to adequately specify the experimental conditions or reported results. Such identification does not imply recommendation or endorsement by the National Institute of Standards and Technology, nor does it imply that the equipment, instruments or materials identified are necessarily the best available for the purpose.

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Author notes

  1. These authors contributed equally: Justin M. Zook, Fritz J. Sedlazeck.

Authors and Affiliations

  1. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA

    Adam C. English & Fritz J. Sedlazeck

  2. Pacific Biosciences of California, Menlo Park, CA, USA

    Egor Dolzhenko & Michael A. Eberle

  3. Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA, USA

    Helyaneh Ziaei Jam, Jonghun Park & Melissa Gymrek

  4. Oxford Nanopore Technologies, Inc., New York, NY, USA

    Sean K. McKenzie

  5. Material Measurement Laboratory, National Institute of Standards and Technology, Gaithersburg, MD, USA

    Nathan D. Olson, Justin Wagner & Justin M. Zook

  6. Applied and Translational Neurogenomics Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

    Wouter De Coster

  7. Applied and Translational Neurogenomics Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

    Wouter De Coster

  8. Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA

    Bida Gu & Mark J. P. Chaisson

  9. Department of Medicine, University of California, San Diego, La Jolla, CA, USA

    Melissa Gymrek

  10. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    Fritz J. Sedlazeck

  11. Department of Computer Science, Rice University, Houston, TX, USA

    Fritz J. Sedlazeck

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Contributions

A.C.E. performed data analysis and software development. E.D., H.Z.J., N.D.O., S.K.M., J.P., B.G., J.W., M.G. and M.J.P.C. contributed to testing and data processing. A.C.E., J.M.Z. and F.J.S. designed the study. A.C.E., E.D., H.Z.J., N.D.O., S.K.M., J.P., W.D.C., M.A.E., B.G., J.W., M.G., M.J.P.C., J.M.Z. and F.J.S. reviewed and edited the paper.

Corresponding authors

Correspondence to Adam C. English or Fritz J. Sedlazeck.

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Competing interests

F.J.S. receives research support from Illumina, Genentech, PacBio and ONT. E.D. and M.A.E. are employees and shareholders of PacBio. S.K.M. is an employee and shareholder of ONT. W.D.C. has received free consumables from ONT. The other authors declare no competing interests.

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Supplementary Information

Supplementary Figs. 1–7, Methods and Tables 1–3, 6 and 8–13.

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Supplementary Tables

Supplementary Tables 4 (assembly sources), 5 (assembly statistics), 7 (replicate tiers) and 14 (pathogenic and phenotypic TRs).

Supplementary Material 1

Laytr HTML report for TRGT.

Supplementary Material 2

Laytr HTML report for Sniffles.

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English, A.C., Dolzhenko, E., Ziaei Jam, H. et al. Analysis and benchmarking of small and large genomic variants across tandem repeats. Nat Biotechnol (2024). https://doi.org/10.1038/s41587-024-02225-z

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