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

Adam C English; Egor Dolzhenko; Helyaneh Ziaei Jam; Sean K McKenzie; Nathan D Olson; Wouter De Coster; Jonghun Park; Bida Gu; Justin Wagner; Michael A Eberle; Melissa Gymrek; Mark J P Chaisson; Justin M Zook; Fritz J Sedlazeck

doi:10.1038/s41587-024-02225-z

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

Nat Biotechnol. 2024 Apr 26. doi: 10.1038/s41587-024-02225-z. Online ahead of print.

Authors

Adam C English¹, Egor Dolzhenko², Helyaneh Ziaei Jam³, Sean K McKenzie⁴, Nathan D Olson⁵, Wouter De Coster^{6

7}, Jonghun Park³, Bida Gu⁸, Justin Wagner⁵, Michael A Eberle², Melissa Gymrek^{3

9}, Mark J P Chaisson⁸, Justin M Zook^#⁵, Fritz J Sedlazeck^#^{10

11

12}

Affiliations

¹ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA. adam.english@bcm.edu.
² Pacific Biosciences of California, Menlo Park, CA, USA.
³ Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA, USA.
⁴ Oxford Nanopore Technologies, Inc., New York, NY, USA.
⁵ Material Measurement Laboratory, National Institute of Standards and Technology, Gaithersburg, MD, USA.
⁶ Applied and Translational Neurogenomics Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
⁷ Applied and Translational Neurogenomics Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
⁸ Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA.
⁹ Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
¹⁰ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA. fritz.sedlazeck@bcm.edu.
¹¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. fritz.sedlazeck@bcm.edu.
¹² Department of Computer Science, Rice University, Houston, TX, USA. fritz.sedlazeck@bcm.edu.

^# Contributed equally.

PMID: 38671154
DOI: 10.1038/s41587-024-02225-z

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.