RT Journal
A1 Tesi, Niccoló
A1 Salazar, Alex
A1 Zhang, Yaran
A1 van der Lee, Sven
A1 Hulsman, Marc
A1 Knoop, Lydian
A1 Wijesekera, Sanduni
A1 Krizova, Jana
A1 Schneider, Anne-Fleur
A1 Pennings, Maartje
A1 Sleegers, Kristel
A1 Kamsteeg, Erik-Jan
A1 Reinders, Marcel
A1 Holstege, Henne
T1 Characterizing tandem repeat complexities across long-read sequencing platforms with TREAT and otter
JF Genome Research 
JO Genome Research 
YR 2024 
FD November 01 
VO 34 
IS 11 
SP 1942 
OP 1953 
DO 10.1101/gr.279351.124 
UL http://genome.cshlp.org/content/34/11/1942.abstract 
AB Tandem repeats (TRs) play important roles in genomic variation and disease risk in humans. Long-read sequencing allows for the accurate characterization of TRs; however, the underlying bioinformatics perspectives remain challenging. We present otter and TREAT: otter is a fast targeted local assembler, cross-compatible across different sequencing platforms. It is integrated in TREAT, an end-to-end workflow for TR characterization, visualization, and analysis across multiple genomes. In a comparison with existing tools based on long-read sequencing data from both Oxford Nanopore Technology (ONT, Simplex and Duplex) and Pacific Bioscience (PacBio, Sequel II and Revio), otter and TREAT achieve state-of-the-art genotyping and motif characterization accuracy. Applied to clinically relevant TRs, TREAT/otter significantly identify individuals with pathogenic TR expansions. When applied to a case-control setting, we replicate previously reported associations of TRs with Alzheimer's disease, including those near or within APOC1 (P = 2.63 × 10−9), SPI1 (P = 6.5 × 10−3), and ABCA7 (P = 0.04) genes. Finally, we use TREAT/otter to systematically evaluate potential biases when genotyping TRs using diverse ONT and PacBio long-read sequencing data sets. We show that, in rare cases (0.06%), long-read sequencing from coverage drops in TRs, including the disease-associated TRs in ABCA7 and RFC1 genes. Such coverage drops can lead to TR misgenotyping, hampering the accurate characterization of TR alleles. Taken together, our tools can accurately genotype TRs across different sequencing technologies and with minimal requirements, allowing end-to-end analysis and comparisons of TRs in human genomes, with broad applications in research and clinical fields.