De Roeck A, De Coster W, Bossaerts L, Cacace R, De Pooter T, Van Dongen J, D'Hert S, De Rijk P, Strazisar M, Van Broeckhoven C, Sleegers K
Technological limitations have hindered the large-scale genetic investigation of tandem repeats in disease. We show that long-read sequencing with a single Oxford Nanopore Technologies PromethION flow cell per individual achieves 30× human genome coverage and enables accurate assessment of tandem repeats including the 10,000-bp Alzheimer's disease-associated ABCA7 VNTR. The Guppy "flip-flop" base caller and tandem-genotypes tandem repeat caller are efficient for large-scale tandem repeat assessment, but base calling and alignment challenges persist. We present NanoSatellite, which analyzes tandem repeats directly on electric current data and improves calling of GC-rich tandem repeats, expanded alleles, and motif interruptions.