Accurate repeat expansion genotyping from whole-genome and real-time targeted nanopore sequencing with Mahi-mahi

Tandem repeat genotyping from nanopore reads: allele-level length, motif composition, interruptions and flags for basecalling artifacts

Mahi-mahi is a tandem repeat genotyper designed for nanopore reads that reports allele-level repeat length, motif composition, interruptions and read-level flags for systematic basecalling artifacts. Across six Genome in a Bottle samples, whole-genome and adaptive sampling data agreed within one repeat unit for 829 of 832 alleles, and 95.6% of compared alleles agreed with orthogonal HiFi data. In 245 samples from the 1000 Genomes Project, 98.6% of 10,927 alleles at 57 loci agreed with assembly-derived calls, and the tool distinguished pathogenic from nonpathogenic RFC1 alleles of overlapping size by motif. Across 14 Coriell reference lines, it identified the expected expansion in every line and agreed with orthogonal assays within two repeat units at HTT, ATXN1, DMPK and PABPN1. In 103 samples from three laboratories, it detected an expanded allele in all samples with a previously reported pathogenic expansion and assigned the same category as the referring laboratory for 98% of 180 genotypes.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Preprint, not peer reviewed. The strength is the validation on 103 clinical samples from three laboratories: this is the kind of data that makes long-read sequencing conceivable as a single assay for expansions, as the authors propose. Distinguishing RFC1 alleles by motif rather than size is directly useful in neurology, but the abstract does not compare Mahi-mahi with other nanopore genotypers and does not state code availability.

Analysis by Dr Thibaut Benquey