Mapping and phasing of structural variation in patient genomes using nanopore sequencing

Despite improvements in genomics technology, the detection of structural variants (SVs) from short-read sequencing still poses challenges, particularly for complex variation. Here we analyse the genomes of two patients with congenital abnormalities using the MinION nanopore sequencerand a novel computational pipeline—NanoSV. We demonstrate that nanoporelong reads are superior to short reads with regard to detection of de novo chromothripsisrearrangements. The long reads also enable efficient phasing of genetic variations, which we leveraged to determine the parental origin of all de novo chromothripsisbreakpoints and to resolve the structure of these complex rearrangements. Additionally, genome-wide surveillance of inherited SVs reveals novel variants, missed in short-read data sets, a large proportion of which are retrotransposoninsertions. We provide a first exploration of patient genome sequencing with a nanopore sequencerand demonstrate the value of long-read sequencing in mapping and phasing of SVs for both clinical and research applications.