Accurate detection of complex structural variations using single-molecule sequencing

• Published in: Nature methods Vol. 15; no. 6; pp. 461 - 468
• Main Authors: Sedlazeck, Fritz J., Rescheneder, Philipp, Smolka, Moritz, Fang, Han, Nattestad, Maria, von Haeseler, Arndt, Schatz, Michael C.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-06-2018; Nature Publishing Group
• Subjects: 631/114/2785; 631/114/794; 631/208/726/649/2157; Accuracy; Bioinformatics; Biological Microscopy; Biological Techniques; Biology; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Computer science; Data processing; Datasets; DNA Mutational Analysis - methods; Gene sequencing; Genetic diversity; Genome, Human; Genomes; Genomics - methods; High-Throughput Nucleotide Sequencing - methods; Humans; Laboratories; Life Sciences; Molecular chains; Proteomics; Sequence Analysis, DNA - methods; Systematic errors
• ISSN: 1548-7091; 1548-7105
• DOI: 10.1038/s41592-018-0001-7

Structural variations are the greatest source of genetic variation, but they remain poorly understood because of technological limitations. Single-molecule long-read sequencing has the potential to dramatically advance the field, although high error rates are a challenge with existing methods. Addressing this need, we introduce open-source methods for long-read alignment (NGMLR;
https://github.com/philres/ngmlr
) and structural variant identification (Sniffles;
https://github.com/fritzsedlazeck/Sniffles
) that provide unprecedented sensitivity and precision for variant detection, even in repeat-rich regions and for complex nested events that can have substantial effects on human health. In several long-read datasets, including healthy and cancerous human genomes, we discovered thousands of novel variants and categorized systematic errors in short-read approaches. NGMLR and Sniffles can automatically filter false events and operate on low-coverage data, thereby reducing the high costs that have hindered the application of long reads in clinical and research settings.
NGMLR and Sniffles perform highly accurate alignment and structural variation detection from long-read sequencing data.