VILOCA: sequencing quality-aware viral haplotype reconstruction and mutation calling for short-read and long-read data

Abstract

RNA viruses exist as large heterogeneous populations within their host. The structure and diversity of virus populations affects disease progression and treatment outcomes. Next-generation sequencing allows detailed viral population analysis, but inferring diversity from error-prone reads is challenging. Here, we present VILOCA (VIral LOcal haplotype reconstruction and mutation CAlling for short and long read data), a method for mutation calling and reconstruction of local haplotypes from short- and long-read viral sequencing data. Local haplotypes refer to genomic regions that have approximately the length of the input reads. VILOCA recovers local haplotypes by using a Dirichlet process mixture model to cluster reads around their unobserved haplotypes and leveraging quality scores of the sequencing reads. We assessed the performance of VILOCA in terms of mutation calling and haplotype reconstruction accuracy on simulated and experimental Illumina, PacBio and Oxford Nanopore data. On simulated and experimental Illumina data, VILOCA performed better or similar to existing methods. On the simulated long-read data, VILOCA is able to recover on average $82\%$ of the ground truth mutations with perfect precision compared to only $69\%$ recall and $68\%$ precision of the second-best method. In summary, VILOCA provides significantly improved accuracy in mutation and haplotype calling, especially for long-read sequencing data, and therefore facilitates the comprehensive characterization of heterogeneous within-host viral populations.