A unified haplotype-based method for accurate and comprehensive variant calling

Haplotype-based variant callers, which consider physical linkage between variant sites, are currently among the best tools for germline variation discovery and genotyping from short-read sequencing data. However, almost all such tools were designed specifically for detecting common germline variation in diploid populations, and give sub-optimal results in other scenarios. Here we present Octopus, a versatile haplotype-based variant caller that uses a polymorphic Bayesian genotyping model capable of modeling sequencing data from a range of experimental designs within a unified haplotype-aware framework. Octopus combines sequencing reads and prior information to phase called genotypes of arbitrary ploidy, including those with somatic mutations.We show that Octopus accurately calls germline variants in individuals, including SNVs, indels, and small complex replacements such as microinversions. Using a carefully designed synthetic-tumor data set derived from clean sequencing data from a sample with known germline haplotypes and observed mutations in large cohort of tumor samples, we show that Octopus is more sensitive to low-frequency somatic variation yet calls considerably fewer false positives than other methods. Octopus also outputs realigned evidence BAMs to aid validation and interpretation.