Enhanced multi-omic viral profiling from microbial community sequencing with BAQLaVa

Abstract Viruses are crucial components of microbial communities, both phage that infect bacterial community members as well as pathogenic and other eukaryotic viruses. However, they remain unobserved by most current technologies, due to combinations of experimental and analytical factors. To address the latter, we developed the BAQLaVa algorithm for high-resolution profiling of >120,000 viral species (viral genome bins, VGBs) via reference-based metagenome (MGX) or metatranscriptome (MTX) alignment to complementary nucleotide markers and proteome sets. In comprehensive benchmarking, BAQLaVa substantially outperformed alternatives, achieving species-level recall and precision regularly over 90%. We applied BAQLaVa to MGX and MTX samples from the HMP2 IBDMDB cohort to identify previously undescribed viral perturbations in inflammatory bowel diseases. Most notably, virome diversity was reduced in tandem with bacterial diversity during inflammation, in contrast to previous findings based on a narrower range of viral detection. A subset of viruses were enriched during IBD, associated with carriage of abortive infection anti-defense systems such as AbiL and PD-λ-2, as well as genes involved in the regulation of lysogeny. Leveraging the corresponding viral profiles, we also inferred phage-host relationships using scalable co-occurrence and covariation signals, even in the absence of host references or genome annotations. By enabling high sensitivity and specificity viral profiling from metagenomes or metatranscriptomes, BAQLaVa provides a scalable framework for virome epidemiology and systematic analysis of virus-host interactions. Competing Interest Statement C.H. declares the following associations: Seres Therapeutics (scientific advisory board, microbiome therapies), Zoe (scientific advisory board), Empress (scientific advisory board, microbiome therapies).