%0 Journal Article %A Katherine J. Siddle %A Hayden C. Metsky %A Adrianne Gladden-Young %A James Qu %A David K. Yang %A Patrick Brehio %A Andrew Goldfarb %A Anne Piantadosi %A Shirlee Wohl %A Aaron E. Lin %A Kayla G. Barnes %A Damien C. Tully %A Scott Hennigan %A Giselle Barbosa-Lima %A Yasmine R. Vieira %A Lauren M. Paul %A Amanda L. Tan %A Kimberly F. Garcia %A Leda A. Parham %A Ikponmwonsa Odia %A Philomena Eromon %A Onikepe A. Folarin %A Augustine Goba %A Viral Hemorrhagic Fever Consortium %A Etienne Simon-Lorière %A Lisa Hensley %A Angel Balmaseda %A Eva Harris %A Todd M. Allen %A Jonathan A. Runstadler %A Sandra Smole %A Fernando A. Bozza %A Thiago M. L. Souza %A Sharon Isern %A Scott F. Michael %A Ivette Lorenzana %A Lee Gehrke %A Irene Bosch %A Gregory Ebel %A Christian Happi %A Donald Grant %A Daniel J. Park %A Andreas Gnirke %A Pardis C. Sabeti %A Christian B. Matranga %T Capturing diverse microbial sequence with comprehensive and scalable probe design %D 2018 %R 10.1101/279570 %J bioRxiv %P 279570 %X Metagenomic sequencing has the potential to transform microbial detection and characterization, but new tools are needed to improve its sensitivity. We developed CATCH (Compact Aggregation of Targets for Comprehensive Hybridization), a computational method to enhance nucleic acid capture for enrichment of diverse microbial taxa, and implemented it in a publicly available software package. CATCH designs compact probe sets that achieve full coverage of known microbial sequence diversity and that scale well with this diversity. Using CATCH, we designed and synthesized multiple probe sets, including one to capture whole genomes of the 356 viral species known to infect humans, and conducted a rigorous evaluation of their performance. Capture with these probe sets enriched unique viral content on average 18 × in sequencing libraries from patient and environmental samples and allowed us to assemble viral genomes that we could not otherwise recover. We show that capture accurately reflects co-infections and within-host nucleotide variation, enriches sequence with substantial divergence from the probe sets, and improves detection of viral infections in samples with unknown microbial content. Our work provides a new approach to probe design and evaluation, and demonstrates a path toward more sensitive, cost-effective metagenomic sequencing. %U https://www.biorxiv.org/content/biorxiv/early/2018/03/12/279570.full.pdf