4.8 Article

Capturing sequence diversity in metagenomes with comprehensive and scalable probe design

Journal

NATURE BIOTECHNOLOGY
Volume 37, Issue 2, Pages 160-+

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41587-018-0006-x

Keywords

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Funding

  1. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [U19AI110818]
  2. NIH NIAID [HHSN272200900049C, HHSN272201400008C, R01AI099210]
  3. Henry M. Jackson Foundation award [W81XWH-11-2-0174]
  4. Bill & Melinda Gates Foundation
  5. Human Frontiers in Science Program [LT000553/2016]
  6. NIH NHGRI [U01HG007480, U54HG007480]
  7. World Bank [ACE019]

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Metagenomic sequencing has the potential to transform microbial detection and characterization, but new tools are needed to improve its sensitivity. Here we present CATCH, a computational method to enhance nucleic acid capture for enrichment of diverse microbial taxa. CATCH designs optimal probe sets, with a specified number of oligonucleotides, that achieve full coverage of, and scale well with, known sequence diversity. We focus on applying CATCH to capture viral genomes in complex metagenomic samples. We design, synthesize, and validate multiple probe sets, including one that targets the whole genomes of the 356 viral species known to infect humans. Capture with these probe sets enriches unique viral content on average 18-fold, allowing us to assemble genomes that could not be recovered without enrichment, and accurately preserves within-sample diversity. We also use these probe sets to recover genomes from the 2018 Lassa fever outbreak in Nigeria and to improve detection of uncharacterized viral infections in human and mosquito samples. The results demonstrate that CATCH enables more sensitive and cost-effective metagenomic sequencing.

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