PT - JOURNAL ARTICLE AU - Eli L. Moss AU - Alex Bishara AU - Ekaterina Tkachenko AU - Joyce B. Kang AU - Tessa M. Andermann AU - Christina Wood AU - Christine Handy AU - Hanlee Ji AU - Serafim Batzoglou AU - Ami S. Bhatt TI - De novo assembly of microbial genomes from human gut metagenomes using barcoded short read sequences AID - 10.1101/125211 DP - 2017 Jan 01 TA - bioRxiv PG - 125211 4099 - http://biorxiv.org/content/early/2017/04/07/125211.short 4100 - http://biorxiv.org/content/early/2017/04/07/125211.full AB - Shotgun short-read sequencing methods facilitate study of the genomic content and strain-level architecture of complex microbial communities. However, existing methodologies do not capture structural differences between closely related co-occurring strains such as those arising from horizontal gene transfer and insertion sequence mobilization. Recent techniques that partition large DNA molecules, then barcode short fragments derived from them, produce short-read sequences containing long-range information. Here, we present a novel application of these short-read barcoding techniques to metagenomic samples, as well as Athena, an assembler that uses these barcodes to produce improved metagenomic assemblies. We apply our approach to longitudinal samples from the gut microbiome of a patient with a hematological malignancy. This patient underwent an intensive regimen of multiple antibiotics, chemotherapeutics and immunosuppressants, resulting in profound disruption of the microbial gut community and eventual domination by Bacteroides caccae. We significantly improve draft completeness over conventional techniques, uncover strains of B. caccae differing in the positions of transposon integration, and find the abundance of individual strains to fluctuate widely over the course of treatment. In addition, we perform RNA sequencing to investigate relative transcription of genes in B. caccae, and find overexpression of antibiotic resistance genes in our de novo assembled draft genome of B. caccae coinciding with both antibiotic administration and the appearance of proximal transposons harboring a putative bacterial promoter region. Our approach produces overall improvements in contiguity of metagenomic assembly and enables assembly of whole classes of genomic elements inaccessible to existing short-read approaches.