Abstract
The human body consists of innumerable multifaceted environments that predispose colonization by a number of distinct microbial communities, which play fundamental roles in human health and disease. In addition to community surveys and shotgun metagenomes that seek to explore the composition and diversity of these microbiomes, there are significant efforts to sequence reference microbial genomes from many body sites of healthy adults. To illustrate the utility of reference genomes when studying more complex metagenomes, we present a reference-based analysis of sequence reads generated from 55 shotgun metagenomes, selected from 5 major body sites, including 16 sub-sites. Interestingly, between 13% and 92% (62.3% average) of these shotgun reads were aligned to a then-complete list of 2780 reference genomes, including 1583 references for the human microbiome. However, no reference genome was universally found in all body sites. For any given metagenome, the body site-specific reference genomes, derived from the same body site as the sample, accounted for an average of 58.8% of the mapped reads. While different body sites did differ in abundant genera, proximal or symmetrical body sites were found to be most similar to one another. The extent of variation observed, both between individuals sampled within the same microenvironment, or at the same site within the same individual over time, calls into question comparative studies across individuals even if sampled at the same body site. This study illustrates the high utility of reference genomes and the need for further site-specific reference microbial genome sequencing, even within the already well-sampled human microbiome.
Highlights
Current data place the number of bacteria living in or on the human body as outnumbering the total number of human cells by a factor of 10 to 1 [1,2]
While most of these studies have relied solely on community 16S rRNA gene amplicon analyses, two recent companion papers published by the Human Microbiome Project Consortium (HMPC) describe both 16S rRNA as well as random shotgun sequencing data of healthy human subjects sampled from 5 major body sites and up to 18 sub-sites [14,15]
Given that most metagenome data from some body site samples can be mapped to available reference genomes while other samples show very poor read-recruitment, we explored the value of having site-specific references
Summary
Current data place the number of bacteria living in or on the human body as outnumbering the total number of human cells by a factor of 10 to 1 [1,2]. While most of these studies have relied solely on community 16S rRNA gene amplicon analyses (which suffer the risk of PCR-induced biases), two recent companion papers published by the Human Microbiome Project Consortium (HMPC) describe both 16S rRNA as well as random shotgun sequencing data of healthy human subjects sampled from 5 major body sites and up to 18 sub-sites [14,15] This large effort used the shotgun metagenomic data to assess functional profiles and to investigate taxonomic classification. More specific species-level assignments were performed using either select pathogen genomes or marker genes [15]
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