Why SV (CNV) is important
each microbial species represents many different strains that may encode considerably different sets of genes and a different number of copies of each gene (reflecting, for example, gene deletions and duplication events)
Within each bacterial species, different strains may vary in the set of genes they encode or in the copy number of these genes
Such intra-species variation endows each strain with potentially distinct functional capacities
- virulence
- motility
- nutrient utilization
drug resistance
taxonomic characterization of the human microbiota is often limited to the species level or to previously sequenced strains, and accordingly, the prevalence of intra-species variation, its functional role, and its relation to host health remain unclear.
the true functional potential of a microbiome cannot be inferred from species composition alone, and species-level comparative analyses may fail to capture important functional differences across samples
current limitations
Gene-centric shotgun metagenomic studies, on the other hand, may identify genes or pathways that are differentially abundant across samples but cannot necessarily attribute these shifts to specific species or strains.
catalog the relative abundance of known strains in human microbiome samples (Kraal et al., 2014) may recover some of these differences but are limited to sequenced reference genomes and are not able to identify novel, yet-to-be-sequenced variation
it is often unclear how much of the observed variation in gene composition is due to variation in the abundances of species and how much is contributed by intra-species variation
gene-level intra-species variation is in the human gut, whether such variation is adaptive and affects specific functions, and how much of this variation has already been captured by reference genomes
the variable presence of genes involved in transport, motility, carbohydrate metabolism, and virulence in two distinct strains
These gene-level studies, however, mostly report small-scale or anecdotal results, focusing on one or a small number of species and often on specific gene families.
A high-throughput, comprehensive analysis of genelevel variation across a large array of species in the human gut is therefore needed to more fully appreciate the extent and functional implications of strain variation in this complex microbiome
How to do it
comprehensive large-scale analysis of intra-species copynumber variation in the gut microbiome, introducing a rigorous computational pipeline for detecting such variation directly from shotgun metagenomic data
infer intra-species compositional profiles, identifying population structure shifts and the presence of yet uncharacterized variants.Our results highlight the complex relationship between microbiome composition and functional capacity, linking metagenome-level compositional shifts to strain-level variation
rigorous and robust pipeline to estimate the copy number of each gene in a large set of prevalent gut microbial species in a given sample directly from metagenomic shotgun data and, furthermore, to detect copy-number variation across samples
Applying this pipeline to 109 metagenomic samples from a recent study of the gut microbiomes of healthy, obese, and inflammatory bowel disease (IBD)-afflicted individuals, we estimate the copy number of more than 4,000 gene groups across 70 species in each of these samples and demonstrate the presence of widespread copy-number variation within many genes in many species.
- We find that specific functions are especially prone to copy-number variation, including functions relevant to a community lifestyle and adaptation to the gut environment, and further detect associations between strain variation and host phenotype
Potetial results
detect variation in gene content and gene copy number in a large set of prevalent human gut microbes directly from metagenomic data
