Abstract:
Shotgun metagenomics has revealed an unprecedented diversity of viruses maintaining interactions with organisms from all divisions of life. Thus, metagenomics changed the perspective on viruses: from mere pathogens to significant players within ecological systems. Viral metagenomics of marine waters revealed the local and global scale impact of virus-host interactions by their influence on biogeochemical and ecological processes. In contrast, the description of viruses and their effect on the human gut is still poorly understood. Bacteria and viruses are the most abundant entities in the human gut, yet the description of the viral fraction lags behind the bacterial fraction. Thus, the objective of this research was to expand existing characterizations of the human gut virome.
First, I analyzed viromes from monozygotic twins to determine whether viral diversity mirrors bacterial diversity in the human gut, an expected ecological pattern but never before verified. The analysis confirmed a highly unique human gut virome dominated by bacteriophages. Comparing metrics of viral and bacterial diversity, I observed that gut microbiome diversity, within and between subjects, is mirrored in their viromes. Moreover, the abundance and diversity of bacteria proved to be indicative of the abundance and diversity of the virome.
Second, I faced the lack of annotated reference genomes impeding the analysis of viral metagenomes. I screened public databases in search of transposable phages from the human gut. Transposable phages are well-described as agents of mutation, genomic rearrangements, and horizontal gene transfer to their hosts. Despite this, only a few dozen genomes are available in public databases. I identified 1,002 good-quality assemblies of putative transposable phage in metagenomic assembly databases. Based on comparative genomics and phylogenetic analysis, I found that transposable phages are not a monophyletic group, contrary to expectations. Finally, I focused on the characterization of assemblies related to the only human intestine transposable phage isolated to date: Mushu (NC_047913). Using Mushu as a reference and following the taxonomic classification guidelines, I defined the Mushu-like family. It includes 9 genera and 72 species of phages that may be involved in the horizontal gene transfer of auxiliary metabolic genes.
This work demonstrated the correlation between bacterial and viral diversity in the human gut; a pattern driven by bacteriophages and not eukaryotic viruses. A major obstacle in studying the human gut virome is the sparse characterization of most viral metagenomes. Thus, improving the description of the viral component of the microbiome is critical. This work retrieved thousands of transposable phages from databases of metagenomic assemblies. The same methods can be applied to find genomes related to all families of tailed bacteriophages. Such an approach has the potential to catalyze the characterization of the viral fraction of the human gut and facilitate future investigation on the role of phages in the assembly and homeostasis of the gut microbiome.
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