Comparative genomic analysis of bacteria species

National Library Of Medicine

Investigators

Linked publications & trials

Abstract

In the past decade, the amount of microbial genomic data has grown considerably. These enormous datasets present new challenges and opportunities to understand and even manipulate the human microbiome for human health. One of the key challenges is that while metagenomic sequence data can be used to identify correlations between microbiome composition and disease states, they should be analyzed in conjunction with experimental approaches to reveal the underlying mechanism for the causal relationship. However, microbiologists have generally focused on model species or a few pathogens when they study a function. Therefore, many functions are known in only one or a few species. In this project, we used comparative genomics and analyses of omics datasets to help identify these functions in different bacterial genomes, providing valuable insights into the relevance of these functions to human health. This fiscal year, we prioritized the delineation of health-related traits within the human gut microbiome. A cornerstone of this pursuit has been the elucidation of a microbial enzyme pivotal to heme degradation: bilirubin reductase. While both human and bacterial enzymes contribute to the heme degradation pathway, the precise bacterial enzyme facilitating the conversion of bilirubin to urobilin has eluded scientific understanding for years. In a collaborative venture with Dr. Brantley Hall's lab at the University of Maryland, we have pinpointed the enzyme responsible for this process. Intriguingly, our findings indicate the widespread presence of this enzyme in the Firmicutes phylum, a dominant constituent of the gut microbiota. Further investigations into adult and infant gut metagenomes revealed the ubiquitous nature of this function among healthy adults, contrasting its conspicuous absence in certain populations, notably those with inflammatory bowel disease and infants predisposed to jaundice. We have encapsulated these insights in a manuscript, which is presently under revision. In tandem with this, our collaboration with the Hall Lab also spanned studies on bacterial azoreductases, integral to drug metabolism within the gut ecosystem. In addition, we have developed the Evolink tool, which facilitates the rapid identification of microbial genes associated with phenotypic traits of interest. Evolink uses paired genotype and phenotype data and microbial phylogeny to predict what genes are positively associated with a trait of interest. This allows for the identification of genes of interest across large, multi-species datasets, something that is challenging to do with comparative genomics or genome-wide association approaches. We demonstrated that Evolink was consistently a top-performing tool in terms of accuracy and efficiency using both simulated and empirical datasets. Overall, Evolink is a valuable tool that can be used to uncover the underlying genomic features that are associated with health-relevant microbial phenotypes. Parallelly, our attention has been steered towards deciphering bacteriophage-host dynamics. Central to this exploration is the understanding of bacteriophage receptor binding proteins - key determinants of the specificity of phage-bacterial interactions. Despite the recognized importance of these proteins in phage host range determination, a comprehensive analysis was hitherto lacking. We've pioneered a deep-learning methodology, tailored for the identification of phage tailspike proteins. Utilizing this technique, we've cataloged receptor binding proteins on prophages nestled within bacterial genomes. This endeavor has culminated in a rich database, linking these proteins to their host's serotype and receptor repertoire, spanning five prominent human pathogens. Notably, our data accentuates the pivotal role of horizontal gene transfer in modulating host susceptibility to phages. We have also collaborated with Dr. Gisela Storz from NICHD on a project where we identified and characterized a novel bacterial phage defense system encoded by a novel genes-withing-genes structure.