Abstract
Mycoplasmas are the smallest self-replicating organisms and obligate parasites of a specific vertebrate host. An in-depth analysis of the functional capabilities of mycoplasma species is fundamental to understand how some of simplest forms of life on Earth succeeded in subverting complex hosts with highly sophisticated immune systems. In this study we present a genome-scale comparison, focused on identification of functional protein domains, of 80 publically available mycoplasma genomes which were consistently re-annotated using a standardized annotation pipeline embedded in a semantic framework to keep track of the data provenance. We examined the pan- and core-domainome and studied predicted functional capability in relation to host specificity and phylogenetic distance. We show that the pan- and core-domainome of mycoplasma species is closed. A comparison with the proteome of the “minimal” synthetic bacterium JCVI-Syn3.0 allowed us to classify domains and proteins essential for minimal life. Many of those essential protein domains, essential Domains of Unknown Function (DUFs) and essential hypothetical proteins are not persistent across mycoplasma genomes suggesting that mycoplasma species support alternative domain configurations that bypass their essentiality. Based on the protein domain composition, we could separate mycoplasma species infecting blood and tissue. For selected genomes of tissue infecting mycoplasmas, we could also predict whether the host is ruminant, pig or human. Functionally closely related mycoplasma species, which have a highly similar protein domain repertoire, but different hosts could not be separated. This study provides a concise overview of the functional capabilities of mycoplasma species, which can be used as a basis to further understand host-pathogen interaction or to design synthetic minimal life.
Highlights
Mycoplasmas have evolved from a common gram-positive ancestor (Razin and Yogev, 1998) and the evolutionary path of genome reduction has led to an obligatory parasitic lifestyle which presumably has selected for those bacteria that best manipulate their hosts and make optimal use of their specific niche with a minimal set of genes
Interactions with the host have been extensively studied (Rottem, 2003) but despite of the wealth of information on this minimal organism we still cannot explain why there is a preference for colonization of human lung tissue
We clustered species based on domain presence to find direct leads and used a random forest classification algorithm on the complete mycoplasma pan-domainome to find sets of domains that predict the specific host or niche of a mycoplasma species
Summary
Mycoplasmas have evolved from a common gram-positive ancestor (Razin and Yogev, 1998) and the evolutionary path of genome reduction has led to an obligatory parasitic lifestyle which presumably has selected for those bacteria that best manipulate their hosts and make optimal use of their specific niche with a minimal set of genes. Research into infectious mechanisms used by mycoplasma species has been focused on identification of adhesive molecules (Rottem, 2003), lipoproteins (Browning et al, 2011), molecular mechanisms used to vary the composition of the surface of the bacterial membrane (Razin and Yogev, 1998) and production of oxidizing components (e.g., hydrogen peroxide and hydrogen sulfide) which cause damage to the host (Vilei and Frey, 2001; Großhennig et al, 2015) While these studies provide insight into the mechanisms used by mycoplasmas to infect the host they do not explain why a mycoplasma species is specific for its host. A major hallmark was achieved by publication of an engineered mycoplasma with a synthetic minimal genome of 473 genes based on the genome of Mycoplasma mycoides subsp. capri (Gibson et al, 2010; Hutchison et al, 2016) providing a benchmark for genome comparison studies aimed at determining gene essentiality
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