Ecology and molecular targets of hypermutation in the global microbiome

Abstract

Changes in the sequence of an organism’s genome, i.e., mutations, are the raw material of evolution. The frequency and location of mutations can be constrained by specific molecular mechanisms, such as diversity-generating retroelements (DGRs). DGRs have been characterized from cultivated bacteria and bacteriophages, and perform error-prone reverse transcription leading to mutations being introduced in specific target genes. DGR loci were also identified in several metagenomes, but the ecological roles and evolutionary drivers of these DGRs remain poorly understood. Here, we analyze a dataset of >30,000 DGRs from public metagenomes, establish six major lineages of DGRs including three primarily encoded by phages and seemingly used to diversify host attachment proteins, and demonstrate that DGRs are broadly active and responsible for >10% of all amino acid changes in some organisms. Overall, these results highlight the constraints under which DGRs evolve, and elucidate several distinct roles these elements play in natural communities.

Eco-evolutionary significance of domesticated retroelements in microbial genomes

“…Although DGRs are predicted to have a role in diversifying attachment proteins for these putative epibionts, most of their diverse target genes remain entirely uncharacterized. Most recently, all publicly available genomic and metagenomic databases have been examined, resulting in a more complete understanding of DGR distribution across taxonomic, functional, and biogeographic scales [ 23 , 24 ]. DGRs are especially prevalent in microbial constituents of the human microbiome, where they are particularly enriched in gut microorganisms [ 23 – 26 ].…”

“…Few molecular targets have been experimentally characterized to date, yet prediction from the wealth of microbial genome sequence data suggests that roughly half of DGR-variable proteins appear to have cellular (i.e. non-viral) functions [ 23 , 24 ]. Hypervariable proteins were characterized in several clinical strains of Legionella pneumophila , which appear to actively diversify genes for a lipoprotein that is displayed on the outer membrane of the cell [ 30 ].…”

“…In the DGR target protein of Treponema denticola (TvpA) , a lipoprotein signal sequence is predicted to be involved in export to the outer membrane, possibly for attachment to other bacterial or epithelial cells [ 3 ]. In the gut microbiome, a diverse array of DGRs appear to have a role in targeting both phage and cellular genes [ 24 – 26 ], yet these variable proteins remain functionally uncharacterized.

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“…To date, comparative genomic investigations into DGRs and retrons have emphasized identification and classification using homology-based tools for feature detection [ 19 , 21 , 23 , 24 , 38 , 46 , 56 ]. These approaches have recently enabled systematic identification of thousands of new retroelements that define a taxonomic and biogeographic distribution, as well as functional diversity of associated protein families [ 24 , 38 ]. The utility of genomes, however, does not extend into capturing the ecological and evolutionary significance of retroelements and their dynamic nature in naturally occurring microbial populations.…”

“…The increasing availability of genomes, metagenomes, and computational strategies presents a new frontier to approach the dynamic yet understudied landscape of genetic variants that emerge within naturally occurring microbial populations due to the activity of domesticated retroelements [ 21 , 24 , 62 ]. Here we offer a glimpse into those opportunities by surveying marine populations of Trichodesmium erythraeum using an isolate genome and marine metagenomes.…”