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Dynamics of bacterial recombination in the human gut microbiome [1]

['Zhiru Liu', 'Department Of Applied Physics', 'Stanford University', 'Stanford', 'California', 'United States Of America', 'Benjamin H. Good', 'Department Of Biology', 'Chan Zuckerberg Biohub San Francisco', 'San Francisco']

Date: 2024-02

Horizontal gene transfer (HGT) is a ubiquitous force in microbial evolution. Previous work has shown that the human gut is a hotspot for gene transfer between species, but the more subtle exchange of variation within species—also known as recombination—remains poorly characterized in this ecosystem. Here, we show that the genetic structure of the human gut microbiome provides an opportunity to measure recent recombination events from sequenced fecal samples, enabling quantitative comparisons across diverse commensal species that inhabit a common environment. By analyzing recent recombination events in the core genomes of 29 human gut bacteria, we observed widespread heterogeneities in the rates and lengths of transferred fragments, which are difficult to explain by existing models of ecological isolation or homology-dependent recombination rates. We also show that natural selection helps facilitate the spread of genetic variants across strain backgrounds, both within individual hosts and across the broader population. These results shed light on the dynamics of in situ recombination, which can strongly constrain the adaptability of gut microbial communities.

Funding: This work was supported in part by a Stanford Bio-X Bowes Fellowship (to Z.L.), the Alfred P. Sloan Foundation grant FG-2021-15708 (B.H.G.), National Institutes of Health Grant No. R35GM146949 (B.H.G.), and a Terman Fellowship from Stanford University (B.H.G.). B.H.G. is a Chan Zuckerberg Biohub - San Francisco Investigator. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data Availability: The raw sequencing reads for the metagenomic samples used in this study were downloaded from public repositories listed in the following publications: 10.1038/nature11209 , 10.1038/nature11450 , 10.1016/j.cels.2016.10.004 , and 10.1101/gr.233940.117 . Data underlying all figures, such as the numerical values of bar plots, can be found in 10.5281/zenodo.10304481 . All other metadata, as well as the source code for the sequencing pipeline, downstream analyses, and figure generation are available at Zenodo ( 10.5281/zenodo.10368227 ) or GitHub ( https://github.com/zhiru-liu/microbiome_evolution ).

Our results reveal extensive heterogeneity in rates and lengths of transferred fragments—both among different species and between different strains of the same species—which are difficult to explain by ecological isolation or reduced efficiencies of recombination. We also find that natural selection can play an important role in facilitating the spread of transferred fragments into different strain backgrounds. Our results suggest that in situ recombination events are shaped by a combination of evolutionary processes, which may strongly depend on the ecological context of their host community.

Here, we show that the genetic structure of the human gut microbiome provides a unique opportunity to address these questions. Using strain-resolved metagenomics, we show that the large sample sizes and host colonization structure of this ecosystem enable systematic comparisons of strains across a broad range of distance and timescales, from the scale of individual hosts to the diversity of the broader global population. We show that some of these strains are closely related enough that one can resolve homologous recombination events directly, without requiring restrictive modeling assumptions or explicit phylogenetic inference. We use these observations to develop a nonparametric approach for identifying large numbers of recent recombination events within 29 prevalent species of human gut bacteria. This comparative data set allows us to systematically explore the landscape of homologous recombination in this host-associated ecosystem.

However, many of these existing methods rely on simplified evolutionary scenarios, which ignore the effects of natural selection, and make additional restrictive assumptions about the demographic structure of the population. Recent work has shown that these simplified models often fail to capture key features of microbial genetic diversity [ 26 – 28 , 42 ], which can strongly bias estimates of the underlying recombination parameters. Our limited understanding of these effects makes it difficult to answer key questions about the role of recombination in natural populations like the gut microbiota: Is recombination fast enough to allow local adaptations to persist within a host, e.g., during fecal microbiota transplants [ 43 ] or sudden dietary shifts [ 44 ]? Does natural selection tend to promote or hinder the spread of genetic variants across different strain backgrounds? And can the rates and lengths of transferred fragments shed light on the underlying mechanisms of recombination in situ?

Multiple methods have been developed for inferring in situ recombination from the fine-scale diversity of natural bacterial isolates [ 26 , 27 , 29 – 33 ]. The key challenge lies in disentangling the effects of recombination from the other evolutionary forces (e.g., mutation, selection, and genetic drift) that shape genetic diversity over the same timescales. Existing studies often address this problem using an inverse approach, by fitting the observed data to simple parametric models from microbial population genetics. Examples range from simple summary statistics like linkage disequilibrium [ 26 , 27 , 34 , 35 ] and related metrics [ 21 , 28 , 32 , 33 , 36 – 40 ] to complete probabilistic reconstructions of the genealogies of the sampled genomes [ 29 – 31 ]. Previous applications of these methods have provided extensive evidence for ongoing recombination within the core genomes of many bacterial species [ 25 , 41 ]—including many species of human gut bacteria [ 27 ].

The horizontal exchange of genetic material—also known as horizontal gene transfer (HGT)—is a pervasive force in microbial ecology and evolution [ 1 ]. HGT is particularly important within the human gut microbiota, where hundreds of species coexist with each other in close physical proximity [ 2 – 4 ]. HGT is often associated with the acquisition of new genes or pathways, which can confer resistance to antibiotics [ 3 – 8 ] or enable novel metabolic capabilities [ 3 , 9 – 14 ]. Genetic material can also be transferred between more closely related strains, where it can overwrite existing regions of the genome via homologous recombination [ 15 , 16 ]. This more subtle form of horizontal exchange acts to reshuffle genetic variants within species, similar to meiotic recombination in sexual organisms. Homologous recombination plays a crucial role in microbial evolution, from the emergence of new bacterial species [ 17 – 20 ] to the transition between clonal and quasi-sexual evolution [ 21 – 23 ]. Homologous recombination can also serve as a scaffold for the incorporation of novel genetic material, which can facilitate the spread of accessory genes across different strain backgrounds [ 24 ]. However, while numerous studies have established the pervasiveness of bacterial recombination [ 21 , 25 – 28 ], the evolutionary dynamics of this process are still poorly understood in natural populations like the gut microbiota.

Results

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[1] Url: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3002472

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