Negative Epistatic Interactions Research Articles

Efficient epistasis inference via higher-order covariance matrix factorization.

Epistasis can profoundly influence evolutionary dynamics. Temporal genetic data, consisting of sequences sampled repeatedly from a population over time, provides a unique resource to understand how epistasis shapes evolution. However, detecting epistatic interactions from sequence data is technically challenging. Existing methods for identifying epistasis are computationally demanding, limiting their applicability to real-world data. Here, we present a novel computational method for inferring epistasis that significantly reduces computational costs without sacrificing accuracy. We validated our approach in simulations and applied it to study HIV-1 evolution over multiple years in a data set of 16 individuals. There we observed a strong excess of negative epistatic interactions between beneficial mutations, especially mutations involved in immune escape. Our method is general and could be used to characterize epistasis in other large data sets.

Epistatic interaction has the reverse effects with its constitutive quantitative trait loci

Epistasis is one of important genetic components for a quantitative trait in plant. Eshed and Zamir found negative epistatic interactions of quantitative trait loci in Tomato first. We detected that positive (negative) QTLs generated mostly negative (positive) epistatic interactions on heading date in rice, and then proposed the hypothese that QTL epistasis plays a role of homeostasis in one of our recent papers. In order to further provide additional evidence, the effects of QTLs and their epistatic effects on two quantitative traits of plant height (ph) and thousand kernel weight (tkw) were analyzed in this study. The same regularity was verified again. We detected that positive ph QTLs and negative tkw QTLs always generated reverse epistatic effects, respectively. Moreover, high-order epistatic effects were estimated on these two traits. The sum of all epistatic effects would partially neutralize the additive of constitutive QTL effects. This feature of epistsis would be the mechanism for bionts to maintain homeostasis while the obstacle for human to achieve the pyramiding breeding objectives. More evidences are still being collected to support our assumption.

Divergent folding-mediated epistasis among unstable membrane protein variants.

Many membrane proteins are prone to misfolding, which compromises their functional expression at the plasma membrane. This is particularly true for the mammalian gonadotropin-releasing hormone receptor GPCRs (GnRHR). We recently demonstrated that evolutionary GnRHR modifications appear to have coincided with adaptive changes in cotranslational folding efficiency. Though protein stability is known to shape evolution, it is unclear how cotranslational folding constraints modulate the synergistic, epistatic interactions between mutations. We therefore compared the pairwise interactions formed by mutations that disrupt the membrane topology (V276T) or tertiary structure (W107A) of GnRHR. Using deep mutational scanning, we evaluated how the plasma membrane expression of these variants is modified by hundreds of secondary mutations. An analysis of 251 mutants in three genetic backgrounds reveals that V276T and W107A form distinct epistatic interactions that depend on both the severity and the mechanism of destabilization. V276T forms predominantly negative epistatic interactions with destabilizing mutations in soluble loops. In contrast, W107A forms positive interactions with mutations in both loops and transmembrane domains that reflect the diminishing impacts of the destabilizing mutations in variants that are already unstable. These findings reveal how epistasis is remodeled by conformational defects in membrane proteins and in unstable proteins more generally.

Divergent folding-mediated epistasis among unstable membrane protein variants

Many membrane proteins are prone to misfolding, which compromises their functional expression at the plasma membrane. This is particularly true for the mammalian gonadotropin-releasing hormone receptor GPCRs (GnRHR). We recently demonstrated that evolutionary GnRHR modifications appear to have coincided with adaptive changes in cotranslational folding efficiency. Though protein stability is known to shape evolution, it is unclear how cotranslational folding constraints modulate the synergistic, epistatic interactions between mutations. We therefore compared the pairwise interactions formed by mutations that disrupt the membrane topology (V276T) or tertiary structure (W107A) of GnRHR. Using deep mutational scanning, we evaluated how the plasma membrane expression of these variants is modified by hundreds of secondary mutations. An analysis of 251 mutants in three genetic backgrounds reveals that V276T and W107A form distinct epistatic interactions that depend on both the severity and the mechanism of destabilization. V276T forms predominantly negative epistatic interactions with destabilizing mutations in soluble loops. In contrast, W107A forms positive interactions with mutations in both loops and transmembrane domains that reflect the diminishing impacts of the destabilizing mutations in variants that are already unstable. These findings reveal how epistasis is remodeled by conformational defects in membrane proteins and in unstable proteins more generally.

Quantifying higher-order epistasis: beware the chimera.

Epistasis, or interactions in which alleles at one locus modify the fitness effects of alleles at other loci, plays a fundamental role in genetics, protein evolution, and many other areas of biology. Epistasis is typically quantified by computing the deviation from the expected fitness under an additive or multiplicative model using one of several formulae. However, these formulae are not all equivalent. Importantly, one widely used formula - which we call the chimeric formula - measures deviations from a multiplicative fitness model on an additive scale, thus mixing two measurement scales. We show that for pairwise interactions, the chimeric formula yields a different magnitude, but the same sign (synergistic vs. antagonistic) of epistasis compared to the multiplicative formula that measures both fitness and deviations on a multiplicative scale. However, for higher-order interactions, we show that the chimeric formula can have both different magnitude and sign compared to the multiplicative formula - thus confusing negative epistatic interactions with positive interactions, and vice versa. We resolve these inconsistencies by deriving fundamental connections between the different epistasis formulae and the parameters of the multivariate Bernoulli distribution . Our results demonstrate that the additive and multiplicative epistasis formulae are more mathematically sound than the chimeric formula. Moreover, we demonstrate that the mathematical issues with the chimeric epistasis formula lead to markedly different biological interpretations of real data. Analyzing multi-gene knockout data in yeast, multi-way drug interactions in E. coli , and deep mutational scanning (DMS) of several proteins, we find that 10 - 60% of higher-order interactions have a change in sign with the multiplicative or additive epistasis formula. These sign changes result in qualitatively different findings on functional divergence in the yeast genome, synergistic vs. antagonistic drug interactions, and and epistasis between protein mutations. In particular, in the yeast data, the more appropriate multiplicative formula identifies nearly 500 additional negative three-way interactions, thus extending the trigenic interaction network by 25%.

Epistasis and pleiotropy-induced variation for plant breeding.

Epistasis refers to nonallelic interaction between genes that cause bias in estimates of genetic parameters for a phenotype with interactions of two or more genes affecting the same trait. Partitioning of epistatic effects allows true estimation of the genetic parameters affecting phenotypes. Multigenic variation plays a central role in the evolution of complex characteristics, among which pleiotropy, where a single gene affects several phenotypic characters, has a large influence. While pleiotropic interactions provide functional specificity, they increase the challenge of gene discovery and functional analysis. Overcoming pleiotropy-based phenotypic trade-offs offers potential for assisting breeding for complex traits. Modelling higher order nonallelic epistatic interaction, pleiotropy and non-pleiotropy-induced variation, and genotype × environment interaction in genomic selection may provide new paths to increase the productivity and stress tolerance for next generation of crop cultivars. Advances in statistical models, software and algorithm developments, and genomic research have facilitated dissecting the nature and extent of pleiotropy and epistasis. We overview emerging approaches to exploit positive (and avoid negative) epistatic and pleiotropic interactions in a plant breeding context, including developing avenues of artificial intelligence, novel exploitation of large-scale genomics and phenomics data, and involvement of genes with minor effects to analyse epistatic interactions and pleiotropic quantitative trait loci, including missing heritability.

Testing for a role of postzygotic incompatibilities in rapidly speciated Lake Victoria cichlids.

Intrinsic postzygotic hybrid incompatibilities are usually due to negative epistatic interactions between alleles from different parental genomes. While such incompatibilities are thought to be uncommon in speciation with gene flow, they may be important if such speciation results from a hybrid population. Here we aimed to test this idea in the endemic cichlid fishes of Lake Victoria. Hundreds of species have evolved within the lake in <15k years from hybrid progenitors. While the importance of prezygotic barriers to gene flow is well established in this system, the possible relevance of postzygotic genetic incompatibilities is unknown. We inferred the presence of negative epistatic interactions from systematic patterns of genotype ratio distortions in experimental crosses and wild samples. We then compared the positions of putative incompatibility loci to regions of high genetic differentiation between sympatric sister species and between members of clades that may have arisen in the early history of this radiation, and further determined if the loci showed fixed differences between the closest living relatives of the lineages ancestral to the hybrid progenitors. Overall, we find little evidence for a major role of intrinsic postzygotic incompatibilities in the Lake Victoria radiation. However, we find putative incompatibility loci significantly more often coinciding with islands of genetic differentiation between species that separated early in the radiation than between the younger sister species, consistent with the hypothesis that such variants segregated in the hybrid swarm and were sorted between species in the early speciation events.

Hybridological analysis of inheritance of length and width of leaves in hybrid combinations Burley tobacco

The way of inheritance, the coefficient of heritability, the manifestations of heterosis, transgression and depression in terms of the length and width of the leaves in hybrid combinations Burley tobaco are established. For that purpose are studied, the Р1 , Р2 , F1 and F2 populations of eight crosses Burley tobacco. The obtained results suggest that inheritance of the length or leaves is overrdominantly, incompletely dominantly or additive, and of the width of leaves is incompletely dominantly and overrdominantly,, as in both indicators it is always in the direction of the parent with higher values. Manifestations of heterosis and transgression are of economic importance only in terms of leaf width. The minimal number of genes that control the expression of the studied indices is small and uniform and the length and width of the leaves. The phenotypic expression of leaf size is strongly influenced by negative epistatic interactions, especially pronounced at their width. The established medium to higher values of the coefficient of heritability of the length of the leaves are an indication of a relatively equal share of influence of genotype and environmental conditions on the phenotypic manifestation of leaf length, which suggests that the selection on this indicator to be effective in earlier hybrid generations. The selection of width of the leaves will be effective in later hybrid generations due to lower values coefficient of the heritability, for this indicator. This shows that the coefficient of heritability and the related coefficient of efficiency of the selection is different in both indicators, making it difficult selection work.

Regulatory Divergence as a Mechanism for X-Autosome Incompatibilities in Caenorhabditis Nematodes.

The world's astounding biodiversity results from speciation, the process of formation of distinct species. Hybrids between species often have reduced fitness due to negative epistatic interactions between divergent genetic factors, as each lineage accumulated substitutions independently in their evolutionary history. Such negative genetic interactions can manifest as gene misexpression due to divergence in gene regulatory controls from mutations in cis-regulatory elements and trans-acting factors. Gene misexpression due to differences in regulatory controls can ultimately contribute to incompatibility within hybrids through developmental defects such as sterility and inviability. We sought to quantify the contributions of regulatory divergence to postzygotic reproductive isolation using sterile interspecies hybrids of two Caenorhabditis nematodes: Caenorhabditis briggsae and Caenorhabditis nigoni. We analyzed previous transcriptome profiles for two introgression lines with distinct homozygous X-linked fragments from C. briggsae in a C. nigoni genomic background that confers male sterility, owing to defects in spermatogenesis (Li R, et al. 2016. Specific down-regulation of spermatogenesis genes targeted by 22G RNAs in hybrid sterile males associated with an X-chromosome introgression. Genome Res. 26:1219-1232). Our analysis identified hundreds of genes that show distinct classes of nonadditive expression inheritance and regulatory divergence. We find that these nonoverlapping introgressions affect many of the same genes in the same way and demonstrate that the preponderance of transgressive gene expression is due to regulatory divergence involving compensatory and joint effects of cis- and trans-acting factors. The similar transcriptomic responses to nonoverlapping genetic perturbations of the X-chromosome implicate multiway incompatibilities as an important feature contributing to hybrid male sterility in this system.

YEvo: experimental evolution in high school classrooms selects for novel mutations that impact clotrimazole resistance in Saccharomyces cerevisiae.

Antifungal resistance in pathogenic fungi is a growing global health concern. Nonpathogenic laboratory strains of Saccharomyces cerevisiae are an important model for studying mechanisms of antifungal resistance that are relevant to understanding the same processes in pathogenic fungi. We have developed a series of laboratory modules in which high school students used experimental evolution to study antifungal resistance by isolating azole-resistant S. cerevisiae mutants and examining the genetic basis of resistance. We have sequenced 99 clones from these experiments and found that all possessed mutations previously shown to impact azole resistance, validating our approach. We additionally found recurrent mutations in an mRNA degradation pathway and an uncharacterized mitochondrial protein (Csf1) that have possible mechanistic connections to azole resistance. The scale of replication in this initiative allowed us to identify candidate epistatic interactions, as evidenced by pairs of mutations that occur in the same clone more frequently than expected by chance (positive epistasis) or less frequently (negative epistasis). We validated one of these pairs, a negative epistatic interaction between gain-of-function mutations in the multidrug resistance transcription factors Pdr1 and Pdr3. This high school-university collaboration can serve as a model for involving members of the broader public in the scientific process to make meaningful discoveries in biomedical research.

Pervasive conditional selection of driver mutations and modular epistasis networks in cancer.

Cancer driver mutations often display mutual exclusion or co-occurrence, underscoring the key role of epistasis in carcinogenesis. However, estimating the magnitude of epistasis and quantifying its effect on tumor evolution remains a challenge. We develop a method (Coselens) to quantify conditional selection on the excess of nonsynonymous substitutions in cancer genes. Coselens infers the number of drivers per gene in different partitions of a cancer genomics dataset using covariance-based mutation models and determines whether coding mutations in a gene affect selection for drivers in any other gene. Using Coselens, we identify 296 conditionally selected gene pairs across 16 cancer types in the TCGA dataset. Conditional selection affects 25%-50% of driver substitutions in tumors with >2 drivers. Conditionally co-selected genes form modular networks, whose structures challenge the traditional interpretation of within-pathway mutual exclusivity and across-pathway synergy, suggesting a more complex scenario where gene-specific across-pathway epistasis shapes differentiated cancer subtypes.

A Multilayer Interactome Network Constructed in a Forest Poplar Population Mediates the Pleiotropic Control of Complex Traits.

The effects of genes on physiological and biochemical processes are interrelated and interdependent; it is common for genes to express pleiotropic control of complex traits. However, the study of gene expression and participating pathways in vivo at the whole-genome level is challenging. Here, we develop a coupled regulatory interaction differential equation to assess overall and independent genetic effects on trait growth. Based on evolutionary game theory and developmental modularity theory, we constructed multilayer, omnigenic networks of bidirectional, weighted, and positive or negative epistatic interactions using a forest poplar tree mapping population, which were organized into metagalactic, intergalactic, and local interstellar networks that describe layers of structure between modules, submodules, and individual single nucleotide polymorphisms, respectively. These multilayer interactomes enable the exploration of complex interactions between genes, and the analysis of not only differential expression of quantitative trait loci but also previously uncharacterized determinant SNPs, which are negatively regulated by other SNPs, based on the deconstruction of genetic effects to their component parts. Our research framework provides a tool to comprehend the pleiotropic control of complex traits and explores the inherent directional connections between genes in the structure of omnigenic networks.

Molecular Mechanisms of Genetic Interaction (Epistasis) in the Evolution and Management of Antibiotic Resistance Tuberculosis: Current Consequence and Future Perspectives

Tuberculosis (TB) is an infectious chronic human disease caused by Mycobacterium tuberculosis (MTB) bacteria. M. tuberculosis has a great capability of resistance with plentiful natural and acquired mechanisms in their genome that contribute to the spread of highly drug resistance strains and became major public health concern. The majority of drug resistance in M. tuberculosis strains has been resulted from a numbers of chromosomal mutation events most of which are due to the mechanisms of epistasis that leads to the creation of resistance genes to anti-TB drugs. Epistasis can occur when two or more mutations interact with each other to express new phenotypic traits to modify their fitness cost. Thus, the objective of this review was to assessed the molecular mechanisms of epistasis and its consequences in the evolution and managements of antibiotic resistance-TB. The epistatic interactions within and between resistance gene mutations in M. tuberculosis could be detected by co-culture competitive fitness experimental assay under optimal growth conditions that showed either significantly negative or improving deleterious positive fitness effect. Molecular mechanisms of epistatic interaction could have important practical consequences in the trajectory of drug resistance, evolution of antimicrobial resistance and management of antibiotic resistance-TB. Understanding the evolution of M. tuberculosis under antibiotic treatments is a burning issue today. Unlike the deleterious positive epistasis, the beneficial negative epistatic interaction of resistance gene mutations under multidrug therapy method and/or collateral drug sensitivity approaches based on the knowledge of drug combinations help to mitigate the spread of drug-resistant strains, reduce treatment duration, minimize adverse drug effects on evolution of MDR/XDR-TB and improve treatment outcomes of TB patients.

Long-term experimental evolution of HIV-1 reveals effects of environment and mutational history.

An often-returning question for not only HIV-1, but also other organisms, is how predictable evolutionary paths are. The environment, mutational history, and random processes can all impact the exact evolutionary paths, but to which extent these factors contribute to the evolutionary dynamics of a particular system is an open question. Especially in a virus like HIV-1, with a large mutation rate and large population sizes, evolution is expected to be highly predictable if the impact of environment and history is low, and evolution is not neutral. We investigated the effect of environment and mutational history by analyzing sequences from a long-term evolution experiment, in which HIV-1 was passaged on 2 different cell types in 8 independent evolutionary lines and 8 derived lines, 4 of which involved a switch of the environment. The experiments lasted for 240-300 passages, corresponding to approximately 400-600 generations or almost 3 years. The sequences show signs of extensive parallel evolution-the majority of mutations that are shared between independent lines appear in both cell types, but we also find that both environment and mutational history significantly impact the evolutionary paths. We conclude that HIV-1 evolution is robust to small changes in the environment, similar to a transmission event in the absence of an immune response or drug pressure. We also find that the fitness landscape of HIV-1 is largely smooth, although we find some evidence for both positive and negative epistatic interactions between mutations.

Integrative Omics Analysis Reveals a Limited Transcriptional Shock After Yeast Interspecies Hybridization.

The formation of interspecific hybrids results in the coexistence of two diverged genomes within the same nucleus. It has been hypothesized that negative epistatic interactions and regulatory interferences between the two sub-genomes may elicit a so-called genomic shock involving, among other alterations, broad transcriptional changes. To assess the magnitude of this shock in hybrid yeasts, we investigated the transcriptomic differences between a newly formed Saccharomyces cerevisiae × Saccharomyces uvarum diploid hybrid and its diploid parentals, which diverged ∼20 mya. RNA sequencing (RNA-Seq) based allele-specific expression (ASE) analysis indicated that gene expression changes in the hybrid genome are limited, with only ∼1–2% of genes significantly altering their expression with respect to a non-hybrid context. In comparison, a thermal shock altered six times more genes. Furthermore, differences in the expression between orthologous genes in the two parental species tended to be diminished for the corresponding homeologous genes in the hybrid. Finally, and consistent with the RNA-Seq results, we show a limited impact of hybridization on chromatin accessibility patterns, as assessed with assay for transposase-accessible chromatin using sequencing (ATAC-Seq). Overall, our results suggest a limited genomic shock in a newly formed yeast hybrid, which may explain the high frequency of successful hybridization in these organisms.

Atypical organizations and epistatic interactions of CRISPRs and cas clusters in genomes and their mobile genetic elements.

Prokaryotes use CRISPR–Cas systems for adaptive immunity, but the reasons for the frequent existence of multiple CRISPRs and cas clusters remain poorly understood. Here, we analysed the joint distribution of CRISPR and cas genes in a large set of fully sequenced bacterial genomes and their mobile genetic elements. Our analysis suggests few negative and many positive epistatic interactions between Cas subtypes. The latter often result in complex genetic organizations, where a locus has a single adaptation module and diverse interference mechanisms that might provide more effective immunity. We typed CRISPRs that could not be unambiguously associated with a cas cluster and found that such complex loci tend to have unique type I repeats in multiple CRISPRs. Many chromosomal CRISPRs lack a neighboring Cas system and they often have repeats compatible with the Cas systems encoded in trans. Phages and 25 000 prophages were almost devoid of CRISPR–Cas systems, whereas 3% of plasmids had CRISPR–Cas systems or isolated CRISPRs. The latter were often compatible with the chromosomal cas clusters, suggesting that plasmids can co-opt the latter. These results highlight the importance of interactions between CRISPRs and cas present in multiple copies and in distinct genomic locations in the function and evolution of bacterial immunity.

Antibiotic Resistance Evolution Is Contingent on the Quorum-Sensing Response in Pseudomonas aeruginosa.

Different works have explored independently the evolution toward antibiotic resistance and the role of eco-adaptive mutations in the adaptation to a new habitat (as the infected host) of bacterial pathogens. However, knowledge about the connection between both processes is still limited. We address this issue by comparing the evolutionary trajectories toward antibiotic resistance of a Pseudomonas aeruginosa lasR defective mutant and its parental wild-type strain, when growing in presence of two ribosome-targeting antibiotics. Quorum-sensing lasR defective mutants are selected in P. aeruginosa populations causing chronic infections. Further, we observed they are also selected in vitro as a first adaptation for growing in culture medium. By using experimental evolution and whole-genome sequencing, we found that the evolutionary trajectories of P. aeruginosa in presence of these antibiotics are different in lasR defective and in wild-type backgrounds, both at the phenotypic and the genotypic levels. Recreation of a set of mutants in both genomic backgrounds (either wild type or lasR defective) allowed us to determine the existence of negative epistatic interactions between lasR and antibiotic resistance determinants. These epistatic interactions could lead to mutual contingency in the evolution of antibiotic resistance when P. aeruginosa colonizes a new habitat in presence of antibiotics. If lasR mutants are selected first, this would constraint antibiotic resistance evolution. Conversely, when resistance mutations (at least those studied in the present work) are selected, lasR mutants may not be selected in presence of antibiotics. These results underlie the importance of contingency and epistatic interactions in modulating antibiotic resistance evolution.

Potential limits to the benefits of admixture during biological invasion.

Species introductions often bring together genetically divergent source populations, resulting in genetic admixture. This geographic reshuffling of diversity has the potential to generate favourable new genetic combinations, facilitating the establishment and invasive spread of introduced populations. Observational support for the superior performance of admixed introductions has been mixed, however, and the broad importance of admixture to invasion questioned. Under most underlying mechanisms, admixture's benefits should be expected to increase with greater divergence among and lower genetic diversity within source populations, though these effects have not been quantified in invaders. We experimentally crossed source populations differing in divergence in the invasive plant Centaurea solstitialis. Crosses resulted in many positive (heterotic) interactions, but fitness benefits declined and were ultimately negative at high source divergence, with patterns suggesting cytonuclear epistasis. We explored the literature to assess whether such negative epistatic interactions might be impeding admixture at high source population divergence. Admixed introductions reported for plants came from sources with a wide range of genetic variation, but were disproportionately absent where there was high genetic divergence among native populations. We conclude that while admixture is common in species introductions and often happens under conditions expected to be beneficial to invaders, these conditions may be constrained by predictable negative genetic interactions, potentially explaining conflicting evidence for admixture's benefits to invasion.

Bacterial Signaling Nucleotides Inhibit Yeast Cell Growth by Impacting Mitochondrial and Other Specifically Eukaryotic Functions.

ABSTRACTWe have engineered Saccharomyces cerevisiae to inducibly synthesize the prokaryotic signaling nucleotides cyclic di-GMP (cdiGMP), cdiAMP, and ppGpp in order to characterize the range of effects these nucleotides exert on eukaryotic cell function during bacterial pathogenesis. Synthetic genetic array (SGA) and transcriptome analyses indicated that, while these compounds elicit some common reactions in yeast, there are also complex and distinctive responses to each of the three nucleotides. All three are capable of inhibiting eukaryotic cell growth, with the guanine nucleotides exhibiting stronger effects than cdiAMP. Mutations compromising mitochondrial function and chromatin remodeling show negative epistatic interactions with all three nucleotides. In contrast, certain mutations that cause defects in chromatin modification and ribosomal protein function show positive epistasis, alleviating growth inhibition by at least two of the three nucleotides. Uniquely, cdiGMP is lethal both to cells growing by respiration on acetate and to obligately fermentative petite mutants. cdiGMP is also synthetically lethal with the ribonucleotide reductase (RNR) inhibitor hydroxyurea. Heterologous expression of the human ppGpp hydrolase Mesh1p prevented the accumulation of ppGpp in the engineered yeast and restored cell growth. Extensive in vivo interactions between bacterial signaling molecules and eukaryotic gene function occur, resulting in outcomes ranging from growth inhibition to death. cdiGMP functions through a mechanism that must be compensated by unhindered RNR activity or by functionally competent mitochondria. Mesh1p may be required for abrogating the damaging effects of ppGpp in human cells subjected to bacterial infection.

Abundance and co-occurrence of extracellular capsules increase environmental breadth: Implications for the emergence of pathogens.

Extracellular capsules constitute the outermost layer of many bacteria, are major virulence factors, and affect antimicrobial therapies. They have been used as epidemiological markers and recently became vaccination targets. Despite the efforts to biochemically serotype capsules in a few model pathogens, little is known of their taxonomic and environmental distribution. We developed, validated, and made available a computational tool, CapsuleFinder, to identify capsules in genomes. The analysis of over 2500 prokaryotic genomes, accessible in a database, revealed that ca. 50% of them—including Archaea—encode a capsule. The Wzx/Wzy-dependent capsular group was by far the most abundant. Surprisingly, a fifth of the genomes encode more than one capsule system—often from different groups—and their non-random co-occurrence suggests the existence of negative and positive epistatic interactions. To understand the role of multiple capsules, we queried more than 6700 metagenomes for the presence of species encoding capsules and showed that their distribution varied between environmental categories and, within the human microbiome, between body locations. Species encoding capsules, and especially those encoding multiple capsules, had larger environmental breadths than the other species. Accordingly, capsules were more frequent in environmental bacteria than in pathogens and, within the latter, they were more frequent among facultative pathogens. Nevertheless, capsules were frequent in clinical samples, and were usually associated with fast-growing bacteria with high infectious doses. Our results suggest that capsules increase the environmental range of bacteria and make them more resilient to environmental perturbations. Capsules might allow opportunistic pathogens to profit from empty ecological niches or environmental perturbations, such as those resulting from antibiotic therapy, to colonize the host. Capsule-associated virulence might thus be a by-product of environmental adaptation. Understanding the role of capsules in natural environments might enlighten their function in pathogenesis.