Evolutionary druggability for low-dimensional fitness landscapes toward new metrics for antimicrobial applications.

The term 'druggability' describes the molecular properties of drugs or targets in pharmacological interventions and is commonly used in work involving drug development for clinical applications. There are no current analogues for this notion that quantify the drug-target interaction with respect to a given target variant's sensitivity across a breadth of drugs in a panel, or a given drug's range of effectiveness across alleles of a target protein. Using data from low-dimensional empirical fitness landscapes composed of 16 ß-lactamase alleles and 7 ß-lactam drugs, we introduce two metrics that capture (i) the average susceptibility of an allelic variant of a drug target to any available drug in a given panel ('variant vulnerability'), and (ii) the average applicability of a drug (or mixture) across allelic variants of a drug target ('drug applicability'). Finally, we (iii) disentangle the quality and magnitude of interactions between loci in the drug target and the seven drug environments in terms of their mutation by mutation by environment (G x G x E) interactions, offering mechanistic insight into the variant variability and drug applicability metrics. Summarizing, we propose that our framework can be applied to other datasets and pathogen-drug systems to understand which pathogen variants in a clinical setting are the most concerning (low variant vulnerability), and which drugs in a panel are most likely to be effective in an infection defined by standing genetic variation in the pathogen drug target (high drug applicability).

Evolutionary Invasion Analysis of Modern Epidemics Highlights the Context-Dependence of Virulence Evolution.

Models are often employed to integrate knowledge about epidemics across scales and simulate disease dynamics. While these approaches have played a central role in studying the mechanics underlying epidemics, we lack ways to reliably predict how the relationship between virulence (the harm to hosts caused by an infection) and transmission will evolve in certain virus-host contexts. In this study, we invoke evolutionary invasion analysis-a method used to identify the evolution of uninvadable strategies in dynamical systems-to examine how the virulence-transmission dichotomy can evolve in models of virus infections defined by different natural histories. We reveal peculiar patterns of virulence evolution between epidemics with different disease natural histories (SARS-CoV-2 and hepatitis C virus). We discuss the findings with regards to the public health implications of predicting virus evolution, and in broader theoretical canon involving virulence evolution in host-parasite systems.

Environment by environment interactions (ExE) differ across genetic backgrounds (ExExG).

While the terms "gene-by-gene interaction" (GxG) and "gene-by-environment interaction" (GxE) are commonplace within the field of quantitative and evolutionary genetics, "environment-by-environment interaction" (ExE) is a term used less often. However, in this study, we find that environment-by-environment interactions are common and differ for different genotypes (ExExG). To reach this conclusion, we analyzed a large dataset of roughly 1,000 mutant yeast strains with varying degrees of resistance to different antifungal drugs. Many researchers endeavor to predict combinations of drugs that are more lethal than either single drug. But we show that the effectiveness of a drug combination, relative to the effectiveness of single drugs, often varies across different drug resistant mutants. Even mutants that differ by only a single nucleotide change can have dramatically different drug x drug (ExE) interactions. Studying how ExE interactions change across genotypes (ExExG) is not only important when modeling the evolution of pathogenic microbes. High throughput screens of GxG and GxE have taught us about the basic cell biology and gene regulatory networks underlying genetic interactions. ExExG has been omitted but stands to impart similar lessons about the architecture of living systems. In this study, we call attention to ExExG, measure its prevalence, introduce a new framework that in some instances better predicts its direction and magnitude, and make the case for further study of this type of genetic interaction.

Metagenomics for Pathogen Detection During a Mass Mortality Event in Songbirds.

Mass mortality events in wildlife can be indications of an emerging infectious disease. During the spring and summer of 2021, hundreds of dead passerines were reported across the eastern US. Birds exhibited a range of clinical signs including swollen conjunctiva, ocular discharge, ataxia, and nystagmus. As part of the diagnostic investigation, high-throughput metagenomic next-generation sequencing was performed across three molecular laboratories on samples from affected birds. Many potentially pathogenic microbes were detected, with bacteria forming the largest proportion; however, no singular agent was consistently identified, with many of the detected microbes also found in unaffected (control) birds and thus considered to be subclinical infections. Congruent results across laboratories have helped drive further investigation into alternative causes, including environmental contaminants and nutritional deficiencies. This work highlights the utility of metagenomic approaches in investigations of emerging diseases and provides a framework for future wildlife mortality events.

Environmental modulation of global epistasis in a drug resistance fitness landscape.

Interactions between mutations (epistasis) can add substantial complexity to genotype-phenotype maps, hampering our ability to predict evolution. Yet, recent studies have shown that the fitness effect of a mutation can often be predicted from the fitness of its genetic background using simple, linear relationships. This phenomenon, termed global epistasis, has been leveraged to reconstruct fitness landscapes and infer adaptive trajectories in a wide variety of contexts. However, little attention has been paid to how patterns of global epistasis may be affected by environmental variation, despite this variation frequently being a major driver of evolution. This is particularly relevant for the evolution of drug resistance, where antimicrobial drugs may change the environment faced by pathogens and shape their adaptive trajectories in ways that can be difficult to predict. By analyzing a fitness landscape of four mutations in a gene encoding an essential enzyme of P. falciparum (a parasite cause of malaria), here we show that patterns of global epistasis can be strongly modulated by the concentration of a drug in the environment. Expanding on previous theoretical results, we demonstrate that this modulation can be quantitatively explained by how specific gene-by-gene interactions are modified by drug dose. Importantly, our results highlight the need to incorporate potential environmental variation into the global epistasis framework in order to predict adaptation in dynamic environments.

Epistasis and pleiotropy shape biophysical protein subspaces associated with drug resistance.

Protein space is a rich analogy for genotype-phenotype maps, where amino acid sequence is organized into a high-dimensional space that highlights the connectivity between protein variants. It is a useful abstraction for understanding the process of evolution, and for efforts to engineer proteins towards desirable phenotypes. Few mentions of protein space consider how protein phenotypes can be described in terms of their biophysical components, nor do they rigorously interrogate how forces like epistasis-describing the nonlinear interaction between mutations and their phenotypic consequences-manifest across these components. In this study, we deconstruct a low-dimensional protein space of a bacterial enzyme (dihydrofolate reductase; DHFR) into "subspaces" corresponding to a set of kinetic and thermodynamic traits [k_{cat}, K_{M}, K_{i}, and T_{m} (melting temperature)]. We then examine how combinations of three mutations (eight alleles in total) display pleiotropy, or unique effects on individual subspace traits. We examine protein spaces across three orthologous DHFR enzymes (Escherichia coli, Listeria grayi, and Chlamydia muridarum), adding a genotypic context dimension through which epistasis occurs across subspaces. In doing so, we reveal that protein space is a deceptively complex notion, and that future applications to bioengineering should consider how interactions between amino acid substitutions manifest across different phenotypic subspaces.

Deconstructing taxa x taxa xenvironment interactions in the microbiota: A theoretical examination.

A major objective of microbial ecology is to identify how the composition of microbial taxa shapes host phenotypes. However, most studies focus on pairwise interactions and ignore the potentially significant effects of higher-order microbial interactions.Here, we quantify the effects of higher-order interactions among taxa on host infection risk. We apply our approach to an in silico dataset that is built to resemble a population of insect hosts with gut-associated microbial communities at risk of infection from an intestinal parasite across a breadth of nutrient environmental contexts.We find that the effect of higher-order interactions is considerable and can change appreciably across environmental contexts. Furthermore, we show that higher-order interactions can stabilize community structure thereby reducing host susceptibility to parasite invasion.Our approach illustrates how incorporating the effects of higher-order interactions among gut microbiota across environments can be essential for understanding their effects on host phenotypes.

Limited Outbreak of Highly Pathogenic Influenza A(H5N1) in Herring Gull Colony, Canada, 2022.

In summer 2022, highly pathogenic influenza A(H5N1) virus reached the herring gull (Larus argentatus subspecies smithsonianus) breeding colony on Kent Island, New Brunswick, Canada. Real-time monitoring revealed a self-limiting outbreak with low mortality. Proactive seabird surveillance is crucial for monitoring such limited outbreaks, protecting seabirds, and tracing zoonotic transmission routes.

Meteorological associations of Vibrio vulnificus clinical infections in tropical settings: Correlations with air pressure, wind speed, and temperature.

V. vulnificus is one of the deadliest waterborne pathogens, yet little is known of the ecological and environmental forces that drive outbreaks. As a nationally notifiable disease, all cases of V. vulnificus diagnosed in the United States are reported to the state in which they occurred, as well as to the Centers for Disease Control (CDC) in Atlanta, Georgia. Given that the state of Florida is a 'hotspot' for V. vulnificus in the United States, we examined the prevalence and incidence of cases reported to the Florida Department of Health (2008-2020). Using a dataset comprised of 448 cases of disease caused by V. vulnificus infection, we identified meteorological variables that were associated with clinical cases and deaths. Combined with data from the National Oceanic and Atmospheric Administration (NOAA), we first utilized correlation analysis to examine the linear relationships between satellite meteorological measurements such as wind speed, air temperature, water temperature, and sea-level pressure. We then measured the correlation of those meteorological variables with coastal cases of V. vulnificus, including the outcome, survival, or death. We also constructed a series of logistic regression models to analyze the relationship between temporal and meteorological variables during months that V. vulnificus cases were reported versus months when V. vulnificus cases were not reported. We report that between 2008 and 2020, V. vulnificus cases generally increased over time, peaking in 2017. As water temperature and air temperature increased, so too did the likelihood that infection with V. vulnificus would lead to patient death. We also found that as mean wind speed and sea-level pressure decreased, the probability that a V. vulnificus case would be reported increased. In summary, we discuss the potential factors that may contribute to the observed correlations and speculate that meteorological variables may increase in their public health relevance in light of rising global temperatures.

Epistasis meets pleiotropy in shaping biophysical protein subspaces associated with antimicrobial resistance.

Protein space is a rich analogy for genotype-phenotype maps, where amino acid sequence is organized into a high-dimensional space that highlights the connectivity between protein variants. It is a useful abstraction for understanding the process of evolution, and for efforts to engineer proteins towards desirable phenotypes. Few framings of protein space consider how higher-level protein phenotypes can be described in terms of their biophysical dimensions, nor do they rigorously interrogate how forces like epistasis-describing the nonlinear interaction between mutations and their phenotypic consequences-manifest across these dimensions. In this study, we deconstruct a low-dimensional protein space of a bacterial enzyme (dihydrofolate reductase; DHFR) into "subspaces" corresponding to a set of kinetic and thermodynamic traits [(kcat, KM, Ki, and Tm (melting temperature)]. We then examine how three mutations (eight alleles in total) display pleiotropy in their interactions across these subspaces. We extend this approach to examine protein spaces across three orthologous DHFR enzymes (Escherichia coli, Listeria grayi, and Chlamydia muridarum), adding a genotypic context dimension through which epistasis occurs across subspaces. In doing so, we reveal that protein space is a deceptively complex notion, and that the process of protein evolution and engineering should consider how interactions between amino acid substitutions manifest across different phenotypic subspaces.

Evolutionary druggability: leveraging low-dimensional fitness landscapes towards new metrics for antimicrobial applications.

The term "druggability" describes the molecular properties of drugs or targets in pharmacological interventions and is commonly used in work involving drug development for clinical applications. There are no current analogues for this notion that quantify the drug-target interaction with respect to a given target variant's sensitivity across a breadth of drugs in a panel, or a given drug's range of effectiveness across alleles of a target protein. Using data from low-dimensional empirical fitness landscapes composed of 16 ß-lactamase alleles and seven ß-lactam drugs, we introduce two metrics that capture (i) the average susceptibility of an allelic variant of a drug target to any available drug in a given panel ("variant vulnerability"), and (ii) the average applicability of a drug (or mixture) across allelic variants of a drug target ("drug applicability"). Finally, we (iii) disentangle the quality and magnitude of interactions between loci in the drug target and the seven drug environments in terms of their mutation by mutation by environment (G × G × E) interactions, offering mechanistic insight into the variant variability and drug applicability metrics. Summarizing, we propose that our framework can be applied to other datasets and pathogen-drug systems to understand which pathogen variants in a clinical setting are the most concerning (low variant vulnerability), and which drugs in a panel are most likely to be effective in an infection defined by standing genetic variation in the pathogen drug target (high drug applicability).

COVID-19 amplified racial disparities in the US criminal legal system.

The criminal legal system in the USA drives an incarceration rate that is the highest on the planet, with disparities by class and race among its signature features1-3. During the first year of the coronavirus disease 2019 (COVID-19) pandemic, the number of incarcerated people in the USA decreased by at least 17%-the largest, fastest reduction in prison population in American history4. Here we ask how this reduction influenced the racial composition of US prisons and consider possible mechanisms for these dynamics. Using an original dataset curated from public sources on prison demographics across all 50 states and the District of Columbia, we show that incarcerated white people benefited disproportionately from the decrease in the US prison population and that the fraction of incarcerated Black and Latino people sharply increased. This pattern of increased racial disparity exists across prison systems in nearly every state and reverses a decade-long trend before 2020 and the onset of COVID-19, when the proportion of incarcerated white people was increasing amid declining numbers of incarcerated Black people5. Although a variety of factors underlie these trends, we find that racial inequities in average sentence length are a major contributor. Ultimately, this study reveals how disruptions caused by COVID-19 exacerbated racial inequalities in the criminal legal system, and highlights key forces that sustain mass incarceration. To advance opportunities for data-driven social science, we publicly released the data associated with this study at Zenodo6.

Viral Evolution Shaped by Host Proteostasis Networks.

Understanding the factors that shape viral evolution is critical for developing effective antiviral strategies, accurately predicting viral evolution, and preventing pandemics. One fundamental determinant of viral evolution is the interplay between viral protein biophysics and the host machineries that regulate protein folding and quality control. Most adaptive mutations in viruses are biophysically deleterious, resulting in a viral protein product with folding defects. In cells, protein folding is assisted by a dynamic system of chaperones and quality control processes known as the proteostasis network. Host proteostasis networks can determine the fates of viral proteins with biophysical defects, either by assisting with folding or by targeting them for degradation. In this review, we discuss and analyze new discoveries revealing that host proteostasis factors can profoundly shape the sequence space accessible to evolving viral proteins. We also discuss the many opportunities for research progress proffered by the proteostasis perspective on viral evolution and adaptation.

When Vibrios Take Flight: A Meta-Analysis of Pathogenic Vibrio Species in Wild and Domestic Birds.

Of the over 100 species in the genus Vibrio, approximately twelve are associated with clinical disease, such as cholera and vibriosis. Crucially, eleven of those twelve, including Vibrio cholerae and Vibrio vulnificus, have been isolated from birds. Since 1965, pathogenic Vibrio species have been consistently isolated from aquatic and ground-foraging bird species, which has implications for public health, as well as the One Health paradigm defined as an ecology-inspired, integrative framework for the study of health and disease, inclusive of environmental, human, and animal health. In this meta-analysis, we identified 76 studies from the primary literature which report on or examine birds as hosts for pathogenic Vibrio species. We found that the burden of disease in birds was most commonly associated with V. cholerae, followed by V. metschnikovii and V. parahaemolyticus. Meta-analysis wide prevalence of our Vibrio pathogens varied from 19% for V. parahaemolyticus to 1% for V. mimicus. Wild and domestic birds were both affected, which may have implications for conservation, as well as agriculturally associated avian species. As pathogenic Vibrios become more abundant throughout the world as a result of warming estuaries and oceans, susceptible avian species should be continually monitored as potential reservoirs for these pathogens.

Exploring the expanse between theoretical questions and experimental approaches in the modern study of evolvability.

Despite several decades of computational and experimental work across many systems, evolvability remains on the periphery with regards to its status as a widely accepted and regularly applied theoretical concept. Here we propose that its marginal status is partly a result of large gaps between the diverse but disconnected theoretical treatments of evolvability and the relatively narrower range of studies that have tested it empirically. To make this case, we draw on a range of examples-from experimental evolution in microbes, to molecular evolution in proteins-where attempts have been made to mend this disconnect. We highlight some examples of progress that has been made and point to areas where synthesis and translation of existing theory can lead to further progress in the still-new field of empirical measurements of evolvability.

Gattaca as a lens on contemporary genetics: marking 25 years into the film's "not-too-distant" future.

The 1997 film Gattaca has emerged as a canonical pop culture reference used to discuss modern controversies in genetics and bioethics. It appeared in theaters a few years prior to the announcement of the "completion" of the human genome (2000), as the science of human genetics was developing a renewed sense of its social implications. The story is set in a near-future world in which parents can, with technological assistance, influence the genetic composition of their offspring on the basis of predicted life outcomes. The current moment-25 years after the film's release-offers an opportunity to reflect on where society currently stands with respect to the ideas explored in Gattaca. Here, we review and discuss several active areas of genetic research-genetic prediction, embryo selection, forensic genetics, and others-that interface directly with scenes and concepts in the film. On its silver anniversary, we argue that Gattaca remains an important reflection of society's expectations and fears with respect to the ways that genetic science has manifested in the real world. In accompanying supplemental material, we offer some thought questions to guide group discussions inside and outside of the classroom.