Universal signatures of transposable element compartmentalization across eukaryotic genomes.

The evolutionary mechanisms that drive the emergence of genome architecture remain poorly understood but can now be assessed with unprecedented power due to the massive accumulation of genome assemblies spanning phylogenetic diversity1,2. Transposable elements (TEs) are a rich source of large-effect mutations since they directly and indirectly drive genomic structural variation and changes in gene expression3. Here, we demonstrate universal patterns of TE compartmentalization across eukaryotic genomes spanning ~1.7 billion years of evolution, in which TEs colocalize with gene families under strong predicted selective pressure for dynamic evolution and involved in specific functions. For non-pathogenic species these genes represent families involved in defense, sensory perception and environmental interaction, whereas for pathogenic species, TE-compartmentalized genes are highly enriched for pathogenic functions. Many TE-compartmentalized gene families display signatures of positive selection at the molecular level. Furthermore, TE-compartmentalized genes exhibit an excess of high-frequency alleles for polymorphic TE insertions in fruit fly populations. We postulate that these patterns reflect selection for adaptive TE insertions as well as TE-associated structural variants. This process may drive the emergence of a shared TE-compartmentalized genome architecture across diverse eukaryotic lineages.

Evaluating the performance of Plasmodium falciparum genetic metrics for inferring National Malaria Control Programme reported incidence in Senegal.

BACKGROUND: Genetic surveillance of the Plasmodium falciparum parasite shows great promise for helping National Malaria Control Programmes (NMCPs) assess parasite transmission. Genetic metrics such as the frequency of polygenomic (multiple strain) infections, genetic clones, and the complexity of infection (COI, number of strains per infection) are correlated with transmission intensity. However, despite these correlations, it is unclear whether genetic metrics alone are sufficient to estimate clinical incidence. METHODS: This study examined parasites from 3147 clinical infections sampled between the years 2012-2020 through passive case detection (PCD) across 16 clinic sites spread throughout Senegal. Samples were genotyped with a 24 single nucleotide polymorphism (SNP) molecular barcode that detects parasite strains, distinguishes polygenomic (multiple strain) from monogenomic (single strain) infections, and identifies clonal infections. To determine whether genetic signals can predict incidence, a series of Poisson generalized linear mixed-effects models were constructed to predict the incidence level at each clinical site from a set of genetic metrics designed to measure parasite clonality, superinfection, and co-transmission rates. RESULTS: Model-predicted incidence was compared with the reported standard incidence data determined by the NMCP for each clinic and found that parasite genetic metrics generally correlated with reported incidence, with departures from expected values at very low annual incidence (< 10/1000/annual [‰]). CONCLUSIONS: When transmission is greater than 10 cases per 1000 annual parasite incidence (annual incidence > 10‰), parasite genetics can be used to accurately infer incidence and is consistent with superinfection-based hypotheses of malaria transmission. When transmission was < 10‰, many of the correlations between parasite genetics and incidence were reversed, which may reflect the disproportionate impact of importation and focal transmission on parasite genetics when local transmission levels are low.

Malaria surveillance reveals parasite relatedness, signatures of selection, and correlates of transmission across Senegal.

We here analyze data from the first year of an ongoing nationwide program of genetic surveillance of Plasmodium falciparum parasites in Senegal. The analysis is based on 1097 samples collected at health facilities during passive malaria case detection in 2019; it provides a baseline for analyzing parasite genetic metrics as they vary over time and geographic space. The study's goal was to identify genetic metrics that were informative about transmission intensity and other aspects of transmission dynamics, focusing on measures of genetic relatedness between parasites. We found the best genetic proxy for local malaria incidence to be the proportion of polygenomic infections (those with multiple genetically distinct parasites), although this relationship broke down at low incidence. The proportion of related parasites was less correlated with incidence while local genetic diversity was uninformative. The type of relatedness could discriminate local transmission patterns: two nearby areas had similarly high fractions of relatives, but one was dominated by clones and the other by outcrossed relatives. Throughout Senegal, 58% of related parasites belonged to a single network of relatives, within which parasites were enriched for shared haplotypes at known and suspected drug resistance loci and at one novel locus, reflective of ongoing selection pressure.

Evaluating the performance of Plasmodium falciparum genetics for inferring National Malaria Control Program reported incidence in Senegal.

Genetic surveillance of the Plasmodium falciparum parasite shows great promise for helping National Malaria Control Programs (NMCPs) assess parasite transmission. Genetic metrics such as the frequency of polygenomic (multiple strain) infections, genetic clones, and the complexity of infection (COI, number of strains per infection) are correlated with transmission intensity. However, despite these correlations, it is unclear whether genetic metrics alone are sufficient to estimate clinical incidence. Here, we examined parasites from 3,147 clinical infections sampled between the years 2012-2020 through passive case detection (PCD) across 16 clinic sites spread throughout Senegal. Samples were genotyped with a 24 single nucleotide polymorphism (SNP) molecular barcode that detects parasite strains, distinguishes polygenomic (multiple strain) from monogenomic (single strain) infections, and identifies clonal infections. To determine whether genetic signals can predict incidence, we constructed a series of Poisson generalized linear mixed-effects models to predict the incidence level at each clinical site from a set of genetic metrics designed to measure parasite clonality, superinfection, and co-transmission rates. We compared the model-predicted incidence with the reported standard incidence data determined by the NMCP for each clinic and found that parasite genetic metrics generally correlated with reported incidence, with departures from expected values at very low annual incidence (<10/1000/annual [‰]). When transmission is greater than 10 cases per 1000 annual parasite incidence (annual incidence >10 ‰), parasite genetics can be used to accurately infer incidence and is consistent with superinfection-based hypotheses of malaria transmission. When transmission was <10 ‰, we found that many of the correlations between parasite genetics and incidence were reversed, which we hypothesize reflects the disproportionate impact of importation and focal transmission on parasite genetics when local transmission levels are low.

Malaria surveillance reveals parasite relatedness, signatures of selection, and correlates of transmission across Senegal.

Parasite genetic surveillance has the potential to play an important role in malaria control. We describe here an analysis of data from the first year of an ongoing, nationwide program of genetic surveillance of Plasmodium falciparum parasites in Senegal, intended to provide actionable information for malaria control efforts. Looking for a good proxy for local malaria incidence, we found that the best predictor was the proportion of polygenomic infections (those with multiple genetically distinct parasites), although that relationship broke down in very low incidence settings (r = 0.77 overall). The proportion of closely related parasites in a site was more weakly correlated ( r = -0.44) with incidence while the local genetic diversity was uninformative. Study of related parasites indicated their potential for discriminating local transmission patterns: two nearby study areas had similarly high fractions of relatives, but one area was dominated by clones and the other by outcrossed relatives. Throughout the country, 58% of related parasites proved to belong to a single network of relatives, within which parasites were enriched for shared haplotypes at known and suspected drug resistance loci as well as at one novel locus, reflective of ongoing selection pressure.

Two decades of molecular surveillance in Senegal reveal changes in known drug resistance mutations associated with historical drug use and seasonal malaria chemoprevention.

Drug resistance in Plasmodium falciparum is a major threat to malaria control efforts. We analyzed data from two decades (2000-2020) of continuous molecular surveillance of P. falciparum parasite strains in Senegal to determine how historical changes in drug administration policy may have affected parasite evolution. We profiled several known drug resistance markers and their surrounding haplotypes using a combination of single nucleotide polymorphism (SNP) molecular surveillance and whole-genome sequence (WGS) based population genomics. We observed rapid changes in drug resistance markers associated with the withdrawal of chloroquine and introduction of sulfadoxine-pyrimethamine in 2003. We also observed a rapid increase in Pfcrt K76T and decline in Pfdhps A437G starting in 2014, which we hypothesize may reflect changes in resistance or fitness caused by seasonal malaria chemoprevention (SMC). Parasite populations evolve rapidly in response to drug use, and SMC preventive efficacy should be closely monitored.

Artemisinin resistance mutations in Pfcoronin impede hemoglobin uptake.

Artemisinin (ART) combination therapies have been critical in reducing malaria morbidity and mortality, but these important drugs are threatened by growing resistance associated with mutations in Pfcoronin and Pfkelch13 . Here, we describe the mechanism of Pfcoronin -mediated ART resistance. Pf Coronin interacts with Pf Actin and localizes to membranes of the parasite periphery, the digestive vacuole (DV), and a putative pre-DV compartment (PPDC)-all structures involved in the trafficking of hemoglobin from the RBC for degradation in the DV. Pfcoronin mutations alter Pf Actin homeostasis and impair the development and morphology of the PPDC. Ultimately, these changes are associated with decreased uptake of red blood cell cytosolic contents by ring-stage Plasmodium falciparum . Previous work has identified decreased hemoglobin uptake as the mechanism of Pfkelch 13-mediated ART resistance. This work demonstrates that Pf Coronin appears to act via a parallel pathway. For both Pfkelch13 -mediated and Pfcoronin -mediated ART resistance, we hypothesize that the decreased hemoglobin uptake in ring stage parasites results in less heme-based activation of the artemisinin endoperoxide ring and reduced cytocidal activity. This study deepens our understanding of ART resistance, as well as hemoglobin uptake and development of the DV in early-stage parasites.

R H: a genetic metric for measuring intrahost Plasmodium falciparum relatedness and distinguishing cotransmission from superinfection.

Multiple-strain (polygenomic) infections are a ubiquitous feature of Plasmodium falciparum parasite population genetics. Under simple assumptions of superinfection, polygenomic infections are hypothesized to be the result of multiple infectious bites. As a result, polygenomic infections have been used as evidence of repeat exposure and used to derive genetic metrics associated with high transmission intensity. However, not all polygenomic infections are the result of multiple infectious bites. Some result from the transmission of multiple, genetically related strains during a single infectious bite (cotransmission). Superinfection and cotransmission represent two distinct transmission processes, and distinguishing between the two could improve inferences regarding parasite transmission intensity. Here, we describe a new metric, R H, that utilizes the correlation in allelic state (heterozygosity) within polygenomic infections to estimate the likelihood that the observed complexity resulted from either superinfection or cotransmission. R H is flexible and can be applied to any type of genetic data. As a proof of concept, we used R H to quantify polygenomic relatedness and estimate cotransmission and superinfection rates from a set of 1,758 malaria infections genotyped with a 24 single nucleotide polymorphism (SNP) molecular barcode. Contrary to expectation, we found that cotransmission was responsible for a significant fraction of 43% to 53% of the polygenomic infections collected in three distinct epidemiological regions in Senegal. The prediction that polygenomic infections frequently result from cotransmission stresses the need to incorporate estimates of relatedness within polygenomic infections to ensure the accuracy of genomic epidemiology surveillance data for informing public health activities.

Gregor Johann Mendel: From peasant to priest, pedagogue, and prelate.

Gregor Mendel was an Augustinian priest in the Monastery of St. Thomas in Brünn (Brno, Czech Republic) as well as a civilian employee who taught natural history and physics in the Brünn Modern School. The monastery's secular function was to provide teachers for the public schools across Moravia. It was a cultural, educational, and artistic center with an elite core of friar-teachers with a well-stocked library and other amenities including a gourmet kitchen. It was wealthy, with far-flung holdings yielding income from agricultural productions. Mendel had failed his tryout as a parish priest and did not complete his examination for teaching certification despite 2 y of study at the University of Vienna. In addition to his teaching and religious obligations, Mendel carried out daily meteorological and astronomical observations, cared for the monastery's fruit orchard and beehives, and tended plants in the greenhouse and small outdoor gardens. In the years 1856 to 1863, he carried out experiments on heredity of traits in garden peas regarded as revolutionary today but not widely recognized during his lifetime and until 16 y after his death. In 1868 he was elected abbot of the monastery, a significantly elevated position in the ecclesiastical and civil hierarchy. While he had hoped to be elected, and was honored to accept, he severely underestimated its administrative responsibilities and gradually had to abandon his scientific interests. The last decade of his life was marred by an ugly dispute with civil authorities over monastery taxation.

Plasmodium falciparum genomic surveillance reveals spatial and temporal trends, association of genetic and physical distance, and household clustering.

Molecular epidemiology using genomic data can help identify relationships between malaria parasite population structure, malaria transmission intensity, and ultimately help generate actionable data to assess the effectiveness of malaria control strategies. Genomic data, coupled with geographic information systems data, can further identify clusters or hotspots of malaria transmission, parasite genetic and spatial connectivity, and parasite movement by human or mosquito mobility over time and space. In this study, we performed longitudinal genomic surveillance in a cohort of 70 participants over four years from different neighborhoods and households in Thiès, Senegal-a region of exceptionally low malaria transmission (entomological inoculation rate less than 1). Genetic identity (identity by state, IBS) was established using a 24-single nucleotide polymorphism molecular barcode, identity by descent was calculated from whole genome sequence data, and a hierarchical Bayesian regression model was used to establish genetic and spatial relationships. Our results show clustering of genetically similar parasites within households and a decline in genetic similarity of parasites with increasing distance. One household showed extremely high diversity and warrants further investigation as to the source of these diverse genetic types. This study illustrates the utility of genomic data with traditional epidemiological approaches for surveillance and detection of trends and patterns in malaria transmission not only by neighborhood but also by household. This approach can be implemented regionally and countrywide to strengthen and support malaria control and elimination efforts.

Switching an active site helix in dihydrofolate reductase reveals limits to subdomain modularity.

To what degree are individual structural elements within proteins modular such that similar structures from unrelated proteins can be interchanged? We study subdomain modularity by creating 20 chimeras of an enzyme, Escherichia coli dihydrofolate reductase (DHFR), in which a catalytically important, 10-residue α-helical sequence is replaced by α-helical sequences from a diverse set of proteins. The chimeras stably fold but have a range of diminished thermal stabilities and catalytic activities. Evolutionary coupling analysis indicates that the residues of this α-helix are under selection pressure to maintain catalytic activity in DHFR. Reversion to phenylalanine at key position 31 was found to partially restore catalytic activity, which could be explained by evolutionary coupling values. We performed molecular dynamics simulations using replica exchange with solute tempering. Chimeras with low catalytic activity exhibit nonhelical conformations that block the binding site and disrupt the positioning of the catalytically essential residue D27. Simulation observables and in vitro measurements of thermal stability and substrate-binding affinity are strongly correlated. Several E. coli strains with chromosomally integrated chimeric DHFRs can grow, with growth rates that follow predictions from a kinetic flux model that depends on the intracellular abundance and catalytic activity of DHFR. Our findings show that although α-helices are not universally substitutable, the molecular and fitness effects of modular segments can be predicted by the biophysical compatibility of the replacement segment.

Genetic surveillance for monitoring the impact of drug use on Plasmodium falciparum populations.

The use of antimalarial drugs is an effective strategy in the fight against malaria. However, selection of drug resistant parasites is a constant threat to the continued use of this approach. Antimalarial drugs are used not only to treat infections but also as part of population-level strategies to reduce malaria transmission toward elimination. While there is strong evidence that the ongoing use of antimalarial drugs increases the risk of the emergence and spread of drug-resistant parasites, it is less clear how population-level use of drug-based interventions like seasonal malaria chemoprevention (SMC) or mass drug administration (MDA) may contribute to drug resistance or loss of drug efficacy. Critical to sustained use of drug-based strategies for reducing the burden of malaria is the surveillance of population-level signals related to transmission reduction and resistance selection. Here we focus on Plasmodium falciparum and discuss the genetic signatures of a parasite population that are correlated with changes in transmission and related to drug pressure and resistance as a result of drug use. We review the evidence for MDA and SMC contributing to malaria burden reduction and drug resistance selection and examine the use and impact of these interventions in Senegal. Throughout we consider best strategies for ongoing surveillance of both population and resistance signals in the context of different parasite population parameters. Finally, we propose a roadmap for ongoing surveillance during population-level drug-based interventions to reduce the global malaria burden.

Fine-scale variation in malaria prevalence across ecological regions in Madagascar: a cross-sectional study.

BACKGROUND: Large-scale variation in ecological parameters across Madagascar is hypothesized to drive varying spatial patterns of malaria infection. However, to date, few studies of parasite prevalence with resolution at finer, sub-regional spatial scales are available. As a result, there is a poor understanding of how Madagascar's diverse local ecologies link with variation in the distribution of infections at the community and household level. Efforts to preserve Madagascar's ecological diversity often focus on improving livelihoods in rural communities near remaining forested areas but are limited by a lack of data on their infectious disease burden. METHODS: To investigate spatial variation in malaria prevalence at the sub-regional scale in Madagascar, we sampled 1476 households (7117 total individuals, all ages) from 31 rural communities divided among five ecologically distinct regions. The sampled regions range from tropical rainforest to semi-arid, spiny forest and include communities near protected areas including the Masoala, Makira, and Mikea forests. Malaria prevalence was estimated by rapid diagnostic test (RDT) cross-sectional surveys performed during malaria transmission seasons over 2013-2017. RESULTS: Indicative of localized hotspots, malaria prevalence varied more than 10-fold between nearby (< 50 km) communities in some cases. Prevalence was highest on average in the west coast region (Morombe district, average community prevalence 29.4%), situated near protected dry deciduous forest habitat. At the household level, communities in southeast Madagascar (Mananjary district) were observed with over 50% of households containing multiple infected individuals at the time of sampling. From simulations accounting for variation in household size and prevalence at the community level, we observed a significant excess of households with multiple infections in rural communities in southwest and southeast Madagascar, suggesting variation in risk within communities. CONCLUSIONS: Our data suggest that the malaria infection burden experienced by rural communities in Madagascar varies greatly at smaller spatial scales (i.e., at the community and household level) and that the southeast and west coast ecological regions warrant further attention from disease control efforts. Conservation and development efforts in these regions may benefit from consideration of the high, and variable, malaria prevalences among communities in these areas.

Relevance of Higher-Order Epistasis in Drug Resistance.

We studied five chemically distinct but related 1,3,5-triazine antifolates with regard to their effects on growth of a set of mutants in dihydrofolate reductase. The mutants comprise a combinatorially complete data set of all 16 possible combinations of four amino acid replacements associated with resistance to pyrimethamine in the malaria parasite Plasmodium falciparum. Pyrimethamine was a mainstay medication for malaria for many years, and it is still in use in intermittent treatment during pregnancy or as a partner drug in artemisinin combination therapy. Our goal was to investigate the extent to which the alleles yield similar adaptive topographies and patterns of epistasis across chemically related drugs. We find that the adaptive topographies are indeed similar with the same or closely related alleles being fixed in computer simulations of stepwise evolution. For all but one of the drugs the topography features at least one suboptimal fitness peak. Our data are consistent with earlier results indicating that third order and higher epistatic interactions appear to contribute only modestly to the overall adaptive topography, and they are largely conserved. In regard to drug development, our data suggest that higher-order interactions are likely to be of little value as an advisory tool in the choice of lead compounds.

Genetic background and PfKelch13 affect artemisinin susceptibility of PfCoronin mutants in Plasmodium falciparum.

Malaria continues to impose a significant health burden in the continent of Africa with 213 million cases in 2018 alone, representing 93% of cases worldwide. Because of high transmission of malaria within the continent, the selection pressures to develop drug resistance in African parasites are distinct compared to the rest of the world. In light of the spread of resistance to artemisinin conferred by the C580Y mutation in the PfKelch13 propeller domain in Southeast Asia, and its independent emergence in South America, it is important to study genetic determinants of resistance in the African context using African parasites. Through in vitro evolution of Senegalese parasites, we had previously generated the artemisinin-resistant parasites Pikine_R and Thiès_R and established pfcoronin mutations to be sufficient to confer artemisinin resistance in the standard ring-stage survival assay (RSA). In the current study, we used genetic analysis of revertants to demonstrate pfcoronin to be the major driver of elevated RSA in the artemisinin-resistant parasites Pikine_R and Thiès_R evolved in vitro. We interrogated the role of a second gene PF3D7_1433800, which also had mutations in both the Pikine_R and Thiès_R selected lines, but found no evidence of a contribution to reduced susceptibility in the RSA survival assay. Nevertheless, our genetic analysis demonstrates that parasite genetic background is important in the level of pfcoronin mediated RSA survival, and therefore we cannot rule out a role for PF3D7_1433800 in other genetic backgrounds. Finally, we tested the potential synergy between the mutations of pfcoronin and pfkelch13 through the generation of single and double mutants in the Pikine genetic background and found that the contribution of pfcoronin to reduced susceptibility is masked by the presence of pfkelch13. This phenomenon was also observed in the 3D7 background, suggesting that pfcoronin may mediate its effects via the same pathway as pfkelch13. Investigating the biology of proteins containing the beta-propeller domain could further elucidate the different pathways that the parasite could use to attain resistance.

Study Protocol: A Cross-Sectional Examination of Socio-Demographic and Ecological Determinants of Nutrition and Disease Across Madagascar.

Madagascar has experienced significant environmental change since 1960, particularly through forest clearing for agricultural expansion. Climatic patterns are undergoing change in Madagascar as well, with increasing temperatures, droughts, and cyclonic activity. The impact of these environmental and climatic changes will pose threats to food availability, income generation, and local ecosystems, with significant potential effects on the spatial and temporal distribution of disease burden. This study seeks to describe the health status of a large sample of geographically and socially diverse Malagasy communities through multiple clinical measurements, detailed social surveys, and paired data on regional variation in local ecologies. With an increased understanding of the current patterns of variation in human health and nutrition, future studies will be better able to identify associations with climate and anticipate and mitigate the burdens expected from larger, longer-term changes. Our mixed-method approach included an observational cross-sectional study. Research subjects were men, women, and children from 1,125 households evenly distributed across 24 communities in four ecologically and socio-demographically distinct regions of Madagascar. For these 1,125 households, all persons of both sexes and all ages therein (for a total of 6,292 individuals) were recruited into the research study and a total of 5,882 individuals were enrolled. Through repeated social survey recalls and focus group meetings, we obtained social and demographic data, including broad categories of seasonal movements, and characterized the fluctuation of income generation, food production and dietary consumption. Through collection of clinical and biological samples for both point-of-care diagnoses and laboratory analyses, we obtained detailed occurrence (and importantly co-occurrence) data on micronutrient nutritional, infectious disease, and non-communicable disease status. Our research highlights the highly variable social, cultural, and environmental contexts of health conditions in Madagascar, and the tremendous inter-regional, inter-community, and intra-community variation in nutritional and disease status. More than 30% of the surveyed population was afflicted by anemia and 14% of the population had a current malaria infection. This type of rich metadata associated with a suite of biological samples and nutritional and disease outcome data should allow disentangling some of the underlying drivers of ill health across the changing landscapes of Madagascar.

Genetic evidence for imported malaria and local transmission in Richard Toll, Senegal.

BACKGROUND: Malaria elimination efforts can be undermined by imported malaria infections. Imported infections are classified based on travel history. METHODS: A genetic strategy was applied to better understand the contribution of imported infections and to test for local transmission in the very low prevalence region of Richard Toll, Senegal. RESULTS: Genetic relatedness analysis, based upon molecular barcode genotyping data derived from diagnostic material, provided evidence for both imported infections and ongoing local transmission in Richard Toll. Evidence for imported malaria included finding that a large proportion of Richard Toll parasites were genetically related to parasites from Thiès, Senegal, a region of moderate transmission with extensive available genotyping data. Evidence for ongoing local transmission included finding parasites of identical genotype that persisted across multiple transmission seasons as well as enrichment of highly related infections within the households of non-travellers compared to travellers. CONCLUSIONS: These data indicate that, while a large number of infections may have been imported, there remains ongoing local malaria transmission in Richard Toll. These proof-of-concept findings underscore the value of genetic data to identify parasite relatedness and patterns of transmission to inform optimal intervention selection and placement.

Evidence for Reduced Malaria Parasite Population after Application of Population-Level Antimalarial Drug Strategies in Southern Province, Zambia.

A mass drug administration trial was carried out in Southern Province, Zambia, between 2014 and 2016, in conjunction with a standard of care package that included improved surveillance, increased access to malaria case management, and sustained high levels of vector control coverage. This was preceded by mass test and treatment in the same area from 2011 to 2013. Concordant decreases in malaria prevalence in Southern Province and deaths attributed to malaria in Zambia over this time suggest that these strategies successfully reduced the malaria burden. Genetic epidemiological studies were used to assess the consequences of these interventions on parasite population structure. Analysis of parasite material derived from 1,620 rapid diagnostic test (RDT)-positive individuals obtained from studies to evaluate trial outcomes revealed a reduction in the average complexity of infection and consequential increase in the proportion of infections that harbored a single parasite genome (monogenomic infections). Highly related parasites, consistent with inbreeding, were detected after interventions were deployed. Geographical analysis indicated that the highly related infections were both clustered focally and dispersed across the study area. These findings provide genetic evidence for a reduced parasite population, with indications of inbreeding following the application of comprehensive interventions, including drug-based campaigns, that reduced the malaria burden in Southern Province. Genetic data additionally revealed the relationship between individual infections in the context of these population-level patterns, which has the potential to provide useful data for stratification and targeting of interventions to reduce the malaria burden.

Experimental evolution for niche breadth in bacteriophage T4 highlights the importance of structural genes.

Ecologists have long studied the evolution of niche breadth, including how variability in environments can drive the evolution of specialism and generalism. This concept is of particular interest in viruses, where niche breadth evolution may explain viral disease emergence, or underlie the potential for therapeutic measures like phage therapy. Despite the significance and potential applications of virus-host interactions, the genetic determinants of niche breadth evolution remain underexplored in many bacteriophages. In this study, we present the results of an evolution experiment with a model bacteriophage system, Escherichia virus T4, in several host environments: exposure to Escherichia coli C, exposure to E. coli K-12, and exposure to both E. coli C and E. coli K-12. This experimental framework allowed us to investigate the phenotypic and molecular manifestations of niche breadth evolution. First, we show that selection on different hosts led to measurable changes in phage productivity in all experimental populations. Second, whole-genome sequencing of experimental populations revealed signatures of selection. Finally, clear and consistent patterns emerged across the host environments, especially the presence of new mutations in phage structural genes-genes encoding proteins that provide morphological and biophysical integrity to a virus. A comparison of mutations found across functional gene categories revealed that structural genes acquired significantly more mutations than other categories. Our findings suggest that structural genes are central determinants in bacteriophage niche breadth.

Cohort Description of the Madagascar Health and Environmental Research-Antongil (MAHERY-Antongil) Study in Madagascar.

The Madagascar Health and Environmental Research-Antongil (MAHERY-Antongil) study cohort was set up in September 2015 to assess the nutritional value of seafood for the coastal Malagasy population living along Antongil Bay in northeastern Madagascar. Over 28 months of surveillance, we aimed to understand the relationships among different marine resource governance models, local people's fish catch, the consumption of seafood, and nutritional status. In the Antongil Bay, fisheries governance takes three general forms: traditional management, marine national parks, and co-management. Traditional management involves little to no involvement by the national government or non-governmental organizations, and focuses on culturally accepted Malagasy community practices. Co-management and marine national parks involve management support from either an non-govermental organization (NGO) or the national government. Five communities of varying governance strategies were enrolled into the study including 225 households and 1031 individuals whose diets, resource acquisition strategies, fisheries and agricultural practices, and other social, demographic and economic indicators were measured over the span of 3 years. Clinical visits with each individual were conducted at two points during the study to measure disease and nutritional status. By analyzing differences in fish catch arising from variation in governance (in addition to intra-annual seasonal changes and minor inter-annual changes), the project will allow us to calculate the public health value of sustainable fisheries management approaches for local populations. There is hope that coastal zones that are managed sustainably can increase the productivity of fisheries, increasing the catch of seafood products for poor, undernourished populations.