Biology subjects

Armstrong, E.

Publications and source records attributed to Armstrong, E..

23 records · Page 2Linked to original sources

bioRxiv2021

Genetic and structural basis for recognition of SARS-CoV-2 spike protein by a two-antibody cocktail

The SARS-CoV-2 pandemic has led to an urgent need to understand the molecular basis for immune recognition of SARS-CoV-2 spike (S) glycoprotein antigenic sites. To define the genetic and structural basis for SARS-CoV-2 neutralization, we determined the structures of two human monoclonal antibodies COV2-2196 and COV2-21301, which form the basis of the investigational antibody cocktail AZD7442, in complex with the receptor binding domain (RBD) of SARS-CoV-2. COV2-2196 forms an "aromatic cage" at the heavy/light chain interface using germline-encoded residues in complementarity determining regions (CDRs) 2 and 3 of the heavy chain and CDRs 1 and 3 of the light chain. These structural features explain why highly similar antibodies (public clonotypes) have been isolated from multiple individuals1-4. The structure of COV2-2130 reveals that an unusually long LCDR1 and HCDR3 make interactions with the opposite face of the RBD from that of COV2-2196. Using deep mutational scanning and neutralization escape selection experiments, we comprehensively mapped the critical residues of both antibodies and identified positions of concern for possible viral escape. Nonetheless, both COV2-2196 and COV2-2130 showed strong neutralizing activity against SARS-CoV-2 strain with recent variations of concern including E484K, N501Y, and D614G substitutions. These studies reveal germline-encoded antibody features enabling recognition of the RBD and demonstrate the activity of a cocktail like AZD7442 in preventing escape from emerging variant viruses.

immunology↗

bioRxiv2020

A holobiont view of island biogeography: unraveling patterns driving the nascent diversification of a Hawaiian spider and its microbial associates

The diversification of a host lineage can be influenced by both the external environment and its assemblage of microbes. Here, we use a young lineage of spiders, distributed along a chronologically arranged series of volcanic mountains, to determine the parallels between the evolutionary histories of the host spiders and their associated microbial communities, together forming the "holobiont". Using the stick spider Ariamnes waikula (Araneae, Theridiidae) on the island of Hawaii, and outgroup taxa on older islands, we tested whether each component of the holobiont (the spider hosts, the intracellular endosymbionts, and the gut microbial communities) showed correlated signatures of diversity due to sequential colonization from older to younger volcanoes. In order to investigate this, we generated ddRAD data for the host spiders and 16S rRNA gene amplicon data from their microbiota. We expected sequential colonizations to result in a (phylo)genetic structuring of the host spiders and in a diversity gradient in microbial communities. Results showed that the host A. waikula is indeed structured by geographic isolation, suggesting sequential colonization from older to younger volcanoes. Similarly, the endosymbiont communities were markedly different between Ariamnes species on different islands, but more homogeneous among A. waikula populations on the island of Hawaii. Conversely, the gut microbiota was largely conserved across all populations and species, which we suspect are generally environmentally derived. Our results highlight that the different components of the holobiont have responded in distinct ways to the dynamic environment of the volcanic archipelago, showing the necessity of understanding the interplay between components to better characterize holobiont evolution.

evolutionary biology↗

bioRxiv2019

Evolution of herbivory remodels a Drosophila genome

One-quarter of extant Eukaryotic species are herbivorous insects, yet the genomic basis of this extraordinary adaptive radiation is unclear. Recently-derived herbivorous species hold promise for understanding how colonization of living plant tissues shaped the evolution of herbivore genomes. Here, we characterized exceptional patterns of evolution coupled with a recent (<15 mya) transition to herbivory of mustard plants (Brassicaceae, including Arabidopsis thaliana) in the fly genus Scaptomyza, nested within the paraphyletic genus Drosophila. We discovered a radiation of mustard-specialized Scaptomyza species, comparable in diversity to the Drosophila melanogaster species subgroup. Stable isotope, behavioral, and viability assays revealed these flies are obligate herbivores. Genome sequencing of one species, S. flava, revealed that the evolution of herbivory drove a contraction in gene families involved in chemosensation and xenobiotic metabolism. Against this backdrop of losses, highly targeted gains (\"blooms\") were found in Phase I and Phase II detoxification gene sub-families, including glutathione S-transferase (Gst) and cytochrome P450 (Cyp450) genes. S. flava has more validated paralogs of a single Cyp450 (N=6 for Cyp6g1) and Gst (N=5 for GstE5-8) than any other drosophilid. Functional studies of the Gst repertoire in S. flava showed that transcription of S. flava GstE5-8 paralogs was differentially regulated by dietary mustard oils, and of 22 heterologously expressed cytosolic S. flava GST enzymes, GSTE5-8 enzymes were exceptionally well-adapted to mustard oil detoxification in vitro. One, GSTE5-8a, was an order of magnitude more efficient at metabolizing mustard oils than GSTs from any other metazoan. The serendipitous intersection of two genetic model organisms, Drosophila and Arabidopsis, helped illuminate how an insect genome was remodeled during the evolutionary transformation to herbivory, identifying mechanisms that facilitated the evolution of the most diverse guild of animal life.\n\nSIGNIFICANCE STATEMENTThe origin of land plants >400 million years ago (mya) spurred the diversification of plant-feeding (herbivorous) insects and triggered an ongoing chemical co-evolutionary arms race. Because ancestors of most herbivorous insects first colonized plants >200 mya, the sands of time have buried evidence of how their genomes changed with their diet. We leveraged the serendipitous intersection of two genetic model systems: a close relative of yeast-feeding fruit fly (Drosophila melanogaster), the \"wasabi fly\" (Scaptomyza flava), that evolved to consume mustard plants including Arabidopsis thaliana. The yeast-to-mustard dietary transition remodeled the flys gene repertoire for sensing and detoxifying chemicals. Although many genes were lost, some underwent duplications that encode the most efficient detoxifying enzymes against mustard oils known from animals.

evolutionary biology↗

bioRxiv2019

Recent evolutionary history of tigers highlights contrasting roles of genetic drift and selection

Formulating strategies for species conservation requires knowledge of evolutionary and genetic history. Tigers are among the most charismatic of endangered species and garner significant conservation attention. However, the evolutionary history and genomic variation of tigers remain poorly known. With 70% of the worlds wild tigers living in India, such knowledge is critical for tiger conservation. We re-sequenced 65 individual tiger genomes across their extant geographic range, representing most extant subspecies with a specific focus on tigers from India. As suggested by earlier studies, we found strong genetic differentiation between the putative tiger subspecies. Despite high total genomic diversity in India, individual tigers host longer runs of homozygosity, potentially suggesting recent inbreeding, possibly because of small and fragmented protected areas. Surprisingly, demographic models suggest recent divergence (within the last 10,000 years) between populations, and strong population bottlenecks. Amur tiger genomes revealed the strongest signals of selection mainly related to metabolic adaptation to cold, while Sumatran tigers show evidence of evolving under weak selection for genes involved in body size regulation. Depending on conservation objectives, our results support the isolation of Amur and Sumatran tigers, while geneflow between Malayan and South Asian tigers may be considered. Further, the impacts of ongoing connectivity loss on the health and persistence of tigers in India should be closely monitored.

genomics↗

bioRxiv2019

Horizontal transfer of prokaryotic cytolethal distending toxin B genes to eukaryotes

Cytolethal distending toxins (CDTs) are tripartite eukaryotic genotoxins encoded in diverse bacterial and phage genomes. The cdtB subunit is a DNAse that causes eukaryotic cell cycle arrest and apoptosis, and in one context, is associated with resistance against parasitoid wasp infections. Here we report the discovery of functional cdtB copies in the nuclear genomes of insect species from two distantly related insect orders, including fruit flies (Diptera: Drosophilidae) and aphids (Hemiptera: Aphididae). Insect cdtB copies are most closely related to bacteriophage copies, were horizontally transferred to insect genomes > 40 million years ago and encode a protein that retains ancestral DNase activity. This phage-derived toxin has been domesticated by diverse insects and we hypothesize that it is used as a defensive weapon against parasitoid wasps. One Sentence SummaryWe report horizontal transfer of the gene cytolethal distending toxin B, which encodes a DNase, into eukaryotic genomes from bacteriophage. SignificanceCytolethal distending toxins (CDTs) are secreted by diverse pathogenic bacterial species to kill animal cells. The cdtB subunit enters cell nuclei, damaging the DNA and leading to mitotic arrest and apoptosis. In the pea aphid, a bacterial endosymbiont provides protection against wasp attack, possibly via cdtB. We discovered that this same endosymbiont-encoded lineage of cdtB was transferred to the genomes of Diptera and Hemiptera species and retains ancestral DNase activity. This is the first report of cdtB outside of bacteria or phages. A toxin that first evolved to kill eukaryotic cells has been co-opted by insects, potentially to their benefit.

evolutionary biology↗