Domestication and divergence of Saccharomyces cerevisiae beer yeasts

Whereas domestication of livestock, pets, and crops is well documented, it is still unclear to what extent microbes associated with the production of food have also undergone human selection and where the plethora of industrial strains originates from. Here, we present the genomes and phenomes of 157 industrial Saccharomyces cerevisiae yeasts. Our analyses reveal that today's industrial yeasts can be divided into five sublineages that are genetically and phenotypically separated from wild strains and originate from only a few ancestors through complex patterns of domestication and local divergence. Large-scale phenotyping and genome analysis further show strong industry-specific selection for stress tolerance, sugar utilization, and flavor production, while the sexual cycle and other phenotypes related to survival in nature show decay, particularly in beer yeasts. Together, these results shed light on the origins, evolutionary history, and phenotypic diversity of industrial yeasts and provide a resource for further selection of superior strains

Advances in Genomics for Drug Development

Drug development (target identification, advancing drug leads to candidates for preclinical and clinical studies) can be facilitated by genetic and genomic knowledge. Here, we review the contribution of population genomics to target identification, the value of bulk and single cell gene expression analysis for understanding the biological relevance of a drug target, and genome-wide CRISPR editing for the prioritization of drug targets. In genomics, we discuss the different scope of genome-wide association studies using genotyping arrays, versus exome and whole genome sequencing. In transcriptomics, we discuss the information from drug perturbation and the selection of biomarkers. For CRISPR screens, we discuss target discovery, mechanism of action and the concept of gene to drug mapping. Harnessing genetic support increases the probability of drug developability and approval

Structure of the prefusion-locking broadly neutralizing antibody RVC20 bound to the rabies virus glycoprotein

International audienceRabies virus (RABV) causes fatal encephalitis in more than 59,000 people yearly. Upon the bite of an infected animal, the development of clinical disease can be prevented with post-exposure prophylaxis (PEP), which includes the administration of Rabies immunoglobulin (RIG). However, the high cost and limited availability of serum-derived RIG severely hamper its wide use in resource-limited countries. A safe low-cost alternative is provided by using broadly neutralizing monoclonal antibodies (bnAbs). Here we report the X-ray structure of one of the most potent and most broadly reactive human bnAbs, RVC20, in complex with its target domain III of the RABV glycoprotein (G). The structure reveals that the RVC20 binding determinants reside in a highly conserved surface of G, rationalizing its broad reactivity. We further show that RVC20 blocks the acid-induced conformational change required for membrane fusion. Our results may guide the future development of direct antiviral small molecules for Rabies treatment

Archetype®: a Modern Comparative Genomics Discovery and Analysis Web Service

<p>In the past few years sequencing technology has made the generation of large quantities of biological sequence data very affordable, but there has been no comparable increase in the ability to mine useful information from it. As sequencing has become an assay the only limitations appear to be ones imagination as to how best to use this resource and how to deal and make sense of the resulting data deluge in a quick and user friendly manner.</p> <p>Archetype® is a web service and software framework developed to manage the analysis of large quantities of metagenomic, microbial, viral and eukaryotic biological sequence data. The system supports automated functional annotation and comparative analysis of microbial and eukaryotic genomes, metagenomes, and transcriptomes. Other components include a powerful text-search engine, automated taxonomic assignment, comparative pathway analysis, transcriptomics analysis, metadata-support, costume user-jobs (Blast, HMMscan, Codon optimization, etc.), and more. It was developed over the last twelve years to meet the demands of a common analysis workflow carried out by scientists when working with biological sequence data. This workflow involves being able to rapidly query across disparate sequence based datasets, identify potential query hits, and rapidly gather sequences for further analysis.</p> <p>At a top level Archetype® consists of a web based user interface, web service, search service, and data model. The web service, search service, and data model are all independent architectural components that scale both independently and horizontally. Each of these components can meet increased service demands by adding machines rather than performing additional software development. The data modeling objectives in Archetype® include management of large quantities of data and the ability to store data in a scalable non-collocated and secure manner. In order to meet these objectives a unique data model was designed to support the backend of Archetype®. As a result, all of these services can be exposed to very large number of users through an intuitive browser based user interface.</p

Predicting the mutational drivers of future SARS-CoV-2 variants of concern

SARS-CoV-2 evolution threatens vaccine- and natural infection–derived immunity and the efficacy of therapeutic antibodies. To improve public health preparedness, we sought to predict which existing amino acid mutations in SARS-CoV-2 might contribute to future variants of concern. We tested the predictive value of features comprising epidemiology, evolution, immunology, and neural network–based protein sequence modeling and identified primary biological drivers of SARS-CoV-2 intrapandemic evolution. We found evidence that ACE2-mediated transmissibility and resistance to population-level host immunity has waxed and waned as a primary driver of SARS-CoV-2 evolution over time. We retroactively identified with high accuracy (area under the receiver operator characteristic curve = 0.92 to 0.97) mutations that will spread, at up to 4 months in advance, across different phases of the pandemic. The behavior of the model was consistent with a plausible causal structure where epidemiological covariates combine the effects of diverse and shifting drivers of viral fitness. We applied our model to forecast mutations that will spread in the future and characterize how these mutations affect the binding of therapeutic antibodies. These findings demonstrate that it is possible to forecast the driver mutations that could appear in emerging SARS-CoV-2 variants of concern. We validated this result against Omicron, showing elevated predictive scores for its component mutations before emergence and rapid score increase across daily forecasts during emergence. This modeling approach may be applied to any rapidly evolving pathogens with sufficiently dense genomic surveillance data, such as influenza, and unknown future pandemic viruses.</jats:p

CRISPR-Cas Systems Impact Pseudomonas aeruginosa Genome Structure

<i>Pseudomonas aeruginosa</i> is both an antibiotic-resistant opportunistic pathogen and an important model of type I clustered regularly interspaced short palindromic repeat (CRISPR) and CRISPR-associated protein (CRISPR-Cas) systems. Comparative genomics has identified several CRISPR-Cas subtypes, and it was previously unclear how these immune modules might influence the genome content of <i>P. aeruginosa</i>. To better understand the distribution of CRISPR-Cas subtypes and their impact on genome composition, we annotated 672 <i>P. aeruginosa</i> clinical isolates. We found that CRISPR-Cas systems modulate genome size and accessory elements. In addition, we identified a novel, putatively mobile type I-C CRISPR-Cas system. In the process, we also created a global spacer library that provides a new means of identifying accessory fragments, and facilitates CRISPR typing of many <i>P. aeruginosa</i> strains. Finally, we have made the assemblies of 282 newly-sequenced <i>P. aeruginosa</i> isolates public as an NCBI BioProject (ID: PRJNA297679)

Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift

The recently emerged SARS-CoV-2 Omicron variant encodes 37 amino acid substitutions in the spike protein, 15 of which are in the receptor-binding domain (RBD), thereby raising concerns about the effectiveness of available vaccines and antibody-based therapeutics. Here we show that the Omicron RBD binds to human ACE2 with enhanced affinity, relative to the Wuhan-Hu-1 RBD, and binds to mouse ACE2. Marked reductions in neutralizing activity were observed against Omicron compared to the ancestral pseudovirus in plasma from convalescent individuals and from individuals who had been vaccinated against SARS-CoV-2, but this loss was less pronounced after a third dose of vaccine. Most monoclonal antibodies that are directed against the receptor-binding motif lost in vitro neutralizing activity against Omicron, with only 3 out of 29 monoclonal antibodies retaining unaltered potency, including the ACE2-mimicking S2K146 antibody1. Furthermore, a fraction of broadly neutralizing sarbecovirus monoclonal antibodies neutralized Omicron through recognition of antigenic sites outside the receptor-binding motif, including sotrovimab2, S2X2593 and S2H974. The magnitude of Omicron-mediated immune evasion marks a major antigenic shift in SARS-CoV-2. Broadly neutralizing monoclonal antibodies that recognize RBD epitopes that are conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers.Fil: Cameroni, Elisabetta. Humabs Biomed; SuizaFil: Bowen, John E.. University of Washington; Estados UnidosFil: Rosen, Laura E.. Vir Biotechnology; Estados UnidosFil: Saliba, Christian. Humabs Biomed; SuizaFil: Zepeda, Samantha K.. University of Washington; Estados UnidosFil: Culap, Katja. Humabs Biomed; SuizaFil: Pinto, Dora. Humabs Biomed; SuizaFil: VanBlargan, Laura A.. Washington University in St. Louis; Estados UnidosFil: De Marco, Anna. Humabs Biomed; SuizaFil: di Iulio, Julia. Vir Biotechnology; Estados UnidosFil: Zatta, Fabrizia. Humabs Biomed; SuizaFil: Kaiser, Hannah. Vir Biotechnology; Estados UnidosFil: Noack, Julia. Vir Biotechnology; Estados UnidosFil: Farhat, Nisar. Vir Biotechnology; Estados UnidosFil: Czudnochowski, Nadine. Vir Biotechnology; Estados UnidosFil: Havenar Daughton, Colin. Vir Biotechnology; Estados UnidosFil: Sprouse, Kaitlin R.. University of Washington; Estados UnidosFil: Dillen, Josh R.. Vir Biotechnology; Estados UnidosFil: Powell, Abigail E.. Vir Biotechnology; Estados UnidosFil: Chen, Alex. Vir Biotechnology; Estados UnidosFil: Maher, Cyrus. Vir Biotechnology; Estados UnidosFil: Yin, Li. Vir Biotechnology; Estados UnidosFil: Sun, David. Vir Biotechnology; Estados UnidosFil: Soriaga, Leah. Vir Biotechnology; Estados UnidosFil: Bassi, Jessica. Humabs Biomed; SuizaFil: Silacci Fregni, Chiara. Humabs Biomed; SuizaFil: Gustafsson, Claes. ATUM; Estados UnidosFil: Franko, Nicholas M.. University of Washington; Estados UnidosFil: Logue, Jenni. University of Washington; Estados UnidosFil: Geffner, Jorge Raúl. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentin

Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift

The recently emerged SARS-CoV-2 Omicron variant encodes 37 amino acid substitutions in the spike protein, 15 of which are in the receptor-binding domain (RBD), thereby raising concerns about the effectiveness of available vaccines and antibody-based therapeutics. Here we show that the Omicron RBD binds to human ACE2 with enhanced affinity, relative to the Wuhan-Hu-1 RBD, and binds to mouse ACE2. Marked reductions in neutralizing activity were observed against Omicron compared to the ancestral pseudovirus in plasma from convalescent individuals and from individuals who had been vaccinated against SARS-CoV-2, but this loss was less pronounced after a third dose of vaccine. Most monoclonal antibodies that are directed against the receptor-binding motif lost in vitro neutralizing activity against Omicron, with only 3 out of 29 monoclonal antibodies retaining unaltered potency, including the ACE2-mimicking S2K146 antibody1. Furthermore, a fraction of broadly neutralizing sarbecovirus monoclonal antibodies neutralized Omicron through recognition of antigenic sites outside the receptor-binding motif, including sotrovimab2, S2X2593 and S2H974. The magnitude of Omicron-mediated immune evasion marks a major antigenic shift in SARS-CoV-2. Broadly neutralizing monoclonal antibodies that recognize RBD epitopes that are conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers

Imprinted antibody responses against SARS-CoV-2 Omicron sublineages

International audienceSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages carry distinct spike mutations and represent an antigenic shift resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity or vaccine boosters elicit plasma neutralizing activity against Omicron BA.1, BA.2, BA.2.12.1 and BA.4/5 and that breakthrough infections, but not vaccination-only, induce neutralizing activity in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1, BA.2, and BA.4/5 receptor-binding domains whereas Omicron primary infections elicit B cells of narrow specificity up to 6 months post infection. Although most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant neutralizing antibody, that is a strong candidate for clinical development