Research Roundup: June 6, 2022

Predicting the next COVID-19 variant, subtleties of recessive genetic disease, a modular toolkit for delivering genes to neurons, and more

Susanna M. Hamilton
Credit: Susanna M. Hamilton

Welcome to the June 6, 2022 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

As easy as PyR0

Fritz Obermeyer, Martin Jankowiak, Nikolaos Barkas, institute member Pardis Sabeti of the Infectious Disease and Microbiome Program (IDMP), Jacob Lemieux, and colleagues have developed a machine-learning model that can predict, based on their genomes, which SARS-CoV-2 lineages are likely to dominate and cause surges in COVID-19 cases. The model, called PyR0 ("Pi-R-nought"), estimates genetic mutations' effects on a virus’s fitness and predicts the fitness of new lineages. PyR0 correctly predicted the rise of the current BA.2 variant when applied to all the data publicly available in January, 2022 and could serve as an early warning system in the future. Read more in Science and a Broad news story.

Carriers of recessive genetic variants may also be at risk for disease

It's been assumed that recessive Mendelian disease variants do not cause illness in people who inherit only one copy from their parents. But scientists have increasingly noticed that some of these heterozygous carriers show puzzling, albeit less severe, symptoms of disease. Alison Barton, associate member Po-Ru Loh of the Program in Medical and Population Genetics (MPG), and colleagues analyzed genetic data from around 500,000 UK Biobank participants, and found 34 recessive diseases where heterozygous carriers exhibit milder phenotypes. Their discovery suggests that Mendelian gene recessiveness could lie on a spectrum of disease severity for heterozygous individuals. Read more in the American Journal of Human Genetics and coverage in GenomeWeb.

A matter of preference

Gene enhancers activate promoters to regulate gene expression, but whether they show a preference for certain promoter classes hasn’t been studied at a large scale in human cells. Drew Bergman, Thouis Jones, Jesse Engreitz, and colleagues developed a high-throughput reporter assay, ExP STARR-seq, to examine the combinatorial capabilities of 1,000 enhancer and 1,000 promoter sequences in human cells. While they saw some specificity in pairs, they found that human enhancers and promoters were broadly compatible, contrary to what’s been seen in Drosophila experiments. The results have implications for modeling gene expression, improving genome-wide enhancer maps, and studying human genetic variation. Read more in Nature and Bergman's tweetorial.

As accurate as a PCR test, as simple as a rapid

RT-PCR tests for COVID-19 require expensive equipment, and rapid antigen-capture tests can lack sensitivity. In 2020, Jon Arizti-Sanz, Catherine Freije, Pardis Sabeti, Cameron Myhrvold, and colleagues developed a method called SHINE that uses CRISPR-Cas13 enzymes to rapidly identify SARS-CoV-2 RNA sequences in samples with minimal equipment. In a new paper in Nature Biomedical Engineering, Arizti-Sanz, Sabeti, Myhrvold (now at Princeton University), and colleagues present SHINEv.2, an improvement on SHINE that eliminates heating steps and the need for cold storage for reagents. The team demonstrated SHINEv.2 to be as accurate as a RT-PCR test while providing results in under 90 minutes. Its creators hope the tool can be implemented in non-laboratory settings.

Inflammatory overlaps

Fibroblasts are found throughout the body, where they help coordinate tissue repair and other immune functions. Breakdowns in that coordination can contribute to a variety of inflammatory diseases. Ilya Korsunsky, Kevin Wei, and institute member Soumya Raychaudhuri of the MPG partnered with Michael Brenner (BWH) and Mathilde Pohin and Christopher Buckley (University of Oxford) and colleagues to profile fibroblasts from four different inflammatory diseases — rheumatoid arthritis, inflammatory bowel disease, interstitial lung disease, and Sjögren’s syndrome — using single-cell RNA sequencing. In Med, they report that all four conditions share two fibroblast subtypes, one that communicates with immune cells, the other with blood vessel cells. 

Gut check of microbial proteins

The gut microbiome is disrupted in inflammatory bowel disease (IBD) but the microbial proteins involved are poorly characterized. Postdoctoral associate Yancong Zhang, IDMP associate member Curtis Huttenhower, associated scientist Eric Franzosa, and colleagues have identified more than 340,000 protein families that may be active in gut inflammation during IBD, more than half of which were previously uncharacterized. Using metagenomics, metatranscriptomics, and metaproteomics, the team profiled the bioactivity of proteins involved in host and microbial cell-cell communication, and also experimentally validated new immunogenic and biofilm-forming properties of specific protein families. The researchers say the proteins they prioritized could aid in understanding mechanisms of microbial involvement in IBD and may be potential drug targets. Read more in Nature.

A versatile viral toolkit for targeting neurons

For better delivery to and control of transgenes expressed in neurons, Gabrielle Pouchelon, Josselyn Vergara, Justin McMahon, Bram Gorissen, Jordane Dimidschstein, and others in the Stanley Center for Psychiatric Research developed a versatile viral toolkit for efficient combinatorial targeting of specific neuronal cell types. The kit includes a set of highly optimized adeno-associated virus backbones that provides users with the flexibility to implement complex targeting strategies. The researchers illustrated the toolkit’s potential by targeting a variety of neuronal cell types and querying their biology with a wide array of genetically encoded tools. Read more in Cell Reports Methods.

PROTAC progress

Proteolysis-targeting chimeras (PROTACs) are small molecules that trick cells into degrading specific proteins by tagging them for elimination by the cell's waste disposal system. However, current assays for measuring PROTACs' potency and effectiveness are inherently slow and low throughput. A team led by IDMP associate member Ralph Mazitschek reports a generalizable, sensitive, and flexible assay system for measuring both binding affinities and target protein abundance at high throughput directly in cell lysates. The team used this approach to explore the natural product celastrol's potential as a building block for next-generation PROTACs. Read more in Cell Chemical Biology.

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