Research Roundup: December 17, 2021

Welcome to the December 17, 2021 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Keeping cells' genetics in context

A cell's genetics and microenvironment both influence its state and function. But most bulk and single-cell sequencing methods lose all information about a cell's original location. In Nature, Tongtong Zhao, Zack Chiang, associate member and Gene Regulation Observatory co-director Jason Buenrostro, core institute member Fei Chen, and colleagues present slide-DNA-seq, a spatial genomics technology that directly sequences cells' DNA in intact tissue slices using slide-bound, molecularly-barcoded microbeads. The team used slide-DNA-seq and the related slide-RNA-seq to identify spatial patterns and distinct clones within animal models and patient tumors, and discover important tumor and microenvironmental genes. Learn more in an HSCRB news story and a tweetorial by Chiang.

Putting polygenic risk in scoring position

The International Common Disease Alliance recently launched its Maps to Mechanisms to Medicine challenge, which calls for datasets, technologies, platforms, and assays needed to propel the next phase of human genetics. In response, ICDA’s Polygenic Risk Score Task Force, including Alicia Martin, Masahiro Kanai, Kate Balaconis, and Samuli Ripatti, authored a perspective piece in Nature Medicine, in which they highlight the current state of polygenic risk score research. They also expose current gaps and risks when translating polygenic risk scores into clinical practice, and key objectives for maximizing responsible use of the scores in clinical settings. 

Molecular insights into metabolic diseases 

The specific molecular events linking obesity-driven intracellular stress with the development of metabolic inflammation (a key feature of obesity and diabetes) still remain unclear. In a study in Science Signaling, Ekin Guney, Ana Paula Arruda, associate member Gökhan Hotamisligil of the Metabolism Program, and colleagues at the Harvard T.H. Chan School of Public Health identified a critical role for the Ca2+ channel receptor IP3R in adipocyte stress and adipose tissue inflammation. Findings from this study, conducted in vitro and in vivo (in mice), demonstrate that IP3R activity is a key link between obesity, inflammation, and insulin resistance, and also suggest that targeting IP3R-mediated Ca2+ homeostasis in adipocytes may offer new therapeutic opportunities against metabolic diseases.

Tracking SARS-CoV-2 samples through sequencing

To sequence SARS-CoV-2 samples, many labs first amplify the virus's genetic material. However, producing trillions of SARS-CoV-2 fragments in a single reaction raises the risk of cross-contamination. In Nature Microbiology, a team led by Kim Lagerborg, Erica Normandin, Matthew Bauer, institute member Pardis Sabeti of the Infectious Disease and Microbiome Program, Steve Reilly, and Katie Siddle, with colleagues from The Jackson Laboratory and Massachusetts General Hospital, describes an approach that uses synthetic DNA "spike-ins," or SDSIs, to barcode samples and track them throughout sequencing. This method enables detection and correction of errors including spillover and sample swaps. The team validated this method across nearly 6,700 diagnostic samples and in a real-time investigation of a suspected SARS-CoV-2 hospital cluster. Read more in tweetorials from Lagerborg and Reilly.

To learn more about research conducted at the Broad, visit broadinstitute.org/publications, and keep an eye on broadinstitute.org/news.