Omicron's expansion, the genetics of heart structure, a new view into cancer risk, and more
Research Roundup: June 17, 2022
Welcome to the June 17, 2022 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.
Documenting Omicron’s takeover
The Omicron variant and its descendants account for >99.5% of COVID-19 cases in the United States. Using data from local universities’ asymptomatic screening programs, Brittany Petros, institute member Pardis Sabeti of the Infectious Disease and Microbiome Program (IDMP), associate member Michael Springer, and colleagues quantified the remarkable speed with which Omicron outcompeted the Delta variant in highly vaccinated populations. They showed that Omicron accounted for >90% of new cases as quickly as nine days after it was introduced, and surpassed Delta at Boston-based universities 1-2 weeks earlier than in Massachusetts or New England in general. Their real-time data prompted some local hospitals to pause elective surgeries in anticipation of increased hospitalizations. Read more in Clinical Infectious Diseases and Petros’ tweetorial.
Machine learning builds a genetic map of heart disease
Many congenital heart diseases are associated with malfunctions in the right side of the heart, which controls blood flow to the lungs. Using MRI images from 40,000 UK Biobank participants, James Pirruccello, Paolo Di Achille, Victor Nauffal, institute member Patrick Ellinor of the Cardiovascular Disease Initiative, and colleagues built a deep learning model that measures the physical dimensions of the right heart chambers and associates those physical features with genetic data. They found 72 loci that were uniquely related to right heart measurements, allowing them to trace the genetic causes of diseases that affect the chambers' size and shape. Read more in Nature Genetics and Pirruccello’s tweetorial.
It's long been thought that CD4+ helper T cells are the main source of inflammatory cytokines in rheumatoid arthritis (RA). After profiling T cells collected from the joints of RA patients, Fan Zhang, institute member Soumya Rauchaudhuri of the Program in Medical and Population Genetics, BWH's Helena Jonsson and Michael Brenner, and colleagues suggest that CD8+ effector T cells, in particular those expressing the cytotoxic enzymes granzyme B and granzyme K, may be the real cytokine producers in RA. After finding granzyme K-expressing CD8+ T cells in several additional tissues, they propose that these cells form an important and anatomically widespread cell population primed to drive inflammation. Learn more in Science Translational Medicine.
Chromatin accessibility uncovers cancer clues
To explore the mechanisms underlying cancer risk variants identified by genome wide association studies, Dennis Grishin (Dana-Farber) and associate member Alexander Gusev of Dana-Farber Cancer Institute, Harvard Medical School, and the Program in Medical and Population Genetics leveraged allelic imbalance — the difference in transcription factor (TF) activity or binding between two alleles of a heterozygous variant — to identify 7,262 germline variants influencing chromatin accessibility across cancers. Most variants altered TF motifs, TF binding, and gene expression. The researchers also introduced the regulome-wide association study (RWAS), which revealed new risk loci in all examined cancer types. The findings suggest that population-scale profiling of epigenomic features from cancers could be a powerful way of studying the genetic architecture of cancer risk. Read more in Nature Genetics.
Targeting a tumor growth mechanism
In Cell Reports, a team supervised by Broad associate member Srinivas Vinod Saladi in the Cancer Program describes a complex molecular pathway that promotes cancer growth in certain head and neck squamous cell carcinomas (HNSCC), with potential for therapeutic intervention. In a subset of HNSCC cases, dysfunction in the Hippo-YAP pathway — which plays critical roles in cell signaling and proliferation — is driven by mutations in the gene FAT1. The team found that FAT1 depletion leads to activation of YAP1, which then couples with BRD4 to maintain an oncogenic chromatin state. BRD4 inhibition could therefore be a potential targeted therapeutic strategy for a subset of HNSCC cases.