Research Roundup: June 13, 2022

Welcome to the June 13, 2022 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Mapping mood and movement symptoms in Parkinson’s disease

In addition to motor deficits, patients with Parkinson’s disease experience motor-learning and mood impairments, but the underlying neural circuitry isn’t well understood. Ying Zhang, Dheeraj Roy, institute member Guoping Feng, and others in the Stanley Center for Psychiatric Research systematically investigated the connectivity and function of parafascicular (PF) thalamic neurons that project to basal ganglia nuclei, and their impact on motor and non-motor phenotypes in a mouse model of Parkinson’s disease. They showed that modulating certain neuronal receptors can regulate these PF circuits, offering a potential new therapeutic avenue for Parkinson’s. Read more in Nature, a research summary, and a tweetorial from Dheeraj.

pHinding how pH affects inflammation

Tissue acidification occurs in inflammation. To learn how pH sensing affects tissue homeostasis, postdoctoral scholar Xiangjun Chen, core institute member Ramnik Xavier and colleagues studied the pH sensor GPR65 and one of its coding variants, Ile231Leu, which is linked to inflammatory bowel disease. They found that mice with this variant had impaired antibacterial defenses in an infection model and heightened inflammation in a colitis model. GPR65 Ile231Leu led to cytokine imbalance and altered metabolism, and increased the release of IL2 and IL3 in dendritic cells at acidic pH, leading to enhanced antigen presentation. The findings highlight the mechanism of how the pH sensor affects inflammatory circuits. Read more in Nature Immunology.

Oncogenic mutations in colorectal cancer

Despite extensive genomic sequencing, the functions of key genetic variants in colorectal cancer remain unknown. Lishan Fang, Dane Ford-Roshon, Steven Corsello, Proteomics Platform associate director Namrata Udeshi, James Berstler, Marios Giannakis, and colleagues studied the function of the G659fs mutation in the RNF43 gene, which occurs in 8 percent of colorectal cancer patients. They report that the mutation drives carcinogenesis without affecting the Wnt pathway, which is commonly impacted by RNF43 mutations. They also found that PI3K inhibitors selectively target cells with this mutation, and could be a therapeutic option for patients. Read more in Nature Communications and a tweetorial by Marios.

How to build equitable research partnerships

More than 80 percent of GWAS participants are of European ancestry. Efforts to increase diversity in genomics are inspiring research partnerships between institutions in high-income and low- and middle-income countries. In a Comment in Nature Genetics, associate members Alicia Martin and Lori Chibnik of the Stanley Center for Psychiatric Research and colleagues describe lessons from designing and implementing the NeuroGAP-Psychosis research study and the GINGER training program in Ethiopia, Kenya, South Africa, Uganda, and the United States. They conclude with five recommendations for building equitable research partnerships: establishing local collaborators, defining clear collaboration agreements, keeping funding flexible, utilizing in-person meetings, and systemically prioritizing diversity through capacity-building.

New function for key Parkinson’s protein uncovered

Parkinson’s disease is characterized by the uncontrolled buildup of a protein called α-synuclein, which binds to cell membranes and helps transport vesicles across cells. Associate member Vikram Khurana and colleagues, led by Erinc Hallacli, have now discovered another function of α-synuclein: the protein binds to “P-body” structures that help regulate gene expression. They found that neurons in Parkinson’s patients often have defunct P-bodies and abnormal mRNA levels, and that people with P-body mutations may be at greater risk for the condition. This new understanding of α-synuclein could help scientists develop new treatments for Parkinson’s disease. Read more in Cell and a Brigham and Women’s news release.

Seven strategies are better than one

Many single-nucleotide polymorphisms (SNPs) regulate faraway genes, and it can be hard to connect the two. Scientists use complex SNP-to-gene (S2G) strategies to identify which disease-associated SNPs regulate which genes. Steven Gazal, associate member Alkes Price of the Medical and Population Genetics Program, and colleagues combined seven different S2G strategies and found that their model predicted more than 5,000 causal SNP-gene relationships for 49 diseases and traits in the UK Biobank. The approach was more than twice as effective at finding such connections as any one strategy on its own, and they hope their combined strategy can be used to identify more causes of genetic disease. Read more in Nature Genetics and a Nature Genetics News & Views article.

Variant-to-function SCAVENGEr hunt 

Identifying disease-specific cell types and states is often affected by sparsity and noise in large datasets, especially single-cell epigenomic data. Fulong Yu, associate member Vijay Sankaran, and colleagues in the Program in Medical and Population Genetics developed SCAVENGE, a computational algorithm that maps causal variants to their relevant cellular context at single-cell resolution. The researchers used SCAVENGE to analyze hematopoietic phenotypes, COVID-19 disease severity, and leukemia risk alleles and gain new biological insights at different levels including cell types, cell sub-states, and cell differentiation trajectories. SCAVENGE provides a framework to gather deeper variant-to-function insights and inferences from single -cell genomic data. Read more in Nature Biotechnology and this tweetorial from Vijay.

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