Research Roundup: May 9, 2022

Welcome to the May 9, 2022 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Uniquely vulnerable neurons in Parkinson's disease

The death of dopamine-producing neurons in the brain's substantia nigra is the key driver of Parkinson's disease. But these cells don't die uniformly; some neurons disappear early in the disease, others survive well into its late stages. To help reveal why, Tushar Kamath, Abdulraouf Abdulraouf, institute member Evan Macosko of the Stanley Center for Psychiatric Research, and colleagues conducted a molecular census of dopaminergic neurons from patients who died from Parkinson's disease. They identified 10 dopamine neuron subtypes, including one uniquely vulnerable subtype with the highest expression of disease-associated risk variants. Their findings could assist efforts to develop cell replacement and disease-modifying therapies for Parkinson's disease. Learn more in Nature Neuroscience, a Broad Q&A with Evan, and coverage in New Scientist (paywall) and Science News.

Disrupted microbiome and repeated urinary tract infections 

A quarter of females who get urinary tract infections (UTIs) experience repeated infections. In Nature Microbiology, Colin Worby, Tim Straub, Lucas van Dijk, Ryan Bronson, Bruce Walker, Sinéad Chapman, Abigail Manson, institute scientist and senior group leader Ashlee Earl in the Genomic Center for Infectious Diseases and Infectious Disease and Microbiome Program and colleagues suggest that different immune system responses and microbiome imbalances could underlie recurrent UTIs. They found that patients with recurrent UTIs and healthy controls carried genetically similar E. coli strains in the gut, and both groups experienced gut-to-bladder transmission of E. coli. However, people with recurrent UTIs had lower levels of other key gut bacteria, as well as signs of increased inflammation. Antibiotics commonly used for UTIs did not clear UTI-causing strains from the gut, and may even increase recurrence by continually disrupting the microbiome. Read more in a Broad news story.

New method improves disease risk prediction in diverse populations

Polygenic risk scores (PRS) use genetic information to predict individuals’ disease risk, but their accuracy is limited in non-European populations. Using recent genomic data collected from underrepresented populations, Yunfeng Ruan of the Cardiovascular Disease Initiative and Shengying Qin, Hailiang Huang, and Tian Ge of the Stanley Center developed a new method, PRS-CSx, that predicts disease risk across populations more accurately than existing methods. They used computational methods that maximize the value of non-European data and improve prediction accuracy in ancestrally diverse individuals. The method could help reduce health disparities when using PRS in the clinic, and support basic studies on genetic risk for disease. Read more in Nature Genetics and an MGH news story.

A better way to prioritize GWAS variants

Prioritizing the extensive variant lists returned by genome-wide association studies (GWAS) for deeper study is a major challenge. In a study in Nature Genetics, Michael Guo and institute member and Cell Circuits Program director Nir Hacohen teamed up with John Ray (Benaroya Research Institute) and Kousuke Mouri and Ryan Tewhey (The Jackson Laboratory) and colleagues to established a two-pronged approach for prioritizing approximately 18,000 variants from GWAS of five autoimmune diseases. Using massively parallel reporter assays and chromatin accessibility studies, they narrowed the list down to 60 potentially causal regulatory variants, examining one in detail in in vitro T cell and mouse models. Learn more in a Jackson Lab/Benaroya/Broad story.

Controlling blood cell mutations

Over time, hematopoietic stem and progenitor cells (HSPCs) — which are responsible for the production of blood and immune cells — can acquire dangerous precancerous mutations. In Cell Stem Cell, Alexandra Schnell, institute member Vijay Kuchroo in the Klarman Cell Observatory, and colleagues from the Heidelberg Institute for Stem Cell Technology and Experimental Medicine describe some of the body's safety mechanisms for eliminating these high-risk cells. The researchers found that, surprisingly, HSPCs actively engage CD4+ T cells, enabling the T cells to recognize aberrations and eliminate them from the stem cell pool. Read more in a Berlin Institute of Health press release and two tweetorials from the team.

Cancer-immune cell crosstalk in melanoma

CD4+ T cells have diverse roles in adaptive immunity, and can influence the outcomes of cancer therapies. However, their interaction with antigens presented by tumor cells' human leukocyte antigen (HLA) class II molecules — which is key to their immune activity — remains poorly understood. Giacomo Oliveira, institute member Catherine Wu of the Cancer Program, and colleagues used single-cell sequencing and T cell receptor reconstruction and screening to profile CD4+ T cells from human melanoma tumors and test their ability to recognize tumor cells. In Nature, they outline three kinds of interactions between tumor-specific CD4+ T cells and melanomas. 

A DIALOGUE among cells

Evidence suggests that interactions between cell types affect health and disease, but most computational methods map single-cell states rather than cell-cell interactions. In Nature Biotechnology, Livnat Jerby-Arnon (Stanford) and institute member (on leave) Aviv Regev present a computational approach called DIALOGUE that systematically identifies multicellular programs (MCPs) — different expression programs in different cell types that are coordinated at the tissue level — in spatial data and single-cell data without spatial information. Testing this approach, they uncovered MCPs that predict therapy response in ulcerative colitis patients, mark both Alzheimer’s and brain aging, and which were associated with immunotherapy resistance in melanoma. Read more in a tweetorial by Regev and Jerby-Arnon.

Risk factors for bone and soft tissue cancer that run in the blood

New work by Riaz Gillani, Saud AlDubayan, and Cancer Program associate members Brian Crompton and Eliezer Van Allen explores the inherited genetic roots of the bone and soft tissue cancer Ewing sarcoma. The researchers screened 141 established cancer predisposition genes in more than 1,500 individuals diagnosed with different pediatric sarcoma subtypes for enrichment of pathogenic germline variants compared to controls. They uncovered known and new risk genes, notably FANCC in Ewing sarcoma, and highlighted the role of inherited variants in DNA damage repair genes. Described in the American Journal of Human Genetics and a tweetorial, the findings open the door to better screening, detection, treatment, and prevention for at-risk children.

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