Research Roundup: June 21, 2019

Welcome to the June 21, 2019 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Revealing the role of recessive genes in autism

Recessive genetic mutations could play a role in 5 percent of total autism spectrum disorder (ASD) cases and up to 10 percent of cases in females, according to a study in this week’s Nature Genetics. A team led by Program in Medical and Population Genetics associate member Timothy Yu at Boston Children's Hospital analyzed exome data from the Autism Sequencing Consortium and found evidence that recessive mutations in both established neurodevelopmental genes and previously unassociated genes,  including one involved in serotonergic circuitry, may contribute to ASD. Expanding this type of analysis to larger cohorts could illuminate previously unknown biological pathways responsible for the condition.

PROSPECTing for new TB drugs

Researchers have been working for decades to find new drugs to combat tuberculosis (TB), one of the world's leading infectious causes of death. This week in Nature, Eachan Johnson, core institute member and Infectious Disease and Microbiome Program co-director Deborah Hung, and collaborators announced a new approach called PROSPECT that uses weakened strains of Mycobacterium tuberculosis to find promising drug candidates. In a screen of 150 such strains and 50,000 chemical compounds, PROSPECT revealed hundreds of chemical hits with previously unrecognized anti-TB activity, and flagged a molecular pump as a new drug development target. Learn more in a Broad news story.

A fold is greater than the sum of its mutations

Naturally occurring genetic variation can help predict how proteins and RNA fold, but it was unclear if lab-made variants could also reveal 3D structures. A team led by Cell Circuits Program associate member Debora Marks at Harvard Medical School developed an experimental method to do just that. They used high-throughput mutational scans to identify pairs of amino acids that, when mutated, have a combined effect different than is expected based on each mutation individually. Appearing in Nature Genetics, the work shows that these pairs can reveal protein folds, suggesting that genomics-based techniques can efficiently predict 3D structure. Read more in a news story by Science.

A new look at cells

In Cell, Joshua Weinstein, core institute member and Klarman Cell Observatory director Aviv Regev, and core institute member Feng Zhang describe a new system for mapping cells that captures both spatial and genetic data simultaneously from a single specimen. The approach, called DNA microscopy, shows how biomolecules such as DNA and RNA are organized in cells and tissues, revealing combined information that is not easily accessible through other microscopy methods. In their report, the team demonstrates the ability to molecularly map the locations of individual human cancer cells in a sample by tagging RNA. Read more in a Broad news story and media coverage from The New York Times and STAT, and see Weinstein discuss the work in a Broad Models, Inference & Algorithms talk.

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