Research Roundup: March 1, 2019

Genetic insights about autism spectrum disorder and insomnia, first cellular atlas of the primate retina, and more.

Kelly David
Credit: Kelly David

Welcome to the March 1, 2019 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Autism’s common sites come to light

Rare genetic variants can greatly increase risk for autism, but a new genome-wide association meta-analysis led by Jakob Grove and Anders Børglum of Aarhus University in Denmark, institute member and Program in Medical and Population Genetics co-director Mark Daly, and colleagues uncovered five new common variants associated with autism spectrum disorder (ASD). The genetic overlap detected between autism risk and higher educational attainment and higher risk for schizophrenia and major depression enabled seven additional common variants to be discovered. Described in Nature Genetics, the results revealed genetic differences among clinical subgroups and offered biological insights related to the development of ASD, in particular, neuronal function and corticogenesis.

Profiling AML's many cellular players

Acute myeloid leukemia (AML) is an aggressive blood cancer fueled by complicated interactions between malignant and normal cells. Using single-cell RNA and genetic technologies, a machine learning model, and more than 38,000 cells from patients and healthy donors, postdocs Peter Van Galen and Volker Hovestadt, institute member and Epigenomics Program director Bradley Bernstein, and colleagues set out to clarify the spectrum of malignant cell types involved in the disease. In Cell, they report finding six AML cell types resembling different stages of blood cell development, with more "mature” cells producing factors that suppress immune responses against the cancer. Learn more in press releases from Massachusetts General Hospital and the Ludwig Institute for Cancer Research.

Base editing for tyrosinaemia

In a mouse model of the fatal genetic disease tyrosinaemia, a team including core institute member and Merkin Institute for Transformative Technologies in Healthcare director David Liu and colleagues — led by Wen Xue (UMass Medical School) — demonstrated that an adenine base editor could correct the relevant mutation and alleviate symptoms of the disorder. The team added plasmid DNA encoding an adenine base editor and guide RNA into the mice, partially restoring the correct gene sequence, generating healthy cells in the liver, and ameliorating the disorder’s hallmark weight loss. They also tested lipid-nanoparticle-mediated delivery of a modified guide RNA and an mRNA of an optimized base editor, which displayed higher base-editing efficiency. Check out the work in Nature Biomedical Engineering.

Losing sleep over genes

Insomnia, a common sleep disorder which affects one-third of the global population, increases the risk of cardiac and psychiatric diseases. However, we have almost no understanding of the underlying mechanisms of this common disorder. A team led by associate member Richa Saxena of the Program in Medical and Population Genetics, postdoc Jacqueline Lane, and collaborators analyzed data from 453,379 UK Biobank participants and identified 57 regions in the genome associated with insomnia and also found a causal link with heart disease. The findings from this study will help researchers understand the genetic causes of this disorder, the biological pathways it affects, and identify therapeutic targets to treat insomnia. Read more in Nature Genetics and an MGH press release.

Close look at the primate eye provides new view of blinding diseases

Core institute member and Klarman Cell Observatory director Aviv Regev and postdoc Karthik Shekhar teamed with Joshua Sanes and Yi-Rong Peng of Harvard and others to create the first cellular atlas of the foveal and peripheral regions of the primate retina. The fovea is a small retinal region that, among mammals, is unique to primates. Using single-cell RNA-seq, the team identified over 65 cell types, most of which were found in both regions but varied in prevalence and gene expression. They also learned that genes associated with seven human blinding diseases, including macular degeneration, exhibited strong cell type- and region-specific expression patterns. This new resource should be invaluable in understanding eye diseases in humans. Read more in the Harvard Gazette and Cell ― and be sure to check out Anna Hupalowska’s cover art while you’re there!

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