Research Roundup: April 11, 2022

Tweaking base editing efficiency, fusion oncogenes in rare cancers, better genetic predictions of disease, and more

Erik Jacobs
Credit: Erik Jacobs

Welcome to the April 11, 2022 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Editorial evolution

DdCBEs are all-protein cytosine base editors that use TALE proteins and a double-stranded DNA-specific cytidine deaminase (DddA) to install precise mutations within mtDNA. However, first-generation DdCBEs are limited in their targeting scope, with low editing efficiencies in some cases. To improve DdCBEs' efficiency and broaden their targeting scope of, Beverly Mok, core institute member and Merkin Institute for Transformative Technologies in Healthcare director David Liu, and colleagues rapidly evolved for two DddA variants using phage-assisted continuous evolution (PACE) and phage-assisted noncontinuous evolution (PANCE). The evolved variants improve the efficiency and broaden the scope of mitochondrial and nuclear base editing. Read more in Nature Biotechnology, in a tweetorial by David, and in GenomeWeb.

A new model of congenital hydrocephalus

Congenital hydrocephalus (CH), characterized by enlarged cerebral ventricles, is commonly attributed to disruptions in cerebrospinal fluid circulation. Studies have linked some genetic mutations to CH, but their links to phenotype, and the cell types involved, remain unknown. In Nature Neuroscience, Phan Duy, associate member Kristopher Kahle, and colleagues combined whole exome sequencing of people with CH with transcriptomic atlases of the developing brain. They found approximately 100 risk genes — including TRIM71/lin41, which harbored the most de novo mutations — mapped to cells lining embryonic brain ventricles. Mice with Trim71 mutations showed signs of hydrocephalus and reduced cell differentiation, suggesting some forms of CH result from congenital brain malformation rather than distorted fluid circulation. 

Fusion oncoproteins in liposarcoma

Many fusion oncoproteins, generated by chromosomal translocations, drive cancer development by interacting with SWI/SNF (or BAF) complexes, which remodel chromatin and modulate gene expression. In Molecular Cell, Hayley Zullow, institute member and Epigenomics Program co-director Cigall Kadoch, and colleagues investigated the role of the FUS::DDIT3 fusion oncoprotein, the hallmark of myxoid liposarcoma, in cell lines and primary tumors. They found that FUS::DDIT3 prevents BAF complexes from remodeling enhancers that regulate adipocyte development by sequestering the transcription factor CEBPB. The findings show how FUS::DDIT3 drives myxoid liposarcoma’s unique gene expression signature, which resembles those of other BAF loss-of-function tumors.

Improving accuracy of disease prediction

Polygenic risk scores (PRS) help assess the risk of some complex diseases by calculating the cumulative effects of genetic changes across millions of locations in the genome. However, PRSs calculated based on Euro-centric datasets tend to be less accurate when applied to populations of non-European ancestry. Omer Weissbrod, Masahiro Kanai, Huwenbo Shi, associate member Alkes Price of the Program in Medical and Population Genetics, and colleagues developed PolyPred, a method that reduces the gap in cross-population PRS accuracy. By applying PolyPred to 49 diseases or traits in four UK Biobank populations, they saw relative improvements in PRS accuracy ranging from 7 percent in south Asian to 32 percent in African populations. Read more in Nature Genetics.

CHIP's role in a complex web

In Science Advances, a team led by Tetsushi Nakao, associate member Pradeep Natarajan of the Program in Medical and Population Genetics, and colleagues investigated the relationship between telomere length, coronary artery disease, and clonal hematopoiesis of indeterminate potential (CHIP). Data from more than 100,000 individuals from the TOPMed program and UK Biobank suggest that leukocytes with longer telomeres increase an individual’s propensity to develop CHIP — but that CHIP, once developed, hastens the shortening of telomeres and increases risk of coronary artery disease. The results shed light on how telomere shortening contributes to age-related disorders, and could inform strategies to prevent coronary artery disease.

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