Research Roundup: March 29, 2019

Welcome to the March 29, 2019 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Understanding schizophrenia — from genomes to phenomes

Genomic studies have identified hundreds of candidate genes associated with the risk for schizophrenia. However, to gain a better understanding of the mechanisms underlying schizophrenia and other neuropsychiatric diseases, it would be useful to identify previously unknown, phenotypic functions of many of these genes. A team led by Summer Thyme and Cell Circuits Program associate member Alexander Schier at Harvard created a phenotypic atlas consisting of whole-brain activity maps, brain structural differences, and behavioral abnormalities — by analyzing zebrafish deficient for human schizophrenia-associated genes. The team was able to prioritize 30 genes for future studies and reported the findings in Cell.

A blood shortage, explained

In the Journal of Experimental Medicine, Nour Abdulhay, Claudia Fiorini, Jeffrey Verboon, Leif Ludwig, Program in Medical and Population Genetics (MPG) associate member Vijay Sankaran at Dana-Farber/Boston Children's Cancer and Blood Disorders Center, and colleagues looked closely at the cases of two unrelated patients, both with dyserythropoietic anemia — a condition characterized by a shortage of red blood cells — and other blood cell production impairments linked to the same, rare genetic mutation in the gene GATA1. The team determined that the mutation alters “splicing,” the process that removes non-coding regions of a gene during transcription, where DNA is transcribed into mRNA for protein production. The work showed how splicing errors reduce levels of the GATA1 protein, leading to distinct changes in human hematopoiesis.

A life or death (molecular) balancing act

Scientists can turn up autophagy — a process whereby cells clear out damaged proteins or broken cell components that accumulate with age — to extend lifespan in animal models like mice and worms. But there's a tipping point: too much autophagy can instead reduce lifespan. In Cell, Ben Zhou, Metabolism Program associate member Alexander Soukas at Massachusetts General Hospital, and colleagues make the case that porous mitochondria are in part to blame. They found that mice and worms lacking a gene called SGK1 have higher levels of autophagy, shorter lifespans, and increased mitochondrial permeability. Making mitochondria less permeable, they noted, returns models' lifespans to normal, suggesting that it balances autophagy's effects.

Cas13b crystal structure

In Cell Reports, a team led by Ian Slaymaker and core institute member Feng Zhang describes the crystal structure of the Cas13b enzyme from Prevotella buccae bacteria at 1.65 Å resolution. This structural analysis, combined with biochemical experiments assaying the stability, kinetics, and function of the enzyme, identified important features that regulate Cas13b’s RNA targeting and cleavage activity. Insights from this work will enable further engineering to improve RNA targeting, base editing, and nucleic acid detection in CRISPR systems.

It takes a village

For a closer look at how shared environments and social interactions shape the human microbiome, a team led by core institute member Eric Alm analyzed data from 287 people who participated in the Fiji Community Microbiome Project. Within isolated villages, they found that bacterial DNA can predict certain relationships, such as mother-to-child or spouse-to-spouse. Described in Nature Microbiology, the work sheds light on how transmission of pathogenic and protective gut and oral microbes within a household or between spouses can impact an individual’s health.

A more detailed slice of life

A new tool developed in the labs of Stanley Center for Psychiatric Research associate member Evan Macosko and Schmidt fellow Fei Chen offers unprecedented views of the cellular organization of tissues, using RNA sequencing and spatially encoded DNA barcoding. Known as Slide-seq and developed by Robert Stickels and Samuel Rodriques, the technique allows end users without a microscope to generate detailed images of tissue slices and to visualize different cell types and gene expression patterns. The researchers used Slide-seq to locate a single-cell-layer of cells in the mouse brain, and to observe gene expression changes after injury, among other findings. Read more in Science or this Broad news story.

Prioritizing diversity for polygenic scores

A team led by Stanley Center associated scientist Alicia Martin and institute member and MPG co-director Mark Daly reports that polygenic scores for common diseases are more precise in a given population if they are developed using genetic data derived from a similar ancestry. For example, the researchers demonstrated that scores developed using UK Biobank data — which contains information for half a million people, about 94 percent of whom have European ancestry — are significantly better at predicting risk of common diseases for people of European ancestry, compared to those of African and East Asian ancestry. The findings, reported in Nature Genetics, underscore the need for expanding genomic studies in non-European ethnic groups. Learn more in a Broad news story.

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