Research Roundup: April 27, 2018

Welcome to the first installment of Research Roundup! This new recurring feature provides a snapshot of studies published by Broad Institute scientists and their collaborators.

A new SHERLOCK for outbreak sleuthing

In Science, a team led by Cameron Myhrvold, Catherine Freije, and Broad institute member Pardis Sabeti describes a new sample-processing technique, dubbed HUDSON, that enables the CRISPR-based diagnostic SHERLOCK to detect viruses directly in clinical samples (such as blood or saliva) without the need for nucleic acid extraction. The team also designed tests that make it easier and faster to distinguish multiple related viruses and showcased the platform’s sensitivity to single-nucleotide mutations with clinical relevance. These advances optimize SHERLOCK for rapid outbreak response in areas with limited equipment. Learn more in a Broad announcement and video.

Mining UK Biobank for protective variants

By mining the massive UK Biobank dataset, two research teams have helped reveal protective mutations that could be new therapeutic targets, described in Nature Communications. In one paper, Broad institute member Sekar Kathiresan, Connor Emdin, Amit Khera, and colleagues describe their analysis of nearly 4,000 mutations predicted to cause a protein’s malfunction in more than 400,000 Biobank participants, identifying 18 rare variants that protect against heart disease, cancer, or other conditions. The other study, by a team led by Broad visiting scientist Manuel Rivas of Stanford University, analyzed more than 18,000 protein-shortening mutations and found 27 that protect against conditions such as asthma, bronchitis, and hypertension.

When starving cells turn inward

Starving cells use organelles called lysosomes and autophagosomes to break proteins down into much-needed nutrients. Using their recently developed LysoIP lysosome collection method, Greg Wyant, Mother Abu-Remaileh, and Broad associate member David Sabatini, all at the Whitehead Institute, and their colleagues took a close look at the proteins that work with lysosomes in starving cells, finding that one called NUFIP1 plays a previously unsuspected but necessary role in delivering ribosomes (the cell's protein-building molecular machines) to autophagosomes for breakdown. Learn more in Science.

Pervasive pleiotropy confounds causality

Mendelian randomization (MR) uses genetic variation to infer whether epidemiological risk factors, such as obesity, exert a causal effect on disease. But a team led by Broad institute member Benjamin Neale, Chia-Yen Chen, and colleagues from Mount Sinai has found that a phenomenon called horizontal pleiotropy — in which genetic variants affect disease-relevant traits beyond those risk factors being tested — distorts results in MR studies. To detect and correct for horizontal pleiotropy, the researchers have developed open-source software called MR-PRESSO. Find the software on GitHub and learn more about the study in Nature Genetics.

Different types of blood biopsies benchmarked

Blood biopsies — a technology for profiling circulating tumor cells (CTCs) or cell-free tumor DNA (cfDNA) — could be a promising disease monitoring tool for patients with cancer. In this week's Nature Communications, a team led by Broad associate member Irene Ghobrial and group leader Viktor Adalsteinsson, both at Dana-Farber Cancer Institute, benchmarked blood biopsy CTC and cfDNA measurements against bone marrow biopsies in patients with multiple myeloma. The team's blood biopsy whole genome and exome data matched their bone marrow data very closely, and revealed the advantages of analyzing CTCs and cfDNA together.

Scoping biology and disease with single-cell epigenomics

Assay for Transpose Accessible Chromatin sequencing (ATAC-seq) is an increasingly popular method for studying the epigenome at single-cell levels. Reporting in Cell, Broad fellow Jason Buenrostro, Broad associate member Martin Aryee at Massachusetts General Hospital, Caleb Lareau, and others present diverse ATAC- and RNA-seq profiles from individual blood cells, creating a resource for scientists interested in building computational tools to discover cell networks. In a separate Nature Medicine study, Buenrostro and colleagues combined single-cell ATAC-seq with T-cell receptor sequencing to compare immune system T cells from healthy volunteers and leukemia patients. They identified distinct epigenetic states and regulatory pathways in leukemia cells — thus underlining the value of using ATAC-seq in cancer and immunotherapy research.

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