Research Roundup: February 7, 2020

Welcome to the February 7, 2020 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Most complete cancer genome map to date

Fifty-two members of the Broad Institute community were part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Project, an international consortium of more than 1,300 researchers from 37 countries that analyzed more than 2,600 whole cancer genomes. The collaborators, including institute member Gad Getz of the Cancer Program, associate member Esther Rheinbay, associate member Rameen Beroukhim, group leader Ignaty Leshchiner, and others generated the most comprehensive map of the cancer genome, bringing researchers closer to identifying all major cancer-causing mutations. Find out more in 23 papers in Nature and its affiliated journals and in a Broad story.

Designating drivers

Driver mutations in cancer affect the function of the cancer cell, while passenger mutations are just random changes in the DNA sequence that “go along for the ride.” A new study has found that some driver mutations occur in “nucleotide contexts” different from those near passengers. The work was led by a team including Shamil Sunyaev, an associate member in the Program in Medical and Population Genetics (MPG); Eli Van Allen, an associate member in the Cancer Program; Felix Dietlein, a postdoctoral fellow in the Sunyaev and Van Allen labs; and Sunyaev lab alum Donate Weghorn (now at the Centre for Genomic Regulation in Barcelona, Spain). Reporting in Nature Genetics, they combined this feature with signals traditionally used to identify driver genes and applied the method to whole-exome sequencing data from nearly 12,000 tumor-normal pairs. They found 460 driver genes clustering in 21 cancer-related pathways, expanding the catalog of driver genes in tumors with high background mutation rates.

Keeping a weather eye out 

Gene therapy holds promise for treating forms of inherited vision loss, but defining the genetic cause of disease in a patient can be challenging, especially when the quarry might be a non-coding variant. In Human Molecular Genetics, MPG associate member Eric Pierce and colleagues present an approach that uses whole genome and transcriptome sequencing of retinal organoids grown from patient-derived induced pluripotent stem cells to pinpoint disease-associated non-coding variants. In a proof-of-concept study, they used the approach to flag a novel, non-coding mutation in CNGB3 as the root of a rare cone dysfunction syndrome in two siblings.

Max-imizing genomic knowledge of lipid storage

Lipid droplets (LDs) are lipid-storing organelles in cells that change their numbers and size depending on the metabolic state of the cell. However, the mechanisms that coordinate lipid storage in LDs are not clearly understood and are relevant to obesity-related diseases. A team led by Metabolism Program associate members Robert Farese, Tobias Walther, and colleagues performed genome-wide screening to identify genes that control lipid storage. Reporting in Molecular Cell, the researchers defined 550 genes governing LD biology and identified a transcription factor called MLX or Max-like protein X as a key regulator of metabolic processes associated with lipid storage levels.

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