Skip to main content
Premium Trial:

Request an Annual Quote

Broad, Whitehead Team Uses Dual-Technology Screen to Identify Essential Genes in Human Genome

NEW YORK (GenomeWeb) — A team of researchers from the Broad Institute and the Whitehead Institute this week reported the results of a study in which they combined a pair of complementary functional genomics methods to scan the human genome and uncover a collection of genes essential for cell viability.

The work, which combined the gene-editing technology CRISPR with the mutation-inducing approach gene trapping, not only provides new insights into the genetics of cellular survival and proliferation, but provides a tool that could potentially be used to identify new therapeutic targets for cancer. 

"The ability to zero in on the essential genes in the highly complex human system will give us new insight into how diseases, such as cancer, continue to resist efforts to defeat them," Eric Lander, director of the Broad Institute and co-author of the study, said in a statement. 

While the systematic identification of essential genes in simple microorganisms like yeast has long been possible using tools such as the gene-silencing technology RNA interference, similar efforts in human cells have been hampered by the cells' greater genomic complexity. 

To address this issue, the scientists applied two independent approaches for inactivating genes at the DNA level.

The first, CRISPR, involves the use of a nuclease known as Cas9 to induce double-strand DNA breaks. These breaks are targeted to specific locations in the genome using a synthetic RNA, known as a guide RNA, that directs Cas9. In the second method, called gene trapping, a cassette containing a promoter-less reporter gene is inserted into the intron of an endogenous gene, simultaneously reporting and disrupting its expression.

In their study, which was published in Science, the investigators began by constructing a genome-wide single-guide RNA library to screen for genes required for proliferation and survival in human cancer cell lines. The library covered just over 18,000 genes, about 10 percent of which were found to be essential, including ones involved in DNA replication, RNA transcription, and mRNA translation.

The researchers then validated their results using a gene-trap screen in haploid cells and compared the results with those from functional profiling studies in yeast. The result is a set of genes that encode different components of fundamental pathways, are expressed at high levels, and contain few inactivating polymorphisms in the human population, according to the study.

Notably, about 300 of the genes identified as essential were previously uncharacterized. Most of these localize within the nucleolus and contained domains associated with RNA processing. This finding, the study's authors wrote, "indicate that the molecular components of many critical cellular processes, especially RNA processing, have yet to be fully defined in mammalian cells."

With an eye to the clinical potential of their approach, the investigators screened four cell lines derived from two well-studied cancers — chronic myelogenous leukemia and Burkitt's lymphoma. They identified several essential genes including ones targeted by existing cancer drugs and others that could potentially serve as new therapeutic targets.

Overall, the study serves as a framework to assess gene essentiality and potential drivers of malignancy, the investigators concluded. "The method can be readily applied to more cell lines per cancer type to eliminate idiosyncrasies particular to a given cell line and to more cancer types to systematically uncover tumor-specific liabilities that might be exploited for targeted therapies," the researchers wrote.

The Scan

Not Yet a Permanent One

NPR says the lack of a permanent Food and Drug Administration commissioner has "flummoxed" public health officials.

Unfair Targeting

Technology Review writes that a new report says the US has been unfairly targeting Chinese and Chinese-American individuals in economic espionage cases.

Limited Rapid Testing

The New York Times wonders why rapid tests for COVID-19 are not widely available in the US.

Genome Research Papers on IPAFinder, Structural Variant Expression Effects, Single-Cell RNA-Seq Markers

In Genome Research this week: IPAFinder method to detect intronic polyadenylation, influence of structural variants on gene expression, and more.