IMAGE:NHGRI scientists are homing in on specific genes in zebrafish to help them better understand the function of genes in people. view more

Credit: Darryl Leja, NHGRI

A relatively new method of targeting specific DNA sequences in zebrafish could dramatically accelerate the discovery of gene function and the identification of disease genes in humans, according to scientists at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH).

In a study posted online on June 5, 2015, and to be published in the July 2015 issue of Genome Research, the researchers reported that the gene-editing technology known as CRISPR/Cas9 is six times more effective than other techniques at homing in on target genes and inserting or deleting specific sequences. The study also demonstrated that the CRISPR/Cas9 method can be used in a "multiplexed" fashion - that is, targeting and mutating multiple genes at the same time to determine their functions.

"It was shown about a year ago that CRISPR can knock out a gene quickly," said Shawn Burgess, Ph.D., a senior investigator with NHGRI's Translational and Functional Genomics Branch and head of the Developmental Genomics Section. "What we have done is to establish an entire pipeline for knocking out many genes and testing their function quickly in a vertebrate model." Researchers often try to determine the role of a gene by knocking it out - turning it off or removing it - and watching the potential effects on an organism lacking it.

Such larger scale - termed "high-throughput" - gene targeting in an animal model could be particularly useful for human genomic research. Only 10 to 20 percent of recognized human genes have been subjected to such rigorous testing, Dr. Burgess said. The functions of many other genes have been inferred based on analyzing proteins or have been identified as possible disease genes, but the functions of those genes have not been confirmed by knocking them out in animal models and seeing what happens.

"This is a way to do that on a more cost-efficient and large scale," Dr. Burgess said.

"The study of zebrafish has already led to advances in our understanding of cancer and other human diseases," said NHGRI Director Eric Green, M.D., Ph.D. "We anticipate that the techniques developed by NHGRI researchers will accelerate understanding the biological function of specific genes and the role they play in human genetic diseases."

The CRISPR/Cas9 method of gene editing is one of the two essential components in the NHGRI team's high-throughput method. Modeled on a defense mechanism evolved by bacteria against viruses, CRISPR/Cas9 activity was first described in 2012. Since then, its use has spread quickly - in other words, has gone "viral" - in genomic research labs in the United States and abroad.

The acronym CRISPR stands for "clustered, regularly interspaced, short palindromic repeat," referring to a pattern of DNA sequences that appears frequently in bacterial DNA. Scientists believe the CRISPR sequences reflect evolutionary responses to past viral attacks.

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