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Developmental Biology - Genetics

A First! CRISPR/Cas9 Edit of Gene Inheritance

UCSD first to use CRISPR/Cas9 to control genetic inheritance in mice...


Biologists at the University of California San Diego have developed the world's first CRISPR/Cas9-based technique sucessfully installing gene inheritance into a mouse.

Scientists around the world are using CRISPR/Cas9 in a variety of plant and animal species in attempts to edit gene transfer. One gene editing approach is to control which of the two copies of a gene is passed on to the next generation. An "active genetics" approach was developed recently in insects, but adapting these tools to mammals is more challenging as mammalian generations take longer to grow and test.

Publishing their work January 23 in the journal Nature, a joint team of UC San Diego researchers developed a new active genetics technology in mice. The achievement of UC San Diego graduate student Hannah Grunwald, Assistant Researcher Valentino Gantz and their colleagues led by Assistant Professor Kimberly Cooper, lays the groundwork for future advances in this technology, including biomedical research on human diseases.

"Our motivation is to develop this as a tool for laboratory researchers to control the inheritance of multiple genes in mice. With further development we think it will be possible to make animal models of complex human genetic diseases, like arthritis and cancer — which are not currently possible," explains Cooper PhD, in the division of Biological Sciences and Cellular and Developmental Biolog at the University of California, San Diego, California.
To demonstrate feasibility of an "active genetics" approach in mice, the researchers engineered a "CopyCat" DNA element into the Tyrosinase gene which controls fur color. When the CopyCat element disrupts both copies of the gene in a mouse, fur that would have been black is instead white, an obvious readout of the success of their approach. The CopyCat element also is designed so it cannot spread through a population on its own, in contrast with CRISPR/Cas9 "gene drive" systems in insects built with a similar molecular mechanism.

The new approach worked in female mice during egg production, but not during the male production of sperm. This might be due to differences in timing between male and female meiosis, the process by which pairs of chromosomes recombine to shuffle genes.
Over the two-year project, researchers built a CopyCat element that copies DNA from one chromosome to another only for repairs targeted by CRISPR/Cas9. Initially present on only one of two chromosomes in a pair — this element copies to the other chromosome as well.

In one family, as many as 86 percent of offspring inherited the CopyCat element from their mother as compared to the usual 50 percent.

According to UC San Diego Professor Ethan Bier, a study co-author, these results "Open the way for various applications...Including the modular assembly of complex genetic systems..."

Cooper and members of her lab are now springboarding off of this first mammalian success, based on a single gene, to attempt expanding to multiple genes. She adds: "We've shown that we can convert one genotype from heterozygous to homozygous. Now we want to see if we can efficiently control the inheritance of three genes in an animal. If this can be implemented for multiple genes at once, it could revolutionize mouse genetics."

While the new technology was developed for laboratory research, some envision future gene drives to restore the balance of natural biodiversity in ecosystems overrun by invasive species, including rodents. Bier: "With additional refinements, it should be possible to develop gene-drive technologies to either modify or possibly reduce mammalian populations that are vectors for disease or cause damage to indigenous species."

However, technical improvements are needed before a practical use in the wild. Careful consideration of each application of new technology should be implemented researchers note. However, their results demonstrate a substantial advance that might already decrease time, cost and number of animals needed to advance biomedical research on human diseases and complex genetic traits.
"We are also interested in understanding the mechanisms of evolution...traits evolved over tens of millions of years. We need to understand what caused bat fingers to grow into a wing...to understand the origins of mammalian diversity."

Kimberly L. Cooper PhD, Division of Biological Sciences Cellular and Developmental Biology, University of California San Diego, La Jolla, California, USA.

Abstract
A gene drive biases the transmission of one of the two copies of a gene such that it is inherited more frequently than by random segregation. Highly efficient gene drive systems have recently been developed in insects, which leverage the sequence-targeted DNA cleavage activity of CRISPR–Cas9 and endogenous homology-directed repair mechanisms to convert heterozygous genotypes to homozygosity1,2,3,4. If implemented in laboratory rodents, similar systems would enable the rapid assembly of currently impractical genotypes that involve multiple homozygous genes (for example, to model multigenic human diseases). To our knowledge, however, such a system has not yet been demonstrated in mammals. Here we use an active genetic element that encodes a guide RNA, which is embedded in the mouse tyrosinase (Tyr) gene, to evaluate whether targeted gene conversion can occur when CRISPR–Cas9 is active in the early embryo or in the developing germline. Although Cas9 efficiently induces double-stranded DNA breaks in the early embryo and male germline, these breaks are not corrected by homology-directed repair. By contrast, Cas9 expression limited to the female germline induces double-stranded breaks that are corrected by homology-directed repair, which copies the active genetic element from the donor to the receiver chromosome and increases its rate of inheritance in the next generation. These results demonstrate the feasibility of CRISPR–Cas9-mediated systems that bias inheritance of desired alleles in mice and that have the potential to transform the use of rodent models in basic and biomedical research.

Authors
Hannah A. Grunwald, Valentino M. Gantz, Gunnar Poplawski, Xiang-Ru S. Xu, Ethan Bier and Kimberly L. Cooper.

Acknowledgements
The authors thank K. Hanley for the DNA extraction protocol; A. Green and A.-C. Chen for genotyping assistance; M. Tran for laser-capture microdissection in an effort to genotype spermatogonia; P. Jain for assistance with fibroblast transfection; H. Cook-Andersen and M. Wilkinson for conversations about mouse germline development; L. Montoliu for discussion of the tyrosinase locus; M. Tuszynski for plasmids and for early support of the project. This work was funded by a Searle Scholar Award from the Kinship Foundation, a Pew Biomedical Scholar Award from the Pew Charitable Trusts, a Packard Fellowship in Science and Engineering from the David and Lucile Packard Foundation, and NIH grant R21GM129448 awarded to K.L.C. E.B. was supported by NIH grant R01GM117321, a Paul G. Allen Frontiers Group Distinguished Investigators Award and a gift from the Tata Trusts in India to TIGS-UCSD and TIGS-India. H.A.G. was supported by a Ruth Stern Graduate Fellowship and by the NIH Cell and Molecular Genetics training grant T32GM724039; V.M.G. was supported by NIH grant DP5OD023098.

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Jan 29, 2018   Fetal Timeline   Maternal Timeline   News   News Archive




UC San Diego researchers used CRISPR/Cas9 to control genetic inheritance in mice
— the first time accomplished in mammals. Image Credit: Cooper Lab, UC San Diego


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