6 minute read
PROGRESSIVE PRODUCER
GENE EDITING:
HOW CAN IT BE INCORPORATED IN BEEF CATTLE BREEDING PROGRAMS?
by Maci Mueller, Ph.D. Candidate, University of California, Davis
Leaders in all segments of the beef industry, from researchers to producers to allied industry partners, gathered this June to discuss and guide the improvement of the beef industry at the 2021 Beef Improvement Federation (BIF) Research Symposium and Convention. The symposium, held in Des Moines, Iowa, featured two and a half days of educational programming and a full day of tours. Thanks to the support of the California Beef Cattle Improvement Association (CBCIA), as a University of California, Davis (UC Davis), graduate student I was able to attend the symposium and gain valuable insight and understanding of the current status of beef cattle genetics and related technologies, in order to be better prepared for my future career as an animal geneticist.
The theme for General Session 2 was “Precision Livestock Technology,” which Alison Van Eenennaam, Ph.D., explained was very fitting for her topic of “Gene Editing Today and in the Future” because gene editing is a form of precision animal breeding. Van Eenennaam, a Cooperative Extension Specialist in Animal Genomics and Biotechnology at the UC Davis first presented about the emerging technology of gene editing at the 2017 BIF during a technical breakout. Over the past five years gene editing has become an increasingly popular topic in animal breeding and recently the Red Angus Association of America announced, “they will provide herdbook registry of Red Angus animals carrying gene-edited traits for heat tolerance and coat color” (https://www.beefmagazine.com/ beef/beef-breed-approves-gene-edited-traitsanimal-registration). Van Eenennaam updated the BIF audience on the latest gene editing research advancements and also discussed how this precision breeding technology could be incorporated into current beef cattle breeding programs.
Before diving into gene editing, Van Eenennaam first described the current state of cattle breeding practices to set the stage for understanding how gene editing could fit in. The bovine genome (~3 billion base pairs) was first sequenced in 2009 and since then thousands of cattle have been sequenced. The ‘1000 Bull Genomes Project’ actually sequenced 2,703 bulls from all over the world and found over 86.5 million genomic variations, including SNPs (single nucleotide polymorphisms) and indels (small insertions/ deletions) between breeds. Van Eenennaam explained that this amazing genetic diversity, “is actually the engine that drives genetic improvement." That is what you are selecting on, this genetic variation that spontaneously occurs and that is the result of why different breeds of cattle exist and why different cattle are adapted to different environments.” Sequencing the bovine genome opened the door to genomics by enabling the development of high-density SNP chips, which were rapidly adopted by the global cattle breeding community. At first, there was some antagonism between genomics and quantitative genetics (i.e., expected progeny difference or EPD), but eventually it all came together to form an integrated system where genomics is incorporated as an additional data source to get a more accurate EPD. Van Eenennaam sees parallels of this genomics pathway with the future incorporation of gene editing to animal breeding.
She explained that gene editing is a method to introduce a double strand break at a targeted location in the genome. The revolutionary part of gene editing is that an animal breeder can tell the gene editors (e.g., Zinc finger nuclease, TALENS, CRISPR/Cas9), which can be thought of as molecular scissors, exactly where in the genome to make the cut. The cell doesn’t like breaks in the DNA so it will try to repair the break. Sometimes the cell repairs the break incorrectly by adding or subtracting extra base pairs which can lead to the gene being inactivated, otherwise known as a “knockout.” Animal breeders may want to knockout
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a gene if it has a negative effect, like makes the animal susceptible to disease. On the other hand, if you want to “knock-in” a gene then you can provide a donor template, which has sequence similarity to the target site, and the cell will incorporate that donor template during repair. The donor template can be a copy of DNA from another breed of cattle (intraspecies) or even a different species (interspecies or transgenic). Using gene editing to knock-in a gene from another breed of cattle enables useful alleles to be introduced into elite germplasm without traditional crossbreeding. Traditional crossbreeding often brings in a lot of undesired genetic information, known as “linkage drag” which refers to all of the unwanted traits that come along with the desired gene. Breeders then have to spend several generations breeding out the unwanted genetics while retaining the desired gene.
To answer the question of “how might gene editing be used in cattle breeding programs?” Van Eenennaam shared a table (Table 1) that listed all the traits that have been reduced to practice (but are not commercially available) and a few examples of what could be envisioned with this technology (e.g., skewing sex ratios). Van Eenenaam pointed out, “If we look at the target trait/ goal, we haven’t gone off the track. We still are interested in productive animals, healthy animals and good product quality.” She noted that gene editing research in cattle to date has focused primarily on monogenic (single gene) traits because that is what is possible with the technology now. However, many of the traits animal breeders care about are multi-genic (e.g., many genes effect marbling, growth, etc.). Moving forward it will be important to continue using quantitative genetics and genomics to improve multi-genic traits and then gene editing can be used to complement this selection by efficiently introducing additional beneficial genes without linkage drag. The Beef Improvement Federation is currently in the process of developing guidelines on what data should be required from gene edited animals for breed association registration (http:// guidelines.beefimprovement.org/ index.php/Data_From_Gene_Edited_ Animals).
“I see editing as a cherry on top of the breeding sundae. It doesn’t replace breed associations, or performance recording, or genomic selection - it doesn’t replace any of that, it’s the cherry,” Van Eenennaam emphasized. She explained that while a cherry on top of an ice cream sundae is nice, you can still have a sundae without the cherry. Likewise, without gene editing we will still have very efficient breeding programs, but gene editing does provide a way to bring in useful genetic variation from other breeds without linkage drag. Van Eenennaam concluded with, “I see so much potential for genomics, reproductive technologies and genome editing to form a troika [a Russian vehicle pulled by a team of three horses abreast] that can really power breeding programs.”
TABLE 1. TRAITS THAT HAVE BEEN OR MIGHT BE TARGETS FOR GENE EDITING IN CATTLE BREEDING PROGRAMS TARGET TARGETED TRAIT/GOAL Animal health/ welfare
Intraspecies POLLED allele substitution No horns/welfare trait Intraspecies SLICK allele knockout Heat tolerance Diluted coat color Heat tolerance Prion protein (PRNP) knockout Disease Resistance (Elimination prion protein) Insertion of lysostaphin/lysozyme transgene Disease Resistance (Mastitis) CD18 gene edit Disease Resistance (Bovine Respiratory Disease) Insertion of SP110, NRAMP1 Disease Resistance (Tuberculosis)
Product yield or quality
Myostatin (MSTN) gene knockout Increased lean muscle yield Beta-lactoglobulin gene knockout Elimination of milk allergen
Reproduction and novel breeding schemes
Calpain/calpastatin allele substitution Improved meat tenderness Omega-3 (Fat-1) transgene Increased omega-3 fatty acids
THE FUTURE GENOMICS REPRODUCTIVE TECHNOLOGIES
Recent developments in the three fields of biotechnology, genomics and reproduction offer a troika of synergistic opportunities to accelerate the rate of genetic improvement in cattle.
