Genetic progress in cattle breeding has been a significant focus for the global agricultural industry over the past several decades. The use of advanced genetic tools and technologies has allowed for the development of more efficient and productive cattle breeds, which has resulted in increased milk and meat production, as well as improved animal health and welfare.
Several countries have made significant strides in cattle breeding and genetic progress. In the United States, for example, the dairy industry has seen an average increase of 1.5% per year in milk production per cow since the 1970s. In Europe, countries such as the Netherlands, Germany, and France have implemented advanced breeding programs and technologies to improve the genetic potential of their cattle populations.
In developing countries, the focus has been on developing and improving indigenous cattle breeds through selective breeding and genetic improvement programs. For example, Brazil has developed several successful breeding programs for its native cattle breeds, resulting in increased productivity and improved meat and milk quality.
Gene editing has led to several current and forthcoming advancements in cow genetics. Breeding programmes may use gene editing to rapidly and precisely introduce desired modifications, which is impossible with traditional selection alone.
Gene editing, as explained by Dr. Alison van Eenennaam, entails directing enzymatic DNA’scissors’ to make a precise cut at a specified DNA sequence. Using gene editing, a geneticist at the University of California, Davis, produced a bull calf (called Cosmo) with the potential to have progeny that are mostly male.
She elaborates, “You can have inactivation of the gene that is located at the target site, or an alteration in the functionality of that gene, depending on how the cut is repaired.” DNA from the same organism, a different organism of the same species, or a DNA repair template from a different species might be injected at the cut spot.
Mendelian or qualitative qualities, which are controlled by a single gene rather than a large number of genes like quantitative features, are ideal candidates for gene editing.
On the other hand, genetic engineering has been around for more than two decades, and it involves inserting foreign genetic material into the genome with the use of a DNA repair template and without the need of site-directed nucleases. In 2020, the first genetically-engineered (transgenic) farmed animals authorised for human consumption in the United States were the ‘GalSafe’ pigs (originally conceived in 2002) and the ‘AquAdvantage’ fish (originally created in 1989).
Heat Tollerance
Gene editing has only been employed in two methods so far, both of which are related to specific genes that govern features linked with heat tolerance (coat colour and hair type), despite the fact that heat tolerance is an overall performance criterion with many contributing qualities (and thus many genes).
The so-called’slick coat’ is the result of a single gene change. These cattle benefit from the heat less than their hairless counterparts since their hair is short, smooth, and occasionally shiny. This characteristic has been shown to reduce the vaginal temperature and the respiratory rate in Holsteins. The reproductive performance of slick-coated Holsteins was also shown to be enhanced in the hot and humid circumstances of Puerto Rico, according to a report published in 2020 by researchers from Mississippi State University and the University of Puerto Rico in Mayagüez.
Geneticists at the Roslin Institute (University of Edinburgh in Scotland) have utilised a gene-editing technology to introduce the’slick gene’ into freshly fertilised eggs from cows without the edit, despite the fact that the’slick gene’ is also employed in traditional breeding plans in other areas of the globe. Native Kenyan cow breeds are a focus of their collaboration with the International Livestock Research Institute in that country.
Two slick-coated beef calves were created via gene editing by a company in the United States called Recombinetics. Data on “significant” gains in performance of these altered beef cattle under heat stress has been collected, according to Dr. Tad Sonstegard, president and CEO of Acceligen (owned by Recombinetics), but it is not yet suitable for publishing.
Lightening the coat colour of cattle (dark hues absorb more UV) is another method of using gene editing to lessen the effects of heat stress. New Zealand geneticists have succeeded in changing the traditional black-and-white Holstein coat pattern to a more modern grey-and-white one.
Dr. Peter J. Hansen of the University of Florida mentions the identification of a heat-tolerance gene in cattle, which is associated with reduced synthesis of heat shock proteins and correspondingly reduced cell death, in a review article regarding the possibilities of gene editing.
The Australian research group Agriculture Victoria has also discovered numerous genes that are highly linked to heat tolerance. Since 2017, breeders in Australia have had access to genomic breeding parameters for heat tolerance that are grounded on natural genetic variation.
Medical advancements
Disease resistance, say specialists like Van Eenennaam, is where gene editing may have the most impact. This is due to the fact that traditional breeding has already substantially improved (some would argue to near maximum) qualities like growth rate and feed conversion in cattle, and that these traits are impacted by a large number of genes.
Despite the complexity of most disease processes, gene editing has been shown to prevent or significantly decrease disease vulnerability in certain circumstances. Deleting a gene that codes for a host cell surface protein that a specific pathogen uses as an attachment site is one such strategy. This precise idea, in relation to the attachment of the virus causing Porcine Reproductive and Respiratory Syndrome (PRRS), has been realised in pigs.
Researchers at Recombinetics, in conjunction with two US institutions and the USDA, have created a gene-edited cow that is resistant to Bovine viral diarrhoea virus (BVDV). To paraphrase the researchers, “dramatically reduced susceptibility to infection, as measured by clinical signs and the lack of viral infection in white blood cells” is the outcome of a gene edit replacement in the BVDV ‘binding domain’ gene on 1 chromosome.
The smooth coat mutation and two targeted mutations in potential genes for African trypanosomiasis resistance have been used in the recombinetic production of ‘Thamani’ Holsteins. “We have bred a small herd of Holstein animals with multiple edits that are still in the pre-regulatory evaluation phase of development,” explains Sonstegard. Since small-holder dairy farms in tropical countries were the intended beneficiaries of this breeding endeavour, such farms will be the first to get permission.
The gene edit for the cow illness is being worked on by one of Van Eenennaam’s graduate students. She explains that, “since the disease affects both sheep and humans, he is knocking out the gene in sheep first; if that works, we’ll try out the edit in cattle, which are more expensive models on which to perform experiments.”
Van Eenennaam explains that China has released papers demonstrating their attempts to breed resistant cattle to TB, a zoonotic disease with worldwide significance.
It cost me money to raise the bull and harvest his sperm, but I don’t have enough money right now to find out whether he has an unbalanced effect on the gender ratio of his progeny. According to Dr. Alison Van Eenennaam, depicted above, “it is very expensive to undertake this type of research in the United States.” Dr. Alison Van Eenennaam, shown.
Changes in many parts of the globe
As Van Eenennaam says, “I had initial funding to produce the bull and collect his semen, but as yet I don’t have funding to confirm if the gender ratio is skewed in his resulting offspring.” This is in reference to Cosmo, the gene-edited calf that Van Eenennaam produced. Since all gene-edited animals are deemed novel animal medicines by the US Food and Drug Administration (FDA), doing this sort of study in the United States is prohibitively costly. This makes it difficult to acquire the substantial funds necessary for such research, since the resulting waste must be burnt rather than sold.
To create sterile bulls and cows into which elite germ lines from unrelated, genetically superior animals may be inserted, one of her graduate students has been attempting to knock off a gene for germline development in cattle. According to her, this technology has the potential to speed up the spread of top genetics in large-scale businesses like beef and sheep production by means of natural service mating.
Several years ago, a group of researchers from several universities and Recombinetics successfully edited the genes of polled (hornless) cattle. According to Van Eenennaam’s 2019 review study, there is a lot of interest in using editing to introduce the polled allele into dairy breeds despite the fact that dehorning is unpleasant but protects animals and people from damage. Due to the lack of genetic value and the rarity of polled dairy sires, polled cow breeding has not been a priority in the past.
Scientists from New Zealand and Recombinetics utilised zygote-mediated genome editing to remove beta-lactoglobulin, a significant allergy in cow’s milk. This was done by some of the same scientists that edited the gene for the grey Holstein coat.
Republic of Korea researchers have created double-muscled cows by manipulating the myostatin gene. According to Van Eenennaam, this has also been accomplished in swine, cattle, and sheep by Chinese researchers. Similarly, Japanese researchers have created myostatin knockouts in 2 fish species, making them the world’s first gene-edited animal food product accessible for commercial sale.
Static regulatory regimes
Many geneticists, like Van Eenennaam, find current laws on gene editing to be too rigid and irrational. In the European Union, for instance, gene editing is subject to the same regulations as genetic engineering. When a gene is knocked out and no unique or foreign DNA is added, the leadership in other countries sees gene editing as similar to traditional breeding. This is the case in Brazil, Australia, and Argentina.
It’s fair to say that US laws and rules are unusual. Currently, the Food and medicine Administration (FDA) oversees livestock gene editing, considering any purposeful genome modification to be the same as a novel animal medicine subject to the same regulatory frameworks.
A first of its kind ‘enforcement discretion judgement’ on gene-edited livestock was issued to Recombinetics in March 2022 over their two beef calves with the slick coat mutation. Since the ‘risk’ connected with these calves and their gene edit was deemed negligible, current new animal rules do not apply to them or their offspring. According to Van Eenennaam, this does not mean that new animal medicine rules have been approved or waived; rather, it means that the products derived from these two animals were not deemed dangerous enough to need special attention from regulators.
In order to meet the goals of Executive Order 14081, “Advancing Biotechnology and Biomanufacturing Innovation for a Sustainable, Safe, and Secure American Bioeconomy,” she recommends that the FDA consider a tiered system of regulatory oversight based on levels of risk and that an update to the regulatory framework be undertaken as soon as possible.
There are “huge opportunity costs” to putting off genetic progress in our food animal species, she warns. It’s been said that “the lack of global regulatory harmonisation around gene-edited animals and products from these animals, including semen and embryos, will pose challenges regarding global trade, and aspects of traceability in both animal breeding and the food chain.”
In the future, as she explains in a recent paper co-authored with PhD candidate Maci L. Mueller, Van Eenennaam thinks gene editing will need to be seamlessly integrated into structured breeding programmes with a clear breeding objective, and will ideally be used to accelerate genetic gain by using it in conjunction with assisted-breeding technologies to simultaneously alter multiple components of the breeder’s selection process.
Many models of gene-editing strategies have been developed for cattle populations, with the most successful strategies depending critically on broad acceptance of assisted reproductive technologies, particularly the use of artificial insemination in the commercial sector.
Artificial insemination with semen from elite, edited males is a simple way to spread desirable edits across dairy cow production systems. For example, Van Eenennaam says, “considering the currently limited adoption of artificial insemination in developing countries, and especially in extensive livestock production systems, novel breeding schemes, such as gene editing applied to produce surrogate sires carrying elite germline genetics, will likely be required to widely disseminate desired traits improved via edits.”
