Genetic Mutations: What, How and When

     For those who have been scrolling through social media and various agriculture-based news outlets in the past 12 to 18 months, it may seem as though there has been quite a few “new” genetic mutations or defects that have been identified. For most producers this is something they have dealt with before. But for others this may be the first time they are being faced with what seems like a “sky is falling” predicament. Regardless of which group you belong to, understanding what genetic mutations are, how they happen, and what to do when they are identified may prove helpful for the future.

    To put this into perspective, cattle have 30 pairs of chromosomes. They inherit one of each pair from their sire and the other from their dam. A typical cattle genome consists of 2.7 billion nucleotides (A, T, G, C), or pieces of DNA, each occurring again in a pair. When they come together to form a fertilized egg, or future fetus, that is 5.4 billion nucleotides that are replicated each time a cell splits and divides into another. How often do you think this occurs perfectly? The answer is never.

    When one of these base pairs is replicated as a “mistake” it is called a mutation. While there are mechanisms in place that look for and repair these replication mistakes, they sometimes still slip through the error checking process. The good news is that to be passed to the next generation, these mutations must occur in cells that form part of reproductive tissue and could appear in the sperm or egg of a reproducing animal. Scientists estimate that these inherited mutations occur approximately 63 times in every mating [1]. There are lots of ways these mutations arise, most of which have no actual repercussions on the performance of an animal. The most common mutation occurs when one nucleotide accidently replicates as another, called a nucleotide substitution [1]. This is shown in Figure 1a where the G nucleotide has been exchanged for an A. The second and third are called ‘insertions’ where nucleotides are added to the DNA (Figure 1b), or ‘deletions’ where nucleotides are removed (Figure 1c).

Figure 1. Visual representations of how genetic mutations occur in DNA via nucleotide substitution, insertion, and deletion.

The moral of the story is that mutations happen in every living thing, and they happen relatively frequently. For easy math, in a herd of 100 cows, there are 6,300 genetic mutations that appear in each calf crop, not including the ones that were inherited from the generation before.

    Now, you may be asking yourself “then why don’t we see more problems in cattle than we currently do?”. The answer is that not all mutations or changes to the DNA occur in genes that control performance of the animal. Furthermore, a mutation in one copy of the chromosome may be hidden by a functional copy in the other – a common occurrence with recessive, or hidden, DNA variants where an animal must have two copies of a gene to phenotypically express a trait. The easiest example of this would be coat color. The calf must inherit one red variant from the sire and another from the dam to be phenotypically red, otherwise it is just a black hided animal who carries a single hidden red gene.

    Because cattle often need two copies of the mutation for producers to see any performance differences, new deleterious mutations (also commonly termed genetic defects), often go unnoticed for generations. Think of it this way, if the new mutation occurs in a terminal animal, it is not reproduced or passed to the next generation. Similarly, if it occurs in a registered bull that is sold to a commercial operation, it is likely to only be passed to replacement females in that herd who are not bred back to that same bull, and therefore never seen. The most likely source of proliferation among a breed is when an influential AI sire passes the mutation on multiple times in his life. Using Figure 2 as an example, an AI sire would be expected to pass down a new mutation to 50% of his offspring. When used heavily, that could result in a lot of carriers within a population in a relatively short period. However, the reason it goes undetected for so long is that it takes quite a few generations for a carrier to be mated back to a carrier and even when they are, the resulting calf would only inherit both copies of the mutation 25% of the time. By the time the performance issues are discovered and reported in enough quantity to merit further investigation, the frequency of the “new” mutation has risen to a moderate frequency through carriers.

Figure 2. An illustration of how a single genetic mutation is propagated among a population of animals.

 

    By now you’ve likely realized that there is a reason this article is titled “What, How, and When” instead of “What, How, and If”. Due to basic biology, the occurrence of genetic mutations is not a matter of “if”, but “when”. But what some people fail to realize is that while the word mutation has a negative connotation, there are a lot of genetic mutations that the cattle industry selects for. There are 8 different genetic mutations linked to the Myostatin gene, also known as double muscling. Genetic evaluations use nucleotide substitutions, also referred to as single nucleotide polymorphisms (SNP), to predict breeding values for economically relevant traits like weaning weight, marbling, and fertility. In fact, there would be no genetic progress if beneficial mutations did not occur in the history of a population. There are a lot of ways that these mutations work in our favor, it’s just not a lot of fun when they don’t.  

    The good news is that with the current state of DNA testing in cattle and the commonplace practice it has become, it is a lot easier to get out in front of a new genetic defect or mutation than it used to be. Prior to genomic technology, the only way to confirm a sire was a carrier of a mutation was to progeny test, and the only way to speed up that process was to mate him to his own daughters – which took time. Today, knowing the pedigree of an animal combined with inexpensive whole genome sequencing make it easier to identify new causal mutations that result in genetic defects than in years before. Once identified, the SNP are then added to current genomic testing solutions, if not present already, so that they can be commercially available for producers to identify whether the mutation is present in their herd or not. Once carrier animals have been identified, mating them to animals who are free of the mutation will decrease its frequency over time, until it is eventually all but eradicated from the population. A practice that was not possible until genomic technology became available.

    If you learn only one thing from this article, I hope it is this: Genetic mutations are normal and expected. Just because a new genetic defect appears in your population of cattle does not mean that all carrier animals are no longer genetically relevant. There are 5.4 billion nucleotides in an animal’s genetic makeup, to cull based on 1 of those nucleotides will not serve you, or the breed, well moving forward. Using technology to identify carrier animals and selectively breed out the mutation is an effective solution.

 

1.            Harland, C., et al., Frequency of mosaicism points towards mutation-prone early cleavage cell divisions in cattle. BioRxiv, 2016: p. 079863.