Our new paper is about using predicted deleterious variants in animal breeding. We use simulation to look at the potential to improve livestock fitness by either selecting on detected deleterious variants or removing deleterious alleles by genome editing.

Summary

Deleterious variants occur when errors in DNA replication that disrupt the function of a gene. Such errors are frequent enough that all organisms carry mildly deleterious variants. Geneticists describe this as a deleterious load, that cause organisms to be less healthy and fit than they could have been if these errors didn’t happen. Load is especially pertinent to livestock populations, because of their relatively small population sizes and inbreeding.

Historically, it has not been possible to observe deleterious variants directly, but as genome sequencing becomes cheaper and new bioinformatic methods are being developed, we can now sequence livestock and detect variants that are likely to be deleterious.

In this study, we used computer simulation to see how future breeding strategies involving selection or genome editing could be used to reduce deleterious load. We tested selection against deleterious load and genome editing strategy we call RAGE (Removal of Alleles by Genome Editing) in simulated livestock populations to see how it improved fitness. The simulations suggest that selecting on deleterious variants identified from genome sequencing may help improve fitness of livestock populations, and that genome editing to remove deleterious variants could improve them even more.

For these strategies to be effective, it is important that detection of deleterious variants is accurate, and genome editing of more than one variant per animal would need to become possible without damaging side-effects. Future research on how to measure deleterious load in large sequence datasets from livestock animals, and how to perform genome editing safely and effectively will be important.

Figure 2 from the paper, showing the average fitness of simulated populations (y-axis) over the generations of breeding (x-axis) with different types of future breeding against deleterious variants.

‘RAGE against …’, what’s with the acronym?

We are very happy with the acronym. In addition to making at least two pop culture references, it’s also a nod to Promotion of Alleles by Genome Editing (PAGE) from Jenko et al. (2015). I like that the acronyms, both PAGE and RAGE, emphasises that we’re dealing with alleles that already exist within a population. We propose using genome editing as a way to promote alleles we like and remove alleles we don’t like in addition to classical breeding. The fancy new biotechnology does not replace selection, but supplements it.

Do you really think one should genome edit farm animals?

Yes, if all the bio- and reproductive technology can be made to work! Currently, genome editing methods like Crispr/Cas9 require many attempts to get precise editing to the desired allele at one place, and it doesn’t scale to multiple edits in the same animal … Not yet. But lots of smart people are competing to make it happen.

Genome editing of farm animals would also need a lot of reproductive technology, that currently isn’t really there (but probably more so for cattle than for other species). Again, lots of clever people work on it.

If it can be made to work, genome editing could be a useful breeding method.

What about the ethics of genome editing?

We don’t discuss ethics much in the paper. In one simple sense, that is because ethics isn’t our expertise. I also think a discussion of the ethics of RAGE, much like an informed discussion about the economics of it, requires empirical knowledge that we don’t have yet.

I am not of the opinion that there is a dignity or integrity to the genome that would prohibit genome editing as a rule. So the question is not ‘genome editing or not’, but ‘under what circumstances and for what applications is genome editing useful and justified?’ and ‘are the benefits of RAGE, PAGE, or whatever -GE, enough to outweigh the risks and costs?’. There is room for uncertainty and disagreement about those questions.

For a good discussion of the ethics of genome editing that is likely to raise more questions than it answers, see Eriksson et al. (2018). Among other things, they make the point that advanced reproductive technologies is a precondition for genome editing, but kind of slips out of the discussion sometimes. I think the most pressing question, both from the ethical and economical perspective, is whether the benefits of genome editing are enough to justify widespread use of reproductive technologies (in species where that isn’t already commonplace). I also like how they make the point that one needs to look at the specific applications of genome editing, in context, when evaluating them.

The simulation looks nifty! I want to simulate breeding programs like that!

You can! The simulations used the quantitative genetic simulation R package AlphaSimR with some modifications for simulating the fitness traits. There is code with the paper. Here are also the slides from when I talked about the paper at the Edinburgh R user group.

You make a ton of assumptions!

We do. Some of them are extremely uncontroversial (the basic framework of segregation and recombination during inheritance), some we can get some idea about by looking at the population genetics literature (we’ve taken inspiration from estimates of deleterious mutation rates and effect distributions estimated from humans), and some we don’t have much knowledge about at all (how does load of deleterious variants relate to the production, reproduction and health traits that are important to breeding? The only way to know is to measure). If you read the paper, don’t skip that part of the Discussion.

Would this work in plants?

Yes, probably! Plant breeding programs are a bit different, so I guess one should simulate them to really know. RAGE would be a part of the ‘Breeding 4.0’ logic of Wallace, Rodgers-Melnick & Butler (2018). In many ways the problems with plants are smaller, with less unknown reproductive technology that needs to be invented first, and an easier time field testing edited individuals.

Literature

Johnsson M, Gaynor RC, Jenko J, Gorjanc G, de Koning D-J, Hickey, JM. (2019) Removal of alleles by genome editing (RAGE) against deleterious load. Genetics Selection Evolution.

Jenko J, Gorjanc G, Cleveland MA, Varshney RK, Whitelaw CBA, Woolliams JA, Hickey JM. (2015). Potential of promotion of alleles by genome editing to improve quantitative traits in livestock breeding programs. Genetics Selection Evolution.

Eriksson, S., Jonas, E., Rydhmer, L., & Röcklinsberg, H. (2018). Invited review: Breeding and ethical perspectives on genetically modified and genome edited cattle. Journal of dairy science, 101(1), 1-17.

Wallace, J. G., Rodgers-Melnick, E., & Buckler, E. S. (2018). On the road to Breeding 4.0: unraveling the good, the bad, and the boring of crop quantitative genomics. Annual review of genetics, 52, 421-444.