Management of Mendelian Traits in Breeding Programs by Gene Editing: A Simulation Study

Abstract

BackgroundGenotypes based on high-density single nucleotide polymorphisms have recently been used to identify a number of novel recessive mutations that adversely affect fertility in dairy cattle as well as to track conditions such as polledness. The use of sequential mate allocation strategies that account for increases in genomic inbreeding and the economic impact of affected matings may result in faster allele frequency changes than strategies that do not consider inbreeding and monetary losses. However, the effect of gene editing on selection programs also should be considered because gene editing has the potential to dramatically change allele frequencies in livestock populations.\n\nMethodsA simulation program developed to evaluate dairy cattle breeding schemes was extended to include the use of clustered regularly interspaced short palindromic repeat (CRISPR), transcription activator-like effector nuclease (TALEN), and zinc finger nuclease (ZFN) technologies for gene editing. A hypothetical technology with a perfect success rate was used to establish an upper limit on attainable progress, and a scenario with no editing served as a baseline for comparison.\n\nResultsThe technologies differed in the rate of success of gene editing as well as the success rate of embryo transfer based on literature estimates. The number of edited alleles was assumed to have no effect on success rate. The two scenarios evaluated considered only the horned locus or 12 recessive alleles that currently are segregating in the U.S. Holstein population. The top 1, 5, or 10% of bulls were edited each generation, and either no cows or the top 1% of cows were edited. Inefficient editing technologies produced less cumulative genetic gain and lower inbreeding than efficient ones. Gene editing was very effective at reducing the frequency of the horned haplotype (increasing the frequency of polled animals in the population), and allele frequencies of the 12 recessives segregating in the U.S. Holstein population decreased faster with editing than without.\n\nConclusionsGene editing can be an effective tool for reducing the rate of harmful alleles in a dairy cattle population even if only a small proportion of elite animals are modified.