Purifying and balancing selection on embryonic semi-lethal haplotypes in a wild mammal

Embryonic lethal mutations are arguably the earliest and most severe manifestation of inbreeding depression, but their impact on wild populations is not well understood. Here, we combined genomic, fitness, and life-history data from 5,925 wild Soay sheep sampled over nearly three decades to explore the impact of embryonic lethal mutations and their evolutionary dynamics. We searched for haplotypes that in their homozygous state are unusually rare in the offspring of known carrier parents and found three putatively semi-lethal haplotypes with 27%-46% fewer homozygous offspring than expected. Two of these haplotypes are decreasing in frequency, and gene-dropping simulations through the pedigree suggest that this is partially due to purifying selection. In contrast, the frequency of the third semi-lethal haplotype remains relatively stable over time. We show that the haplotype could be maintained by balancing selection because it is also associated with increased postnatal survival and body weight and because its cumulative frequency change is lower than in most drift-only simulations. Our study highlights embryonic mutations as a largely neglected contributor to inbreeding depression and provides a rare example of how harmful genetic variation can be maintained through balancing selection in a wild mammal population. Every time DNA is copied, mistakes happen. Most often, these mistakes, called mutations, are deleterious to the organism carrying them. In the worst case, embryonic lethal mutations can prevent an individual from being born in the first place. However, natural selection tends to remove such strongly deleterious mutations from populations very quickly, because when their carriers die early, the mutations disappear too. Unfortunately, especially in small populations, deleterious mutations sometimes spread to higher frequencies. This is due to genetic drift and the fact that deleterious mutations are usually recessive, so their full detrimental effects are only expressed if an individual inherits two identical copies of the mutation from their parents, causing the mutation to be homozygous.In this study, we explored the impact of embryonic lethal mutations in a small, wild population of Bronze Age sheep on the Scottish St. Kilda archipelago. Overall, we detected three semi-lethal mutations, which caused mortality in some, but not all embryos. Two of these mutations have decreased in frequency in the population over the last 25 years, and simulations show that this is partly due to natural selection rather than mere chance. Against our expectations, however, the third mutation has persisted in the population without signs of decrease, and we went on to explore why this is. We found that the mutation is linked not only to embryonic lethality but also to increased survival and body weight in lambs. This demonstrates that the same part of the genome can be subject to opposing forces of selection, which balance each other out and therefore cause the mutation to persist in the population. Overall, our study shows that embryonic mutations can prevent substantial numbers of individuals from being born in wild populations and explores the complicated evolutionary dynamics of deleterious mutations.