3-Phosphoglycerate dehydrogenase deficiency: an inborn error of serine biosynthesis.

Abstract Theory predicts that the ability of selection and recombination to purge mutation load is enhanced if selection against deleterious genetic variants operates more strongly in males than females. However, direct empirical support for this tenet is limited, perhaps because traditional quantitative genetic approaches allow dominance and intermediate-frequency polymorphisms to obscure the effects of rare and partially recessive deleterious alleles that make up the main part of a population’s mutation load. Here, we exposed the mutation load of a population of Callosobruchus maculatus seed beetles via successive generations of inbreeding, and quantified its effects by measuring heterosis – the increase in fitness upon the masking of deleterious alleles by heterozygosity – in a fully factorial sex-specific diallel cross among 16 inbred strains. Competitive lifetime reproductive success (i.e. fitness) was measured in male and female outcrossed F1s as well as inbred parental ‘selfs’, and we estimated the 4×4 male-female inbred-outbred genetic covariance matrix (G) for fitness using Bayesian Markov chain Monte Carlo simulations of a custom-made general linear mixed effects model. We found that heterosis estimated in males and females was highly correlated among strains, and that heterosis was strongly negatively correlated to strains’ outcrossed breeding values for male fitness, but not female fitness. This suggests that the additive genetic variation for fitness in the males, but not females, of this population reflect the amount of (partially) recessive deleterious alleles segregating at mutation-selection balance, and that the population’s mutation load therefore has greater potential to be purged via selection in males. These findings contribute to our understanding of the prevalence of sexual reproduction in nature and the maintenance of genetic variation in fitness-related traits. Impact statement A mainstay evolutionary question has been: why do the large majority of eukaryotic species reproduce sexually if such females must spend half of their reproductive effort producing sons, which produce no offspring themselves? In principle, a lineage of a mutant asexual female that simply clones herself into daughters would grow at twice the rate of her sexual competitors (all else equal). What prevents this from being the predominant mode of reproduction throughout eukaryotes? One category of hypotheses regards the role of males in facilitating the purging of deleterious mutations from the population’s genome since very strong selection in males, unlike females, can occur in many species without direct consequence to population offspring numbers. Due to the inherent difficulties of detecting selection on segregating genetic variation, empirical evidence for this theory is limited to indirect evidence from manipulative experiments and experimental evolution studies. Here we demonstrate that the standing deleterious allelic variation in a population of the seed beetle, Callosobruchus maculatus, is selected against strongly in males but not females. Using a fully factorial diallel cross among 16 inbred strains, we measured the degree to which fitness in the outbred offspring of those crosses improved relative to their inbred parents. This measure is known as heterosis and offers an estimate of the relative number of deleterious alleles carried among strains. We then analyzed the relationship between strains’ heterosis values and their sex-specific additive genetic breeding values for fitness, revealing the extent to which those segregating deleterious alleles are selected against in males and females. We found that strains heterosis values were strongly correlated with male fitness, but not female fitness. This demonstrates that the population’s deleterious mutations can be efficiently selected against (i.e. purged) via selection in males. This process would offer a benefit to sexual reproduction that may outweigh its costs, and therefore yields insight to the prevalence of sex in nature.