Balancing selection on a recessive lethal deletion with pleiotropic effects on two neighboring genes in the porcine genome

Livestock populations can be used to study recessive defects caused by deleterious alleles. The frequency of deleterious alleles including recessive lethal alleles can stay at high or moderate frequency within a population, especially if recessive lethal alleles exhibit an advantage for favourable traits in heterozygotes. In this study, we report such a recessive lethal deletion of 212kb (del) within the BBS9 gene in a breeding population of pigs. The deletion produces a truncated BBS9 protein expected to cause a complete loss-of-function, and we find a reduction of approximately 20% on the total number of piglets born from carrier by carrier matings. Homozygous del/del animals die mid- to late-gestation, as observed from high increase in numbers of mummified piglets resulting from carrier-by-carrier crosses. The moderate 10.8% carrier frequency (5.4% allele frequency) in this pig population suggests an advantage on a favourable trait in heterozygotes. Indeed, heterozygous carriers exhibit increased growth rate, an important selection trait in pig breeding. Increased growth and appetite together with a lower birth weight for carriers of the BBS9 null allele in pigs is analogous to the phenotype described in human and mouse for (naturally occurring) BBS9 null-mutants. We show that fetal death, however, is induced by reduced expression of the downstream BMPER gene, an essential gene for normal foetal development. In conclusion, this study describes a lethal 212kb deletion with pleiotropic effects on two different genes, one resulting in fetal death in homozygous state (BMPER), and the other increasing growth (BBS9) in heterozygous state. We provide strong evidence for balancing selection resulting in an unexpected high frequency of a lethal allele in the population. This study shows that the large amounts of genomic and phenotypic data routinely generated in modern commercial breeding programs deliver a powerful tool to monitor and control lethal alleles much more efficiently.
Author summary We report a large deletion within the BBS9 gene that induces late fetal mortality in homozygous affected animals in a commercial pig population. This late fetal mortality causes the fetus to become encapsulated and desiccated during the remaining time of the pregnancy, a process called mummification. The unusually high carrier frequency for this lethal deletion (10.8%) likely results from its strong positive association with growth rate in heterozygous individuals, an important selection trait in the pig breeding industry. Interestingly, we show that the positive effect on growth is induced by a heterozygous loss-of-function of the BBS9 gene, associated with obesity in human and mouse. However, late fetal mortality is induced by insufficient expression of the BMPER gene located directly downstream of the deletion which affects its regulatory elements required for gene expression. Together, our study shows an unique example of allelic pleiotropy in which one allele (deletion) is responsible for both increased growth and late fetal mortality by affecting two different genes.