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

Abstract

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.

Fig 1

A) Log R Ratio (LRR) signal intensities on the 50K SNPchip for homozygotes (del/del) carriers (wt/del), and non-carriers (wt/wt). Four markers within the 212kb deletion show reduced LRR intensities. B) Screen capture of the alignment of carrier animal PigWUR166. The aligned region on SSC18 shows reduced coverage in the deletion within the BBS9 gene.

Fig 2. BBS9 “Wild-type” (top) and mutant (bottom) transcripts.

The deletion transcript skips four coding and four 3’UTR exons, resulting in a frameshift (indicated with an arrow in the alignment) introducing 11 AAs before a preliminary stop codon.

Fig 3. SSC18 carrier frequency from 2006–2018.

The frequency has changed significantly over the past 12 years (p = 0.012).

Fig 4. Simulation of the SSC18 carrier frequency with current selective advantage over 100 generations starting with current carrier frequency (11%).

Figure shows a decrease in carrier frequency in the first generations due to the loss of homozygotes which outweighs the heterozygous advantage (~3%) perceived in the selection index (TSI). Figure shows a trade-off at approximately 6% carrier frequency at which the heterozygous advantage is compensated by the loss of homozygous offspring.

Fig 5. Schematic representation of the SSC18 deletion affecting BMPER gene expression and BBS9 protein structure.

A heterozygous loss of function of the BBS9 gene results in increased growth rates, while reduced expression of the BMPER gene results in foetal mortality in homozygous del/del animals.