Loss of function mutations in essential genes cause embryonic lethality in pigs.

Lethal recessive alleles cause pre- or postnatal death in homozygous affected individuals, reducing fertility. Especially in small size domestic and wild populations, those alleles might be exposed by inbreeding, caused by matings between related parents that inherited the same recessive lethal allele from a common ancestor. In this study we report five relatively common (up to 13.4% carrier frequency) recessive lethal haplotypes in two commercial pig populations. The lethal haplotypes have a large effect on carrier-by-carrier matings, decreasing litter sizes by 15.1 to 21.6%. The causal mutations are of different type including two splice-site variants (affecting POLR1B and TADA2A genes), one frameshift (URB1), and one missense (PNKP) variant, resulting in a complete loss-of-function of these essential genes. The recessive lethal alleles affect up to 2.9% of the litters within a single population and are responsible for the death of 0.52% of the total population of embryos. Moreover, we provide compelling evidence that the identified embryonic lethal alleles contribute to the observed heterosis effect for fertility (i.e. larger litters in crossbred offspring). Together, this work marks specific recessive lethal variation describing its functional consequences at the molecular, phenotypic, and population level, providing a unique model to better understand fertility and heterosis in livestock. Author summary Lethal recessives are mutations that cause early lethality in homozygous state that usually occur at very low frequency in wild and domestic populations. In livestock, however, those mutations might become more prevalent as a result of inbreeding. In this study, we report five such recessive lethal haplotypes that cause embryonic lethality in homozygous state in pigs. The causal mutations are of different type but all destroy the structure of essential genes involved in cellular housekeeping processes, essential for embryonic development. The lethal recessives have substantial impact on the population fitness affecting up to 3% of the population litters, causing the death of 0.52% of the total population of embryos. Moreover, these 'natural knockouts' can increase understanding of gene function within the mammalian clade. Together, our study will allow monitoring, and facilitate the purging and partial elimination of recessive lethal mutations in frequently used pig breeds.