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. 2019 Mar 15;15(3):e1008055.
doi: 10.1371/journal.pgen.1008055. eCollection 2019 Mar.

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

Martijn F L Derks  1 , Arne B Gjuvsland  2 , Mirte Bosse  1 , Marcos S Lopes  3   4 , Maren van Son  2 , Barbara Harlizius  3 , Beatrice F Tan  1 , Hanne Hamland  2 , Eli Grindflek  2 , Martien A M Groenen  1 , Hendrik-Jan Megens  1
Affiliations
Free PMC article

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

Martijn F L Derks et al. PLoS Genet. .
Free PMC article

Abstract

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.

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Conflict of interest statement

MSL, BH, ABG, EG, MvS, and HH are employees of Topigs Norsvin Research Center, a research institute closely related to one of the funders (Topigs Norsvin). All authors declare that the results are presented in full and as such present no conflict of interest. The other Breed4Food partners Cobb Europe, CRV, Hendrix Genetics, declare to have no competing interests for this study.

Figures

Fig 1
Fig 1
A) Example of a carrier-by-carrier mating in Landrace. CxC litters will result in a 1:2 genotype ratio instead of the normal 1:2:1 genotype ratio. B) Fertility phenotypes for lethal recessives. A significant reduction in total number born (TNB) is observed for CxC compared to CxNC matings. C) Carrier frequency for lethal alleles in the period 2012–2018. Figure shows relative stable carrier frequencies over a time period of 6 years (except for LA4).
Fig 2
Fig 2
A) POLR1B gene model. The location of the mutation on the splice-donor site of intron 14 is indicated with a red star. B) Illustration of the affected exon-intron splice region. The causal 3:g.43952776T>G mutation is indicated in red. C) Exon skipping of POLR1B. The mutation causes complete exon skipping of exon 14, resulting in a truncated mRNA. D) Alignment of the mutant (Mt) and wildtype (Wt) POLR1B protein sequence. Skipping of exon 14 introduces a glutamic acid and a premature stop codon in the second codon of the terminal exon.
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Grants and funding

This research was funded by the STW-Breed4Food Partnership, project number 14283: From sequence to phenotype: detecting deleterious variation by prediction of functionality. This study was financially supported by NWO-TTW and the Breed4Food partners Cobb Europe, CRV, Hendrix Genetics and Topigs Norsvin. In addition, this study was supported by the IMAGE project (Horizon 2020, No. 677353). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The use of the HPC cluster was made possible by CATAgroFood (Shared Research Facilities Wageningen UR). The data and some of the analyses used in this study was partly financed by the Research Council of Norway through the projects “Precision whole genome sequence to precision breeding” – NFR no. 255297/E50 and “Investigation of boar fertility by genetic characterization and detection of traits important in sperm production and quality” - NFR no. 207568/O99. The samples and phenotypes are provided by NORSVIN SA.