Abstract
BackgroundLethal recessive variation can cause prenatal death of homozygous offspring. Although usually present at low-frequency in populations, the impact on individual fitness can be substantial. Until recently, the presence of recessive embryonic lethal variation could only be measured indirectly through reduced fertility. In this study, we estimate the presence of genetic loci associated with both early and late termination of development during gestation in pigs from the wealth of genome data routinely generated by a commercial breeding company.ResultsWe examined three commercial pig (Sus scrofa) populations for potentially deleterious genetic variation based on 80 K SNP-chip genotypes, and estimate the effects on reproductive traits. 24,000 pigs from three populations were analyzed for missing or depletion of homozygous haplotypes. We identified 145 haplotypes (ranging from 0.5–4 Mb in size) in the genome with complete absence or depletion of homozygous animals. Thirty-five haplotypes show a negative effect on at least one of the analysed reproductive traits (total number born, number of stillborn, and number of mummified piglets). One variant in particular appeared to result in relative late termination of development of fetuses, responsible for a significant fraction of observed stillborn piglets (‘mummies’), as they die mid-gestation. Moreover, we identified the BMPER gene as a likely candidate underlying this phenomenon.ConclusionsOur study shows that although lethal recessive variation is present, the frequency of these alleles is invariably low in these highly managed populations. Nevertheless, due to cumulative effects of deleterious variants, large numbers of affected offspring are produced. Furthermore, our study demonstrates the use of a large-scale commercial genetic experiment to systematically screen for ‘natural knockouts’ that can increase understanding of gene function.
Highlights
Lethal recessive variation can cause prenatal death of homozygous offspring
Elite breeding lines are generally kept as closed populations, and selection is done within these populations
These breeding lines meet two criteria for the method applied in this study to be successful: a) we can expect that not all deleterious variation is effectively purged from the population, and that low to moderate allele frequencies for some deleterious variation remains in the population, and b) because we examine C x C matings, we expect 25% of the offspring to be homozygous for the carrier haplotype, a necessary prerequisite when scanning for missing homozygotes
Summary
Lethal recessive variation can cause prenatal death of homozygous offspring. usually present at low-frequency in populations, the impact on individual fitness can be substantial. Recessive deleterious variants can be identified by testing for statistical depletion, or even the absence, of specific haplotypes in homozygous state This haplotype approach is a powerful tool [6,7,8,9,10] originally developed for cattle by vanRaden et al (2011). If applied to tens of thousands of genotyped animals, a number prohibitively large usually for academic budget, but routinely attained in many commercial breeding lines nowadays, even very rare deleterious haplotypes can be detected (frequency < 2%). Genotyping large numbers of domestic animals currently still relies on the use of dedicated SNP assays (‘SNP chips’) Since these assays are designed with a bias towards high minor allele frequency (MAF), causal variants of serious syndromes are unlikely to be present on the assay. Studies in mouse showed a lethal knockout phenotype for about 30% of mouse genes in homozygous state, suggesting a large proportion of potential embryonic lethal genes in Mammalia [11]
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