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

Derks, Martijn F.L.; Lopes, M.S.; Bosse, Mirte; Madsen, Ole; Dibbits, Bert; Harlizius, B.; Groenen, M.A.M.; Megens, Hendrik Jan

doi:10.1371/journal.pgen.1007661

Cited by 42 publications

(47 citation statements)

References 55 publications

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“…Therefore, it is likely that the MSTN c.820G>T mutation was maintained at moderate frequency in this line despite its deleterious impact on piglet mortality due to heterozygous advantage for muscle and fat traits. Similar examples of balancing selection have observed to explain the maintenance of deleterious alleles at moderate frequency in commercial cattle [10, 31] and pig [14] populations. The results described herein have major implications for the targeted ablation of MSTN via gene editing to increase lean growth in pigs, and provide a plausible explanation of why MSTN loss-of-function mutations have not previously been reported in pigs despite decades of selection for lean growth.…”

Section: Discussionsupporting

confidence: 55%

“…Examples of such balancing selection in cattle include a frame-shift mutation in the mannose receptor C typed 2 (MRC2) gene responsible for crooked tail syndrome and also associated with increased muscle mass in Belgian Blue [11], and a large deletion with antagonistic effects on fertility and milk production traits in Nordic Red [12, 13] is likely to have caused an increase in incidence of porcine stress syndrome (also known as malignant hyperthermia) in the 1970s and 1980s, due to the association of the causative missense mutation with reduced backfat - a trait under selection. More recently, a recessive embryonic lethal deletion in the bone structure and strength QTL 9 (BSS9) gene was associated with heterozygous advantage for growth rate, explaining an unexpectedly high frequency of this allele in a commercial pig line [14].…”

Section: Introductionmentioning

confidence: 99%

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Balancing selection at a premature stop mutation in themyostatingene underlies a recessive leg weakness syndrome in pigs

Matika

Robledo

Pong‐Wong

et al. 2018

Preprint

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12Balancing selection provides a plausible explanation for the maintenance of deleterious 13 alleles at moderate frequency in livestock, including lethal recessives exhibiting 14 heterozygous advantage in carriers. In the current study, a leg weakness syndrome 15 causing mortality of piglets in a commercial line showed monogenic recessive 16 inheritance, and a region on chromosome 15 associated with the syndrome was identified 17 by homozygosity mapping. Whole genome resequencing of cases and controls identified 18 a mutation coding for a premature stop codon within exon 3 of the porcine Myostatin 19 (MSTN) gene, similar to those causing a double-muscling phenotype observed in several 20 mammalian species. The MSTN mutation was in Hardy-Weinberg equilibrium in the 21 population at birth, but significantly distorted amongst animals still in the herd at 110 kg, 22 due to an absence of homozygous mutant genotypes. In heterozygous form, the MSTN 23 mutation was associated with a major increase in muscle depth and decrease in fat depth, 24 suggesting that the deleterious allele was maintained at moderate frequency due to 2 25 heterozygous advantage. Knockout of the porcine MSTN by gene editing has previously 26 been linked to problems of low piglet survival and lameness. This MSTN mutation is an 27 example of putative balancing selection in livestock, providing a plausible explanation 28 for the lack of disrupting MSTN mutations in pigs despite many generations of selection 29 for lean growth. 30 Introduction 32 Leg weakness is heterogeneous condition causing lameness in pigs, and has negative 33 impacts on both animal welfare and productivity [1, 2]. Significant heritability estimates 34 have been reported for leg weakness traits [reviewed in 3], with moderate to high 35 estimates in certain pig breeds, e.g. h 2 = 0.45 in Landrace [4]. Several quantitative trait 36 loci (QTL) have been identified for these traits, albeit they are generally not consistent 37 across studies and breeds [5-8], which may be partly due to the heterogeneity of this 38 condition. Interestingly, significant genetic correlations between leg weakness and other 39 production traits (such as growth and muscle depth) have been detected [4]. Further, in a 40 divergent selection experiment in Duroc lines, selection for high leg weakness was 41 associated with a significant increase in muscle length and weight [9]. Taken together, 42 these results suggest a degree of antagonistic genetic relationship between leg weakness 43 and muscle growth traits in pigs, potentially explaining increases in the syndrome 44 observed with intense selection for lean growth in recent decades. 45 Deleterious alleles can be maintained at relatively high frequency in commercial livestock 46 populations due to heterozygous advantage for traits under selection [10]. Examples of 47 65mass and reduced fat depth than wild type homozygotes. Therefore, we propose that the 66 MSTN mutant allele is highly deleterious in this population in homozygous form, but was 67 maintained ...

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Section: Discussionsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Balancing selection at a premature stop mutation in themyostatingene underlies a recessive leg weakness syndrome in pigs

Matika

Robledo

Pong‐Wong

et al. 2018

Preprint

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“…Recent work demonstrates that some variants that cause lethality in homozygous state are present at relatively high frequency in commercial pig lines [64,65]. Knowing these recessive lethal mutations can aid in avoiding matings between carriers of such mutations within the breeding scheme.…”

Section: Breeding and Genomics Go Hand In Handmentioning

confidence: 99%

A Genomics Perspective on Pig Domestication

Bosse¹

2019

Animal Domestication

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Land animal domestication has typically led to remarkable phenotypic diversity, stemming from a broad genetic background. The process of land animal domestication turns out to be a complex, long-term event with extensive gene-flow between wild and captive populations. Using pig as model, this chapter provides an in-depth overview of domesticationrelated events leading towards the genetic diversity in extant pig breeds. Five events in the evolutionary history and domestication of pigs can be recognized that are important for the genetic variation in modern pig genomes: (1) Speciation of Sus species in Island SouthEast Asia (ISEA); (2) Divergence between European and Asian lineages; (3) Independent domestication leading to separate domesticated clades in Europe and Asia; (4) Hybridization between domesticated pigs from Asia and Europe; and (5) Breed formation. Remarkably, the extensive mixture of genetic material leading towards the current European commercial pigs has resulted in domestic breeds that are genetically more diverse than their wild ancestors. Nowadays, commercial breeding and genomics go hand in hand. Genomics has not only proven useful to provide understanding about the domestication history of pigs but also about the molecular mechanisms underlying traits of interest. Moreover, genomic selection is an important tool integral to modern commercial breeding.

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“…Analysis of the number of mummified piglets revealed five haplotypes with a significant increase in mummified piglets per litter (Table 2. 4). The increase ranged from 37.1 to 479.4%, accounting for an increase of 0.16 to 1.64 mummified piglets per litter for C x C matings compared to C x NC matings.…”

Section: Number Of Mummified Pigletsmentioning

confidence: 94%

From sequence to phenotype: the impact of deleterious variation in livestock

Derks¹

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2-A systematic survey to identify lethal recessive variation in highly managed pig populations 3-Early and late feathering in turkey and chicken: same gene but different mutations 4-A survey of functional genomic variation in domesticated chickens 5-Balancing selection on a recessive lethal deletion with pleiotropic effects on two neighboring genes in the porcine genome 6-Loss of function mutations in essential genes cause embryonic lethality in pigs 7-Detection of a frameshift deletion in the SPTBN4 gene leads to prevention of severe myopathy and postnatal mortality in pigs 8-Accelerated discovery of functional variation in pigs 9-General discussion References Summary Curriculum Vitae Acknowledgements 1 General introduction 13 1.3 Deleterious alleles In animal breeding and genomics we try to predict the effect of specific genetic variants on the phenotype or performance of farm animals. The genetic variants can usually be classified in three categories (though context-dependent): (1) Variants with positive effects; (2) variants that are benign (neutral); and (3) variants with deleterious effects. With the emergence of noticeable genetic defects and a decline Glossary SNP: Single nucleotide polymorphism, resulting in another nucleotide at one single base in the genome. Indel: Small deletion or insertion of bases in the genome. Haplotype: A group of alleles in an organism that are inherited together from a single parent. Genetic drift: The random fluctuations of allele frequencies from generation to generation. Mutation load: The total genetic burden in a population resulting from accumulated deleterious mutations Recessive lethal: A variant resulting in a lethal phenotype in homozygous state (two copies of the variant) SNP array: A type of DNA microarray which is used to detect polymorphisms within a population WGS: Whole genome sequence Effective population size: The number of individuals in a population who contribute offspring to the next generation LoF variant: A variant that lead to a loss of function of a gene and the associated protein. Missense variant: A point mutation in which a single nucleotide change results in a codon that codes for a different amino acid

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

Cited by 42 publications

References 55 publications

Balancing selection at a premature stop mutation in themyostatingene underlies a recessive leg weakness syndrome in pigs

Balancing selection at a premature stop mutation in themyostatingene underlies a recessive leg weakness syndrome in pigs

A Genomics Perspective on Pig Domestication

From sequence to phenotype: the impact of deleterious variation in livestock

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