- 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). - For instance, when a homozygous deleterious phenotype leads to very early death of the developing embryo, the only observed consequence is a (somewhat) lower fertility of the parents. - It is estimated that live- stock species harbour 2–4 fold higher variation in the genome compared to humans [3, 4]. - Accordingly, the number of non-synonymous mutations has been shown to be greater in livestock animals, suggesting a large res- ervoir of potentially deleterious variation in livestock [3].. - Full list of author information is available at the end of the article. - 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0. - With the adop- tion of genomic selection, a large proportion of the ani- mals in the pure bred elite lines, i.e. - However, the availability of a large number of genotyped, pedi- greed individuals enables the unravelling of the genetic basis of rare disorders in the population. - The power of this method heavily depends on the number of genotyped individuals. - In theory, assuming prenatal death of homozygotes, a loss of 25% of each litter is expected if two heterozygous carriers of the lethal variant mate (C x C mating). - In mammals, death of an embryo or foetus usually does not result in spontaneous termination of the pregnancy, when also carrying living young. - Pa- rameters, such as time of death and any morphological abnormalities found in mummified piglets [12], can pro- vide insights in the developmental consequences of a specific genetic defect without any further welfare con- cerns for the mother or live siblings. - Moreover, we examine the occurrence and frequency of lethal haplotypes in the studied breeds, as well as their impact on fertility related traits. - Be- cause of this characteristic, these breeding lines meet two criteria for the method applied in this study to be successful: a) we can expect that not all deleterious vari- ation 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 specifically examine C x C matings, we expect 25% of the offspring to be homozygous for the carrier haplo- type, a necessary prerequisite when scanning for missing homozygotes. - We identified 22, 10, and 56 haplotypes with missing homozygosity (MH), and 19, 6, 32 haplotypes exhibiting a statistically significant deficit homozygosity (DH) in the BR, LR, and LW line, respectively (Table 1, Additional file 1:. - DH haplotypes have either incomplete LD with the causal variant or incom- plete penetrance of the variant at the phenotypic level in homozygous state. - The larger number of genotyped animals and trios (both parents and offspring genotyped) in the LW breed allowed for the identification of a high number of low frequency haplotypes (<. - Hence, the percentage of heterozygous carrier offspring is greater than 50% for the majority of the haplotypes in all three breeds (Table 1, Additional file 2).. - Together these four regions account for 42 of the total of 145 identified haplotypes identified in all three lines. - Table 1 Description of the data for missing and depleted homozygous haplotypes in three pig breeds. - The number of loci harbours the unique number of genomic windows containing significant haplotypes. - Number of samples . - Number of trios . - Number of haplotypes 41 16 88. - Number of loci 32 16 70. - Number of carriers . - Figure 1 shows the genomic distribution of the haplotypes affecting fertility per breed.. - We identified 26 haplotypes exhibiting a significant re- duction in TNB (Table 2), three in the BR line, 4 in LR, and 19 in LW. - 1 Genomic locations of the haplotypes affecting fertility in the BR (purple), LR (red), and LW (green) breed. - Pig graphics in the figure legend provided by Topigs-Norsvin, all rights reserved. - this haplotype has been associated with a large increase in the number of mummified piglets and a strong can- didate gene could be identified (BMPER described below: LW19 homozygous foetuses become mummified in Large White).. - Number of stillborn. - Four haplotypes with a significant increase in the num- ber of stillborn were identified (Table 3). - Number of mummified piglets. - Analysis of the number of mummified piglets revealed five haplotypes with a significant increase in mummified piglets per litter (Table 4). - Finally, three haplotypes were identified on SSC18, one of these, LW19, exhibits a complete lack of homozygotes, and shows the largest increase (about 5-fold) in the number of mummified piglets. - Information on carrier x carrier (C x C) matings and progeny is provided in the “ matings ” section. - Effect on the phenotype is provided in the “ reduction in TNB ” section. - Haplotype LW19 (SSC18:43–44 Mb) shows a five-fold increase in the number of mummified piglets, and a 18.71% decrease in TNB calculated from 88 C x C mat- ings (Table 5). - This locus has not been previously re- ported to be associated with an increase in the number of mummified piglets.. - Moreover these 173 mummified piglets are responsible for 1.98% of the total number of mum- mified piglets (8726) recorded for this breed in a decade (December 2006–April 2016). - The difference in the ratio MUM/NSB/NBA between C x C com- pared to C x NC is highly significant (P. - The carrier frequency for this haplotype is 8.6%, mean- ing that about 0.74% of the litters in this breed are af- fected assuming random matings, and 0.185% of all. - Effect on the phenotype is provided in the “ Increase in mummified ” section. - Effect on the phenotype is provided in the “ Increase in stillborn ” section. - Moreover, some of these le- thal alleles are maintained in the population as a result of balancing selection, where heterozygotes show an ad- vantageous phenotype [25]. - It is unlikely that purging can remove all or even most of the detrimental variation because even modern gen- omic breeding programs are inefficient in capturing genotype-phenotype relations of low frequency alleles.. - Our study reveals that the frequency of the haplotypes exhibiting missing homozygosity ranges from 0.5–11%, showing that we have the statistical power to detect very rare deleterious haplotypes in our populations, but also confirming that, as expected, truly lethal recessive vari- ants are invariably infrequent.. - The approach chosen for this study relies on the premise that unexpected absence of homozygotes results from unviability of the homozygous deleterious allelic state. - percentual difference in the average TNB and MUM for C x C and C x NC matings. - Number of markers 26. - 2 Fraction of the number of mummified piglets per litter for haplotype LW19. - The axes indicate the fraction of the total litters (y) with a certain number of mummified piglets (x). - However, rare variants that coincide with rare haplotypes can be robustly detected, with the number of genotyped offspring being the limiting factor for stat- istical power.. - Of these, 35 haplotypes showed a negative effect on at least one of the three fertility traits exam- ined, indicating that indeed these 145 haplotypes are highly enriched for variation that can lead to embryonic lethality or prenatal death. - Several of the identified haplotypes did not show a sig- nificant effect on fertility. - In some cases, the number of C x C matings was too low to obtain significant statis- tical support. - growth rate, back fat, fertility, number of teats, and leg quality. - One example of such a phenotype in pig breeding is the number of teats. - The red bars on top indicate all significant haplotypes in the Large White, with the haplotype LW19 (SSC18:43-44 Mb) indicated in black. - b Local breakdown of LD in the Large White population at the LW19 haplotype locus. - The bifurcation diagram displays haplotypes starting at the BMPER locus and extending either up- or downstream of the BMPER gene. - are very likely to produce a far higher number of ova than can be accommodated in the uterus.. - One explanation for this discrepancy is that the whole litter might potentially be aborted if a large pro- portion of the litter dies during gestation, and will there- fore not be recorded. - BMPER is in- volved in the negative regulation of bone morphogenetic proteins (BMPs), a group of growth factors involved in the formation of bone and cartilage [29]. - Interestingly, these haplotypes are surrounding a region under selection, despite low LD with the selected haplotype, we hypothesize that this could be a remnant of genetic hitchhiking in the past as this locus has previously been associated with increased body weight and ovulation rate [17, 32]. - More recent recombination might have lowered the LD, but as a result of previous hitchhiking the haplotype still segregates in the population.. - Our study can directly impact positively on current breeding pro- grammes, by avoiding C x C matings to lower the fre- quency of the lethal recessive haplotypes in the elite breeding lines. - Many risk factors have been associated with an increase in mummified piglets [33], most of them, however, are independent of the foetus’s genetic mater- ial. - In our study, we found that about 2% of all recorded mummies in the Large White breed can be attributed to C x C matings for the LW19 haplotype. - We believe that the majority of the total recorded mummified piglets are not a direct effect of a genetic defect carried by the un- born foetus, because several other factors, especially many pathogens can cause mummified or stillborn pig- lets. - Therefore, this proportion of 2% likely represents a much larger fraction of the total number of mummified piglets directly caused by a genetic defect carried by the unborn foetus.. - We show that these haplotypes, apart from reduced fertility in the par- ent animal, also cause large numbers (several hundred at population level) of stillbirths (‘mummified piglets. - An overview of the number of animals per panel is provided in Additional file 1: Table S1. - Additional file 1: Table S2 provides an overview of the number of SNPs that met the following requirements:. - This differs for the boar line in which we imputed 10 K samples directly to 80 K due to the smaller number of 60 K reference samples for this line. - Thereafter 60 K was imputed to 80 K and one final round of phasing was performed to make full use of the family relationships (parent offspring duos and trios).. - The expected number of homozygotes was estimated using the parental haplotype information with the formula de- scribed in Fritz et al., 2013. - Moreover, the number of heterozygous offspring from carrier matings was calcu- lated to verify whether there is a deviation from HWE.. - An exact binomial test was applied to test the number of observed homozygotes with the number of expected ho- mozygotes. - In total, records of TNB for 4041 matings comprising 1566 sows and 432 boars were available in the boar line. - Records of TNB, NSB, and MUM were available for 15,174 matings com- prising 3159 sows and 1485 boars in the Landrace line and 26,961 matings comprising 6745 sows and 1671 boars in the Large White line. - We examined each identi- fied haplotype and records on TNB, NSB, and MUM are listed for all C x C matings identified in the phenotypic records. - EHH was generated for each SNP in both populations, identifying long and frequent haplotypes as implemented in the R package rehh [42]. - Genomic locations from missing (red) and depleted (blue) homozygotes in the Boar breed. - Overview of animals genotyped per panel and number of total animals in trio (both parents and offspring genotyped) in all three breeding lines.. - MUM: Number of mummified pigs;. - NSB: Number of stillborn. - This study was financially supported by NWO-TTW and the Breed4Food partners Cobb Europe, CRV, Hendrix Genetics and Topigs- Norsvin 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. - All haplotypes, genetic markers, and allele coding used in this study are available in the supplementary material. - MSL and BH are employees of Topigs Norsvin Research Center, a research institute closely related to one of the funders (Topigs Norsvin). - Mouse large-scale phenotyping initiatives: overview of the European mouse disease clinic (EUMODIC) and of the Wellcome Trust Sanger institute mouse genetics project. - Copy number variation in the speciation of pigs: a possible prominent role for olfactory receptors. - Developmental progress and current status of the animal QTLdb. - Homozygosity mapping identified a novel protein truncating mutation (p.Ser100Leufs*24) of the BBS9 gene in a consanguineous Pakistani family with Bardet Biedl syndrome.. - Associations between allelic polymorphism of the BMP binding endothelial regulator and phenotypic variation of cattle. - The effect of variants in the promoter of BMPER on the intramuscular fat deposition in longissimus dorsi muscle of pigs. - Detecting recent positive selection in the human genome from haplotype structure
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