👤 Claudia A Sevillano

Most deleterious variants are recessive and segregate at relatively low frequency. Therefore, high sample sizes are required to identify these variants. In this study we report a large-scale sequence based genome-wide association study (GWAS) in pigs, with a total of 120,000 Large White and 80,000 Synthetic breed animals imputed to sequence using a reference population of approximately 1,100 whole genome sequenced pigs. We imputed over 20 million variants with high accuracies (R2>0.9) even for low frequency variants (1-5% minor allele frequency). This sequence-based analysis revealed a total of 14 additive and 9 non-additive significant quantitative trait loci (QTLs) for growth rate and backfat thickness. With the non-additive (recessive) model, we identified a deleterious missense SNP in the CDHR2 gene reducing growth rate and backfat in homozygous Large White animals. For the Synthetic breed, we revealed a QTL on chromosome 15 with a frameshift variant in the OBSL1 gene. This QTL has a major impact on both growth rate and backfat, resembling human 3M-syndrome 2 which is related to the same gene. With the additive model, we confirmed known QTLs on chromosomes 1 and 5 for both breeds, including variants in the MC4R and CCND2 genes. On chromosome 1, we disentangled a complex QTL region with multiple variants affecting both traits, harboring 4 independent QTLs in the span of 5 Mb. Together we present a large scale sequence-based association study that provides a key resource to scan for novel variants at high resolution for breeding and to further reduce the frequency of deleterious alleles at an early stage in the breeding program. Show less

Cofactors are essential for driving recombinant prion protein into pathogenic conformers. Polyanions promote prion aggregation in vitro, yet the cofactors that modulate prion assembly in vivo remain largely unknown. Here we report that the endogenous glycosaminoglycan, heparan sulfate (HS), impacts prion propagation kinetics and deposition sites in the brain. Exostosin-1 haploinsufficient (Ext1 Show less

This study investigated if the allele effect of a given single nucleotide polymorphism (SNP) for crossbred performance in pigs estimated in a genomic prediction model differs depending on its breed-of-origin, and how these are related to estimated effects for purebred performance. SNP-allele substitution effects were estimated for a commonly used SNP panel using a genomic best linear unbiased prediction model with breed-specific partial relationship matrices. Estimated breeding values for purebred and crossbred performance were converted to SNP-allele effects by breed-of-origin. Differences between purebred and crossbred, and between breeds-of-origin were evaluated by comparing percentage of variance explained by genomic regions for back fat thickness (BF), average daily gain (ADG), and residual feed intake (RFI). From ten regions explaining most additive genetic variance for crossbred performance, 1 to 5 regions also appeared in the top ten for purebred performance. The proportion of genetic variance explained by a genomic region and the estimated effect of a haplotype in such a region were different depending upon the breed-of-origin. To illustrate underlying mechanisms, we evaluated the estimated effects across breeds-of-origin for haplotypes associated to the melanocortin 4 receptor (MC4R) gene, and for the MC4Rsnp itself which is a missense mutation with a known effect on BF and ADG. Although estimated allele substitution effects of the MC4Rsnp mutation were very similar across breeds, explained genetic variance of haplotypes associated to the MC4R gene using a SNP panel that does not include the mutation, was considerably lower in one of the breeds where the allele frequency of the mutation was the lowest. Similar regions explaining similar additive genetic variance were observed across purebred and crossbred performance. Moreover, there was some overlap across breeds-of-origin between regions that explained relatively large proportions of genetic variance for crossbred performance; albeit that the actual proportion of variance deviated across breeds-of-origin. Results based on a missense mutation in MC4R confirmed that even if a causal locus has similar effects across breeds-of-origin, estimated effects and explained variance in its region using a commonly used SNP panel can strongly depend on the allele frequency of the underlying causal mutation. Show less