Large scale sequence-based screen for recessive variants allows for identification and monitoring of rare deleterious variants in pigs

• Published in: PLoS genetics Vol. 20; no. 1; p. e1011034
• Main Authors: Boshove, Anne, Derks, Martijn F L, Sevillano, Claudia A, Lopes, Marcos S, van Son, Maren, Knol, Egbert F, Dibbits, Bert, Harlizius, Barbara
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10.01.2024; Public Library of Science (PLoS)
• Subjects: Alleles; Analysis; Animals; Biology and Life Sciences; Breeding; Chromosome 1; Chromosome 15; Chromosomes; Cytoskeletal Proteins - genetics; Gene Frequency; Genes; Genetic aspects; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; Genotype; Growth; Growth rate; Hogs; Humans; Nucleotide sequence; Phenotype; Polymorphism, Single Nucleotide - genetics; Quantitative genetics; Quantitative trait loci; Quantitative Trait Loci - genetics; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Swine; Swine - genetics; Norway
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1011034

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.