Fine Mapping of a Major Backfat QTL Reveals a Causal Regulatory Variant Affecting the CCND2 Gene

Abstract

Backfat is an important trait in pork production, and it has been included in the breeding objectives of genetic companies for decades. Although adipose tissue is a good energy storage, excessive fat results in reduced efficiency and economical losses. A large QTL for backfat thickness on chromosome 5 is still segregating in different commercial pig breeds. We fine mapped this QTL region using a genome-wide association analysis (GWAS) with 133,358 genotyped animals from five commercial populations (Landrace, Pietrain, Large White, Synthetic, and Duroc) imputed to the porcine 660K SNP chip. The lead SNP was located at 5:66103958 (G/A) within the third intron of the CCND2 gene, with the G allele associated with more backfat, while the A allele is associated with less backfat. We further phased the QTL region to discover a core haplotype of five SNPs associated with low backfat across three breeds. Linkage disequilibrium analysis using whole-genome sequence data revealed three candidate causal variants within intronic regions and downstream of the CCND2 gene, including the lead SNP. We evaluated the association of the lead SNP with the expression of the genes in the QTL region (including CCND2) in a large cohort of 100 crossbred samples, sequenced in four different tissues (lung, spleen, liver, muscle). Results show that the A allele increases the expression of CCND2 in an additive way in three out of four tissues. Our findings indicate that the causal variant for this QTL region is a regulatory variant within the third intron of the CCND2 gene affecting the expression of CCND2.

Comparison of two multi-trait association testing methods and sequence-based fine mapping of six QTL in Swiss Large White pigs

“…rs346219461 was 7.60 kb downstream the fibroblast growth factor 6 ( FGF6 ) encoding gene and it had MAF of 0.41, and it was imputed from the reference panel with high accuracy (DR2 = 0.99). The rs346219461 was in LD (R 2 = 0.82) with a non-coding variant (rs80985094 at 66,103,958 bp, P = 6.41 × 10 −10 ) in the third intron of CCND2 , that was previously proposed as putative causal variant for backfat thickness [34].…”

“…Fat deposition and weight gain-related traits have been considered frequently in these GWAS as they are economically relevant and highly heritable. Previous GWAS led to tens of proposed candidate genes affecting these traits, including MC4R, BMP2, IGF2 , and CCND2 [19, 30–34].…”

“…Previous GWAS led to tens of proposed candidate genes affecting these traits, including MC4R, BMP2, IGF2, and CCND2 [19,[30][31][32][33][34].…”

Comparison of two multi-trait association testing methods and sequence-based fine mapping of six additive QTL in Swiss Large White pigs

“…Fat deposition and weight gain-related traits have been considered frequently in these GWAS as they are economically relevant and highly heritable. Previous GWAS led to tens of proposed candidate genes affecting these traits, including MC4R , BMP2 , IGF2 , and CCND2 [ 30 – 35 ].…”

Animal-SNPAtlas: a comprehensive SNP database for multiple animals

“…For example, a genome-wide LD-based fine-mapping identified pleiotropic and functional variants that could predict many traits across global cattle populations ( 26 ). Another study using LD analysis based on whole-genome sequence data has revealed three candidate causal variants for backfat within intronic regions and downstream of the CCND2 gene in pig ( 27 ).…”