Identification of biological pathways involved in residual feed intake in Hereford cattle through gene set enrichment analysis

Understanding the biological differences between animals with different feed efficiency phenotypes enhances our understanding of the trait. The objective was to use gene set enrichment analysis-SNP (GSEA-SNP) to identify gene sets (GS) associated with the residual feed intake (RFI) phenotype in Hereford cattle. Feed intake and BW gain were measured on 847 steers and heifers at Olsen Ranches in Harrisburg, NE. Animals were genotyped using the Illumina BovineSNP50 (n = 358) or BovineHD BeadChips (n = 459). BovineSNP50 genotypes were imputed with Beagle 4.1 to the density of the Illumina BovineHD BeadChip using the BovineHD genotyped Herefords as a reference. Genomewide association analysis (GWAA) was performed using GRAMMAR mixed model software, and the most significant SNP for each of 19,723 genes from the UMD-3.1 reference assembly were selected as a proxy for that gene. Gene proxies were considered only for SNP that were located within 8.5 kb of a gene, as this is representative of the average haplotype block size in Herefords (determined by a haplotype block analysis). Following GWAA, GSEA-SNP was conducted with 4,389 GS from Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, Biocarta, and Panther. Significance was calculated using the null distribution estimated from 10,000 permutations for each GS using GenABEL in R. An enrichment score was calculated for each GS using a modified Kolmogorov-Smirnov statistic and normalized (NES) based on the size of each GS. The GS associated (NES > 3.0) with RFI were centrosome (37 leading edge genes [LEG]) and cytoskeleton (97 LEG) from GO and peroxisome from KEGG (30 LEG). The centrosome GS is involved in mitosis and cell cycle regulation and the peroxisome GS is involved in lipid homeostasis. The cytoskeleton organization GS contained four differentially expressed LEG: Type I keratin 19 (KRT19), a 1 actin I (ACTA1), a 1 actinin (ACTN1), and cysteine and glycine-rich protein 3 (CSRP3). These genes were previously found by this consortium to be differentially expressed between the high- and low-RFI groups of Herefords. In the low-RFI group, expression of KRT19 in the liver was greater than in the high-RFI cattle. Low-RFI Herefords also had reduced expression of ACTA1 in the liver and pituitary, ACTN1 in the hypothalamus, and CSRP3 in the liver. Alterations in lipid metabolism and cell cycle regulation are associated with the RFI phenotype. This project was supported by AFRI Competitive Gran