Gene variants in the pheromone vomeronasal receptors and QTLs around behavioral and fat metabolism genes associated with altered feed efficiency in cattle

Improving feed efficiency in cattle is increasingly important for both environmental and economic reasons. Although feed efficiency traits are under considerable genetic control, with an average moderate heritability estimate of 0.33, genetic evaluations are limited by the difficulties in measuring feed intake and the lack of records from most commercial herds. Most genetic evaluations rely on small numbers of records from research farms, resulting in under-represented genetic variation and pronounced sampling errors in heritability estimates. To enhance the discovery of genetic mechanisms underlying feed efficiency and to address measurement limitations and the under-representation of genetic variation, we used joint phenotypic and genotypic measurements from two distinct herds for GWAS and in-depth genomic analysis. By applying this approach, our exploratory analysis discovered fourteen significant markers with effects on residual feed intake (RFI) ranging from -1.41 to 1.44 kg/day. Quantitative trait loci (QTLs) enrichment analysis specifically pointed to traits that contributed to RFI, including dry matter intake (DMI), body weight (BW), and protein yield. Gene enrichment analysis, which was largely biased by a local cluster of vomeronasal receptor genes within a single ~ 500 kb region on BTA18, suggested three sets of genes of interest: a vomeronasal pheromone receptor cluster (VN1R1 and four additional response to pheromone genes on BTA18), genes linked to social and behavioral responses (EPC2 on BTA2; SYN3 on BTA5), and fat metabolism-related genes (KIF5C on BTA2; SV2B on BTA21). Of these candidate genes, likely functional amino acid (AA) variations were observed in the VN1R1 putative protein (314 AA) after screening a sample of 27 Israeli Holstein genomes. These functional variations included two truncation mutations that could encode 89 and 239 AA polypeptides. Consistent with these findings, whole-genome sequence data analysis of RFI-characterized Irish bulls identified a significant association between the 89 AA truncation and high RFI, further validating our results and indicating that although such variation was common, the presence of an intact VN1R1 receptor was associated with a beneficial effect on feed efficiency. Moreover, the 89 AA truncation was observed in diverse cattle breeds, including American, Israeli, Irish, and New Zealand Holstein. These findings are compatible with feed efficiency, a complex trait governed by neural (behavioral) and metabolic components. Further characterization of these factors would allow genetic selection to reduce feed costs and environmental footprints.