Gene co-expression network and differential expression analyses reveal key genes for weaning weight in Fleckvieh-Holstein crossbred cattle

Weaning weight is a key indicator of the early growth performance of cattle. An understanding of the genetic mechanisms underlying weaning weight will helps increase the accuracy of selection of breeding animals. In order to identify candidate genes associated with weaning weight in Fleckvieh-Holstein crossbred cattle, this study generated RNA-Sequencing (RNA-seq) data from 86 crossbred calves and measured their weaning weight and body size traits (wither height, body length, chest girth, rump width, and rump length). Differential gene expression analysis and weighted gene co-expression network analysis (WGCNA) were performed to identify key genes influencing weaning weight and body size measurements. A total of 498 differentially expressed genes (DEGs) were identified between the low weaning weight (LWW) and the high weaning weight (HWW) groups. Weaning weight was transcriptionally correlated (FDR < 0.05) with four of the eleven co-expression gene modules. DEGs and genes of the four modules were significantly enriched in growth, development, or immune-related biological processes (P < 0.05). By intersecting DEGs, hub genes of the four modules, we identified a final set of 37 candidate genes enriched in growth, development, or immune-related processes. In addition, one co-expression module was significantly correlated with all the five body size measurement traits (P < 0.05), from which MX1 was identified as a key candidate gene through protein-protein interaction (PPI) analysis of hub genes. Further evidence from cattle transcriptome-wide association study analysis (TWAS) and human phenome-wide association study (PheWAS) validated significant associations of CACNA1S, SEMA7A, VCAN, CD101, CD19, and CSF2RB with growth and development traits (P<0.05). Notably, CACNA1S and CD19 were also associated with typical immune traits such as B cell proliferation, differentiation, and activation. This study provides a basis for further exploration of the genetic mechanisms behind weaning weight in Fleckvieh-Holstein crossbred cattle.