Including gene networks to predict calving difficulty in Holstein, Brown Swiss and Jersey cattle

Calving difficulty or dystocia has a great economic impact in the US dairy industry. Reported risk factors associated with calving difficulty are feto-pelvic disproportion, gestation length and conformation. Different dairy cattle breeds have different incidence of calving difficulty, with Holstein having the highest dystocia rates and Jersey the lowest. Genomic selection becomes important especially for complex traits with low heritability, where the accuracy of conventional selection is lower. However, for complex traits where a large number of genes influence the phenotype, genome-wide association studies showed limitations. Biological networks could overcome some of these limitations and better capture the genetic architecture of complex traits. In this paper, we characterize Holstein, Brown Swiss and Jersey breed-specific dystocia networks and employ them in genomic predictions.

Marker association analysis identified single nucleotide polymorphisms explaining the largest average proportion of genetic variance on BTA18 in Holstein, BTA25 in Brown Swiss, and BTA15 in Jersey. Gene networks derived from the genome-wide association included 1272 genes in Holstein, 1454 genes in Brown Swiss, and 1455 genes in Jersey. Furthermore, 256 genes in Holstein network, 275 genes in the Brown Swiss network, and 253 genes in the Jersey network were within previously reported dystocia quantitative trait loci. The across-breed network included 80 genes, with 9 genes being within previously reported dystocia quantitative trait loci. The gene-gene interactions in this network differed in the different breeds. Gene ontology enrichment analysis of genes in the networks showed Regulation of ARF GTPase was very significant (FDR ≤ 0.0098) on Holstein. Neuron morphogenesis and differentiation was the term most enriched (FDR ≤ 0.0539) on the across-breed network. Genomic prediction models enriched with network-derived relationship matrices did not outperform regular GBLUP models.

Regions identified in the genome were in the proximity of previously described quantitative trait loci that would most likely affect calving difficulty by altering the feto-pelvic proportion. Inclusion of identified networks did not increase prediction accuracy. The approach used in this paper could be extended to any instance with asymmetric distribution of phenotypes, for example, resistance to disease data.