Characterization of genetic regulatory variants acting on livestock gene expression is essential for interpreting the molecular mechanisms underlying traits of economic value and for increasing the rate of genetic gain through artificial selection. Here we build a Cattle Genotype–Tissue Expression atlas (CattleGTEx) as part of the pilot phase of the Farm animal GTEx (FarmGTEx) project for the research community based on 7,180 publicly available RNA-sequencing (RNA-seq) samples. We describe the transcriptomic landscape of more than 100 tissues/cell types and report hundreds of thousands of genetic associations with gene expression and alternative splicing for 23 distinct tissues. We evaluate the tissue-sharing patterns of these genetic regulatory effects, and functionally annotate them using multiomics data. Finally, we link gene expression in different tissues to 43 economically important traits using both transcriptome-wide association and colocalization analyses to decipher the molecular regulatory mechanisms underpinning such agronomic traits in cattle.

Many genome variants shaping mammalian phenotype are hypothesized to regulate gene transcription and/or to be under selection. However, most of the evidence to support this hypothesis comes from human studies. Systematic evidence for regulatory and evolutionary signals contributing to complex traits in a different mammalian model is needed. Sequence variants associated with gene expression (expression quantitative trait loci [eQTLs]) and concentration of metabolites (metabolic quantitative trait loci [mQTLs]) and under histone-modification marks in several tissues were discovered from multiomics data of over 400 cattle. Variants under selection and evolutionary constraint were identified using genome databases of multiple species. These analyses defined 30 sets of variants, and for each set, we estimated the genetic variance the set explained across 34 complex traits in 11,923 bulls and 32,347 cows with 17,669,372 imputed variants. The per-variant trait heritability of these sets across traits was highly consistent ( r > 0.94) between bulls and cows. Based on the per-variant heritability, conserved sites across 100 vertebrate species and mQTLs ranked the highest, followed by eQTLs, young variants, those under histone-modification marks, and selection signatures. From these results, we defined a Functional-And-Evolutionary Trait Heritability (FAETH) score indicating the functionality and predicted heritability of each variant. In additional 7,551 cattle, the high FAETH-ranking variants had significantly increased genetic variances and genomic prediction accuracies in 3 production traits compared to the low FAETH-ranking variants. The FAETH framework combines the information of gene regulation, evolution, and trait heritability to rank variants, and the publicly available FAETH data provide a set of biological priors for cattle genomic selection worldwide.

The difficulty in finding causative mutations has hampered their use in genomic prediction. Here, we present a methodology to fine-map potentially causal variants genome-wide by integrating the functional, evolutionary and pleiotropic information of variants using GWAS, variant clustering and Bayesian mixture models. Our analysis of 17 million sequence variants in 44,000+ Australian dairy cattle for 34 traits suggests, on average, one pleiotropic QTL existing in each 50 kb chromosome-segment. We selected a set of 80k variants representing potentially causal variants within each chromosome segment to develop a bovine XT-50K genotyping array. The custom array contains many pleiotropic variants with biological functions, including splicing QTLs and variants at conserved sites across 100 vertebrate species. This biology-informed custom array outperformed the standard array in predicting genetic value of multiple traits across populations in independent datasets of 90,000+ dairy cattle from the USA, Australia and New Zealand.

Background.Ruminants are successful herbivorous mammals, in part due to their specialized forestomachs, the rumen complex, which facilitates the conversion of feed to soluble nutrients by micro-organisms. Is the rumen complex a modified stomach expressing new epithelial (cornification) and metabolic programs, or a specialised stratified epithelium that has acquired new metabolic activities, potentially similar to those of the colon? How has the presence of the rumen affected other sections of the gastrointestinal tract (GIT) of ruminants compared to non-ruminants?Methods.Transcriptome data from 11 tissues covering the sheep GIT, two stratified epithelial and two control tissues, was analysed using principal components to cluster tissues based on gene expression profile similarity. Expression profiles of genes along the sheep GIT were used to generate a network to identify genes enriched for expression in different compartments of the GIT. The data from sheep was compared to similar data sets from two non-ruminants, pigs (closely related) and humans (more distantly related).Results.The rumen transcriptome clustered with the skin and tonsil, but not the GIT transcriptomes, driven by genes from the epidermal differentiation complex, and genes encoding stratified epithelium keratins and innate immunity proteins. By analysing all of the gene expression profiles across tissues together 16 major clusters were identified. The strongest of these, and consistent with the high turnover rate of the GIT, showed a marked enrichment of cell cycle process genes (P= 1.4 E−46), across the whole GIT, relative to liver and muscle, with highest expression in the caecum followed by colon and rumen. The expression patterns of several membrane transporters (chloride, zinc, nucleosides, amino acids, fatty acids, cholesterol and bile acids) along the GIT was very similar in sheep, pig and humans. In contrast, short chain fatty acid uptake and metabolism appeared to be different between the species and different between the rumen and colon in sheep. The importance of nitrogen and iodine recycling in sheep was highlighted by the highly preferential expression ofSLC14A1-urea (rumen), RHBG-ammonia (intestines) andSLC5A5-iodine (abomasum). The gene encoding a poorly characterized member of the maltase-glucoamylase family (MGAM2), predicted to play a role in the degradation of starch or glycogen, was highly expressed in the small and large intestines.Discussion.The rumen appears to be a specialised stratified cornified epithelium, probably derived from the oesophagus, which has gained some liver-like and other specialized metabolic functions, but probably not by expression of pre-existing colon metabolic programs. Changes in gene transcription downstream of the rumen also appear have occurred as a consequence of the evolution of the rumen and its effect on nutrient composition flowing down the GIT.