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.

The Farm Animal Genotype-Tissue Expression (FarmGTEx) project has been established to develop a public resource of genetic regulatory variants in livestock, which is essential for linking genetic polymorphisms to variation in phenotypes, helping fundamental biological discovery and exploitation in animal breeding and human biomedicine. Here we show results from the pilot phase of PigGTEx by processing 5,457 RNA-sequencing and 1,602 whole-genome sequencing samples passing quality control from pigs. We build a pig genotype imputation panel and associate millions of genetic variants with five types of transcriptomic phenotypes in 34 tissues. We evaluate tissue specificity of regulatory effects and elucidate molecular mechanisms of their action using multi-omics data. Leveraging this resource, we decipher regulatory mechanisms underlying 207 pig complex phenotypes and demonstrate the similarity of pigs to humans in gene expression and the genetic regulation behind complex phenotypes, supporting the importance of pigs as a human biomedical model.

The functional annotation of livestock genomes is crucial for understanding the molecular mechanisms that underpin complex traits of economic importance, adaptive evolution and comparative genomics. Here, we provide the most comprehensive catalogue to date of regulatory elements in the pig (Sus scrofa) by integrating 223 epigenomic and transcriptomic data sets, representing 14 biologically important tissues. We systematically describe the dynamic epigenetic landscape across tissues by functionally annotating 15 different chromatin states and defining their tissue-specific regulatory activities. We demonstrate that genomic variants associated with complex traits and adaptive evolution in pig are significantly enriched in active promoters and enhancers. Furthermore, we reveal distinct tissue-specific regulatory selection between Asian and European pig domestication processes. Compared with human and mouse epigenomes, we show that porcine regulatory elements are more conserved in DNA sequence, under both rapid and slow evolution, than those under neutral evolution across pig, mouse, and human. Finally, we provide biological insights on tissue-specific regulatory conservation, and by integrating 47 human genome-wide association studies, we demonstrate that, depending on the traits, mouse or pig might be more appropriate biomedical models for different complex traits and diseases.

By uniformly analyzing 723 RNA-seq data from 91 tissues and cell types, we built a comprehensive gene atlas and studied tissue specificity of genes in cattle. We demonstrated that tissue-specific genes significantly reflected the tissue-relevant biology, showing distinct promoter methylation and evolution patterns (e.g., brain-specific genes evolve slowest, whereas testis-specific genes evolve fastest). Through integrative analyses of those tissue-specific genes with large-scale genome-wide association studies, we detected relevant tissues/cell types and candidate genes for 45 economically important traits in cattle, including blood/immune system (e.g., CCDC88C) for male fertility, brain (e.g., TRIM46 and RAB6A) for milk production, and multiple growth-related tissues (e.g., FGF6 and CCND2) for body conformation. We validated these findings by using epigenomic data across major somatic tissues and sperm. Collectively, our findings provided novel insights into the genetic and biological mechanisms underlying complex traits in cattle, and our transcriptome atlas can serve as a primary source for biological interpretation, functional validation, studies of adaptive evolution, and genomic improvement in livestock.

Background: Health traits are of significant economic importance to the dairy industry due to their effects on milk production and associated treatment costs. Genome-wide association studies (GWAS) provide a means to identify associated genomic variants and thus reveal insights into the genetic architecture of complex traits and diseases. The objective of this study is to investigate the genetic basis of seven health traits in dairy cattle and to identify potential candidate genes associated with cattle health using GWAS, fine mapping, and analyses of multi-tissue transcriptome data. Results: We studied cow livability and six direct disease traits, mastitis, ketosis, hypocalcemia, displaced abomasum, metritis, and retained placenta, using de-regressed breeding values and more than three million imputed DNA sequence variants. After data edits and filtering on reliability, the number of bulls included in the analyses ranged from 11,880 (hypocalcemia) to 24,699 (livability). GWAS was performed using a mixed-model association test, and a Bayesian fine-mapping procedure was conducted to calculate a posterior probability of causality to each variant and gene in the candidate regions. The GWAS detected a total of eight genome-wide significant associations for three traits, cow livability, ketosis, and hypocalcemia, including the bovine Major Histocompatibility Complex (MHC) region associated with livability. Our fine-mapping of associated regions reported 20 candidate genes with the highest posterior probabilities of causality for cattle health. Combined with transcriptome data across multiple tissues in cattle, we further exploited these candidate genes to identify specific expression patterns in disease-related tissues and relevant biological explanations such as the expression of Group-specific Component (GC) in the liver and association with mastitis as well as the Coiled-Coil Domain Containing 88C (CCDC88C) expression in CD8 cells and association with cow livability. Conclusions: Collectively, our analyses report six significant associations and 20 candidate genes of cattle health. With the integration of multi-tissue transcriptome data, our results provide useful information for future functional studies and better understanding of the biological relationship between genetics and disease susceptibility in cattle.

A comprehensive characterization of regulatory elements in the chicken genome across tissues will have substantial impacts on both fundamental and applied research. Here, we systematically identified and characterized regulatory elements in the chicken genome by integrating 377 genome-wide sequencing datasets from 23 adult tissues. In total, we annotated 1.57 million regulatory elements, representing 15 distinct chromatin states, and predicted about 1.2 million enhancer-gene pairs and 7662 super-enhancers. This functional annotation of the chicken genome should have wide utility on identifying regulatory elements accounting for gene regulation underlying domestication, selection, and complex trait regulation, which we explored. In short, this comprehensive atlas of regulatory elements provides the scientific community with a valuable resource for chicken genetics and genomics.