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Background: Lack of comprehensive functional annotations across a wide range of tissues and cell types severely hinders the biological interpretations of phenotypic variation, adaptive evolution, and domestication in livestock. Here we used a combination of comparative epigenomics, genome-wide association study (GWAS), and selection signature analysis, to shed light on potential adaptive evolution in cattle. Results: We cross-mapped 8 histone marks of 1300 samples from human to cattle, covering 178 unique tissues/cell types. By uniformly analyzing 723 RNA-seq and 40 whole genome bisulfite sequencing (WGBS) datasets in cattle, we validated that cross-mapped histone marks captured tissue-specific expression and methylation, reflecting tissue-relevant biology. Through integrating cross-mapped tissue-specific histone marks with large-scale GWAS and selection signature results, we for the first time detected relevant tissues and cell types for 45 economically important traits and artificial selection in cattle. For instance, immune tissues are significantly associated with health and reproduction traits, multiple tissues for milk production and body conformation traits (reflecting their highly polygenic architecture), and thyroid for the different selection between beef and dairy cattle. Similarly, we detected relevant tissues for 58 complex traits and diseases in humans and observed that immune and fertility traits in humans significantly correlated with those in cattle in terms of relevant tissues, which facilitated the identification of causal genes for such traits. For instance, PIK3CG, a gene highly specifically expressed in mononuclear cells, was significantly associated with both age-at-menopause in human and daughter-still-birth in cattle. ICAM, a T cell-specific gene, was significantly associated with both allergic diseases in human and metritis in cattle. Conclusion: Collectively, our results highlighted that comparative epigenomics in conjunction with GWAS and selection signature analyses could provide biological insights into the phenotypic variation and adaptive evolution. Cattle may serve as a model for human complex traits, by providing additional information beyond laboratory model organisms, particularly when more novel phenotypes become available in the near future. [ABSTRACT FROM AUTHOR]

Background: Insights into the genetic basis of complex traits and disease in both human and livestock species have been achieved over the past decade through detection of genetic variants in genome-wide association studies (GWAS). A majority of such variants were found located in noncoding genomic regions, and though the involvement of numerous regulatory elements (REs) has been predicted across multiple tissues in domesticated animals, their evolutionary conservation and effects on complex traits have not been fully elucidated, particularly in ruminants. Here, we systematically analyzed 137 epigenomic and transcriptomic datasets of six mammals, including cattle, sheep, goats, pigs, mice, and humans, and then integrated them with large-scale GWAS of complex traits. Results: Using 40 ChIP-seq datasets of H3K4me3 and H3K27ac, we detected 68,479, 58,562, 63,273, 97,244, 111,881, and 87,049 REs in the liver of cattle, sheep, goats, pigs, humans and mice, respectively. We then systematically characterized the dynamic functional landscapes of these REs by integrating multi-omics datasets, including gene expression, chromatin accessibility, and DNA methylation. We identified a core set (n = 6359) of ruminant-specific REs that are involved in liver development, metabolism, and immune processes. Genes with more complex cis-REs exhibited higher gene expression levels and stronger conservation across species. Furthermore, we integrated expression quantitative trait loci (eQTLs) and GWAS from 44 and 52 complex traits/diseases in cattle and humans, respectively. These results demonstrated that REs with different degrees of evolutionary conservation across species exhibited distinct enrichments for GWAS signals of complex traits. Conclusions: We systematically annotated genome-wide functional REs in liver across six mammals and demonstrated the evolution of REs and their associations with transcriptional output and conservation. Detecting lineage-specific REs allows us to decipher the evolutionary and genetic basis of complex phenotypes in livestock and humans, which may benefit the discovery of potential biomedical models for functional variants and genes of specific human diseases. [ABSTRACT FROM AUTHOR]

Background: The early death and health problems of calves caused substantial economic losses in the dairy industry. As the immune system of neonates has not been fully developed, the absorption of maternal immunoglobulin (Ig) from colostrum is essential in protecting newborn calves against common disease organisms in their early life. The overwhelming majority of Ig in bovine whey is transported from the serum. Therefore, Ig concentration in the colostrum and serum of dairy cows are critical traits when estimating the potential disease resistance of its offspring. Results: Colostrum, blood, and hair follicle samples were collected from 588 Chinese Holstein cows within 24 h after calving. The concentration of total IgG, IgG1, IgG2, IgA and IgM in both colostrum and serum were detected via ELISA methods. With GCTA software, genome-wide association studies (GWASs) were performed with 91,620 SNPs genotyped by GeneSeek 150 K (140,668 SNPs) chips. As a result, 1, 5, 1 and 29 significant SNPs were detected associated with the concentrations of colostrum IgG1, IgG2, IgA IgM, and serum IgG2 at the genome-wide level (P < 3.08E–6); 11, 2, 13, 2, 12, 8, 2, 27, 1 and 4 SNPs were found significantly associated with total IgG, IgG1, IgG2, IgA and IgM in colostrum and serum at the suggestive level (P < 6.15E–5). Such SNPs located in or proximate to (±1 Mb) 423 genes, which were functionally implicated in biological processes and pathways, such as immune response, B cell activation, inflammatory response and NF-kappaB signaling pathways. By combining the biological functions and the known QTL data for immune traits in bovine, 14 promising candidate functional genes were identified for immunoglobulin concentrations in colostrum and serum in dairy cattle, they were FGFR4, FGFR2, NCF1, IKBKG, SORBS3, IGHV1S18, KIT, PTGS2, BAX, GRB2, TAOK1, ICAM1, TGFB1 and RAC3. Conclusions: In this study, we identified 14 candidate genes related to concentrations of immunoglobulins in colostrum and serum in dairy cattle by performing GWASs. Our findings provide a groundwork for unraveling the key genes and causal mutations affecting immunoglobulin concentrations in colostrum and important information for genetic improvement of such traits in dairy cattle. [ABSTRACT FROM AUTHOR]

Background: Characterization of the molecular mechanisms underlying hair follicle development is of paramount importance in the genetic improvement of wool-related traits in sheep and skin-related traits in humans. The Merino is the most important breed of fine-wooled sheep in the world. In this study, we systematically investigated the complexity of sheep hair follicle development by integrating transcriptome and methylome datasets from Merino sheep skin. Results: We analysed 72 sequence datasets, including DNA methylome and the whole transcriptome of four gene types, i.e. protein-coding genes (PCGs), lncRNAs, circRNAs, and miRNAs, across four embryonic days (E65, E85, E105, and E135) and two postnatal days (P7 and P30) from the skin tissue of 18 Merino sheep. We revealed distinct expression profiles of these four gene types across six hair follicle developmental stages, and demonstrated their complex interactions with DNA methylation. PCGs with stage-specific expression or regulated by stage-specific lncRNAs, circRNAs, and miRNAs were significantly enriched in epithelial differentiation and hair follicle morphogenesis. Regulatory network and gene co-expression analyses identified key transcripts controlling hair follicle development. We further predicted transcriptional factors (e.g. KLF4, LEF1, HOXC13, RBPJ, VDR, RARA, and STAT3) with stage-specific involvement in hair follicle morphogenesis. Through integrating these stage-specific genomic features with results from genome-wide association studies (GWAS) of five wool-related traits in 7135 Merino sheep, we detected developmental stages and genes that were relevant with wool-related traits in sheep. For instance, genes that were specifically upregulated at E105 were significantly associated with most of wool-related traits. A phenome-wide association study (PheWAS) demonstrated that candidate genes of wool-related traits (e.g. SPHK1, GHR, PPP1R27, CSRP2, EEF1A2, and PTPN1) in sheep were also significantly associated with dermatological, metabolic, and immune traits in humans. Conclusions: Our study provides novel insights into the molecular basis of hair follicle morphogenesis and will serve as a foundation to improve breeding for wool traits in sheep. It also indicates the importance of studying gene expression in the normal development of organs in understanding the genetic architecture of economically important traits in livestock. The datasets generated here are useful resources for functionally annotating the sheep genome, and for elucidating early skin development in mammals, including humans. [ABSTRACT FROM AUTHOR]

Background: Our previous genome-wide association study (GWAS) on milk fatty acid traits in Chinese Holstein cows revealed, the SNP, BTB-01556197, was significantly associated with C10:0 at genome-wide level (P = 0.0239). It was located in the down-stream of 5-hydroxytryptamine receptor 1B (HTR1B) gene that has been shown to play an important role in the regulation of fatty acid oxidation. Hence, we considered it as a promising candidate gene for milk fatty acids in dairy cattle. In this study, we aimed to investigate whether the HTR1B gene had significant genetic effects on milk fatty acid traits. Results: We re-sequenced the entire coding region and 3000 bp of 5′ and 3′ flanking regions of HTR1B gene. A total of 13 SNPs was identified, containing one in 5′ flanking region, two in 5′ untranslated region (UTR), two in exon 1, five in 3′ UTR, and three in 3′ flanking region. By performing genotype-phenotype association analysis with SAS9.2 software, we observed that 13 SNPs were significantly associated with medium-chain saturated fatty acids such as C6:0, C8:0 and C10:0 (P < 0.0001 ~ 0.042). With Haploview 4.1 software, linkage disequilibrium (LD) analysis was performed. Two haplotype blocks formed by two and ten SNPs were observed. Haplotype-based association analysis indicated that both haplotype blocks were strongly associated with C6:0, C8:0 and C10:0 as well (P < 0.0001 ~ 0.0071). With regards to the missense mutation in exon 1 (g.17303383G > T) that reduced amino acid change from alanine to serine, we predicted that it altered the secondary structure of HTR1B protein with SOPMA. In addition, we predicted that three SNPs in promoter region, g.17307103A > T, g.17305206 T > G and g.17303761C > T, altered the binding sites of transcription factors (TFs) HMX2, PAX2, FOXP1ES, MIZ1, CUX2, DREAM, and PPAR-RXR by Genomatix. Of them, luciferase assay experiment further confirmed that the allele T of g.17307103A > T significantly increased the transcriptional activity of HTR1B gene than allele A (P = 0.0007). Conclusions: In conclusion, our findings provided first evidence that the HTR1B gene had significant genetic effects on milk fatty acids in dairy cattle. [ABSTRACT FROM AUTHOR]

Background: DNA methylation has been shown to be involved in many biological processes, including X chromosome inactivation in females, paternal genomic imprinting, and others. Results: Based on the correlation patterns of methylation levels of neighboring CpG sites among 28 sperm whole genome bisulfite sequencing (WGBS) data (486 × coverage), we obtained 31,272 methylation haplotype blocks (MHBs). Among them, we defined conserved methylated regions (CMRs), variably methylated regions (VMRs) and highly variably methylated regions (HVMRs) among individuals, and showed that HVMRs might play roles in transcriptional regulation and function in complex traits variation and adaptive evolution by integrating evidence from traditional and molecular quantitative trait loci (QTL), and selection signatures. Using a weighted correlation network analysis (WGCNA), we also detected a co-regulated module of HVMRs that was significantly associated with reproduction traits, and enriched for glycosyltransferase genes, which play critical roles in spermatogenesis and fertilization. Additionally, we identified 46 VMRs significantly associated with reproduction traits, nine of which were regulated by cis-SNPs, implying the possible intrinsic relationships among genomic variations, DNA methylation, and phenotypes. These significant VMRs were co-localized (± 10 kb) with genes related to sperm motility and reproduction, including ZFP36L1, CRISP2 and HGF. We provided further evidence that rs109326022 within a predominant QTL on BTA18 might influence the reproduction traits through regulating the methylation level of nearby genes JOSD2 and ASPDH in sperm. Conclusion: In summary, our results demonstrated associations of sperm DNA methylation with reproduction traits, highlighting the potential of epigenomic information in genomic improvement programs for cattle. [ABSTRACT FROM AUTHOR]

Background: Semen traits are important for the widespread use of superior bulls. Thus, the objective of this study was to estimate the heritability of five semen traits, ejaculate volume (VE), progressive sperm motility (SM), sperm concentration (SC), number of sperm (NSP), and number of progressive motile sperm (NMSP), and their genetic correlations (rg). The dataset being studied consisted of 1450 Chinese Holstein bulls with full pedigree information, born between 1996 and 2012, representing 11 AI centers. Genetic parameters were estimated in a multivariate analysis using the average information restricted maximum likelihood estimation of variance (AI-REML). Results: The estimates of heritability for VE, SM, SC, NSP, and NMSP were 0.15, 0.12, 0.22, 0.16 and 0.12, respectively. The genetic correlations among the five semen traits ranged from 0.02 (VE and SC) to 0.99 (NSP and NMSP). Conclusions: Our findings provide useful information on the heritability of semen traits in Holstein bulls and the relationships among them, and should assist in selection for improvement of semen traits in Chinese Holstein bulls. [ABSTRACT FROM AUTHOR]

Background: Fatty acids are important traits that affect meat quality and nutritive values in beef cattle. Detection of genetic variants for fatty acid composition can help to elucidate the genetic mechanism underpinning these traits and promote the improvement of fatty acid profiles. In this study, we performed a genome-wide association study (GWAS) on fatty acid composition using high-density single nucleotide polymorphism (SNP) arrays in Chinese Wagyu cattle. Results: In total, we detected 15 and 8 significant genome-wide SNPs for individual fatty acids and fatty acid groups in Chinese Wagyu cattle, respectively. Also, we identified nine candidate genes based on 100 kb regions around associated SNPs. Four SNPs significantly associated with C14:1 cis-9 were embedded with stearoyl-CoA desaturase (SCD), while three SNPs in total were identified for C22:6 n-3 within Phospholipid scramblase family member 5 (PLSCR5), Cytoplasmic linker associated protein 1 (CLASP1), and Chymosin (CYM). Notably, we found the top candidate SNP within SCD can explain ~ 7.37% of phenotypic variance for C14:1 cis-9. Moreover, we detected several blocks with high LD in the 100 kb region around SCD. In addition, we found three significant SNPs within a 100 kb region showing pleiotropic effects related to multiple FA groups (PUFA, n-6, and PUFA/SFA), which contains BAI1 associated protein 2 like 2 (BAIAP2L2), MAF bZIP transcription factor F (MAFF), and transmembrane protein 184B (TMEM184B). Conclusions: Our study identified several significant SNPs and candidate genes for individual fatty acids and fatty acid groups in Chinese Wagyu cattle, and these findings will further assist the design of breeding programs for meat quality in cattle. [ABSTRACT FROM AUTHOR]