Development of ketosis in high-producing dairy cows contributes to animal health issues and highlights the need for better understanding the genetic basis of metabolic diseases. Thus, the aim of this study was to evaluate the pattern of differential gene expression in liver of cows under negative energy balance (NEB), subclinical, and clinical ketosis through a systematic review and meta-analysis of published gene expression and genome-wide association studies (GWAS) results. After screening of the 118 articles found in the systematic review, 20 articles were included in the analysis. For this, 430 significant SNPs identified by GWAS were investigated to see if they were located within genes reported in gene expression studies. A permutation approach was used to identify the biological pathways associated with the metabolic conditions studied. A gene network was created using the differentially expressed genes harboring significant SNPs and a QTL enrichment analysis was performed to identify potential positional candidate loci. This study revealed 14 genes that are differentially expressed in the liver of cows in different metabolic conditions, which harbor 24 significant polymorphisms in reported GWAS. Three significant metabolic pathways were associated with NEB, subclinical and clinical ketosis. In addition, two important genes, PPARA and ACACA, were identified as differentially expressed in the three metabolic conditions. Gene network analysis revealed co-expression interactions among 34 genes associated with functions involving fatty acid transport and metabolism. The genes FN1 and PTK2 were enriched for QTL previously associated with the trait “ketosis” on chromosome 2 and with the trait “milk iron content” on chromosome 14, respectively. These findings improve the understanding of negative energy balance and ketosis in dairy cows, which could enhance selection for cows less susceptible to ketosis and help with the development of potential biomarkers for early diagnosis and prevention of ketosis.
The mRNA identification and associated splice variants affecting meat marbling in Nellore cattle could contribute to a better understanding of the genetic architecture of this complex trait. Longissimus thoracis samples from the 20 most extreme bulls (out of 80 bulls set) for marbling [high (n=10) and low (n=10) groups] trait were used to perform transcriptomic analysis using RNA-Sequencing. The CLC Genomics Workbench software was used to align the fragments of each sample to the bovine reference genome (ARS-UCD1.2) and to perform differential expressed transcript analysis (DE). An average of 37,000 transcripts and 14 mRNA DE (P ≤ 0.001; FC > 2) were detected in the muscle transcriptome. Among them, three transcripts were up-regulated (COL4A2-202, GHRH-201 and ENSBTAT00000070459.1) and 11 down-regulated (HBB-201, HBA-201, RPL14-202, CATHL1-201, CATHL4-201, MAPKAPK2-204, PCBD1-201, RPL30-203, NEURL1-202, PGLYRP1-201 and ENSBTAT00000038384.2) in high marbling group in relation to low group. Structural variants, including Single Nucleotide Variant (SNV), insertion or deletion were also found in the mRNA DE (4 in high and 6 in low marbling groups), causing possible splice site disruption. For high marbling group, in the COL4A2-202 transcript, three SNVs [one guanine (G) located on chromosome 12 at 85,104,867 bp, two cytosine (C), at the positions: 85,119,139 and 85,145,937 bp] were found. From these, one is a non-synonyms mutation [SNV (G) 85,145,937bp], causing an amino acid change (ENSBTAP00000005916.5: p.Glu1088Asp) in Collagen alpha-2(IV) chain protein (COL4A2). Interestingly, animals with low marbling presented also deletions (85,100,930 pb) in this same gene, causing an amino acid change (ENSBTAP00000005916.5:p.Pro113fs)in the COL4A2 protein. Functional enrichment analysis, using the DE mRNAs list, identified significant metabolic pathways (FDR < 0.05), such as O2/CO2 exchange in erythrocytes, tyrosine biosynthesis and phenylalanine degradation. The results suggest potential key regulatory genes associated with marbling, an economically important trait for the beef industry and for the consumer. Funding FAPESP (#2009/16118-5, #11/21241-0, #2017/02470-3, #2017/10630–2, #2018/ 20026–8, #2018/11154-2) and CAPES (#001).
For the dairy industry, animal welfare and economic viability are key factors in determining the long-term sustainability of the industry. One challenge in lactating dairy cows is mastitis, as there are significant costs associated with each mastitis case due to treatment, milk loss, and potential cow culling. Differentially expressed (DE) genes, DE mRNA isoforms and DE long non-coding RNA (lncRNA) candidates were previously identified by our group between healthy and mastitic samples from six Holstein dairy cows. In total, 7 candidate genes, 5 mRNA isoforms and 4 lncRNA were targeted as they play an important role due to their association with mastitis or the immune system. The aim of the current research is to identify new structural variants in the transcriptome of these previously identified potential candidates using RNA-Sequencing. These structural variants could occur in both coding and intergenic regions of the genome and potentially impact the amino acid that is transcribed, creating a new functional or non-functional protein. In addition, whole genome sequencing (WGS) analysis was performed using hair samples collected from ten Holstein dairy cows (first lactation). Five of these animals had no previous reports of mastitis and five animals had at least one report of mastitis in her lifespan. The WGS results will be used to identify additional structural variants, especially within introns, of the previously identified candidates that could cause a genetic variation in individuals and an association to their susceptibility to mastitis disease.
The objective of this study was to investigate genetic markers associated with different responses to ketosis treatment when compared to ketosis-free Holstein cows. Holstein cows (N=964) from four commercial farms, located in New York State/USA, were included in a randomized controlled trial for ketosis treatment for a period of 2 months (5/19/2019 to 7/20/2019). The cows were screened for BHB (β-hydroxybutyrate ≥1.2 mmol/L) in the first two weeks postpartum (0-14 DIM). Cows with negative results (BHB < 1.2 mmol/L) in the first week (0-7 DIM) were retested in the second week of lactation (8-14 DIM), if negative at both screening tests, cows were categorized as ketosis-free (control group). The cows with positive results in the screening period (0-14 DIM) were treated as detailed in Capel et al. (2020) and reassessed in the following two weeks. According to the cow`s response to the treatment, they were classified as CURED, RECURRENT, SEVERE, and CHRONIC. Out of the 964 cows, 489 were genotyped using the 50k Illumina Bead Chip array. A mixed linear model-based genome-wide association study (GWAS) was carried out in GCTA software. The GWAS was performed for each ketosis outcome compared to the control group. Several potential genomic regions were identified on chromosomes 1, 3, 4, 7, 8, 14, and 17. Overall, the highlighted genes included COL1A1, NEDD4l, DIP2A, CARD6, ITGA7, and MMP19, which have shared functions with genes previously associated with ketosis (e.g., CASP9, ACACA, and Interleukins) in pathways such as the transport of glucose and other sugars, bile salts and organic acids, metal ions and amine compounds, Cell adhesion_ECM remodeling Pathway, TGF-beta signaling, Nucleotide-binding Oligomerization Domain (NOD), and Mesodermal commitment. These findings contribute to a better understanding of the mechanisms that trigger response to ketosis treatment and warrant further investigation.
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