Multi-Omics Integration and Network Analysis Reveal Potential Hub Genes and Genetic Mechanisms Regulating Bovine Mastitis

Mastitis, inflammation of the mammary gland, is the most prevalent disease in dairy cattle that has a potential impact on profitability and animal welfare. Specifically designed multi-omics studies can be used to prioritize candidate genes and identify biomarkers and the molecular mechanisms underlying mastitis in dairy cattle. Hence, the present study aimed to explore the genetic basis of bovine mastitis by integrating microarray and RNA-Seq data containing healthy and mastitic samples in comparative transcriptome analysis with the results of published genome-wide association studies (GWAS) using a literature mining approach. The integration of different information sources resulted in the identification of 33 common and relevant genes associated with bovine mastitis. Among these, seven genes—CXCR1, HCK, IL1RN, MMP9, S100A9, GRO1, and SOCS3—were identified as the hub genes (highly connected genes) for mastitis susceptibility and resistance, and were subjected to protein-protein interaction (PPI) network and gene regulatory network construction. Gene ontology annotation and enrichment analysis revealed 23, 7, and 4 GO terms related to mastitis in the biological process, molecular function, and cellular component categories, respectively. Moreover, the main metabolic-signalling pathways responsible for the regulation of immune or inflammatory responses were significantly enriched in cytokine–cytokine-receptor interaction, the IL-17 signaling pathway, viral protein interaction with cytokines and cytokine receptors, and the chemokine signaling pathway. Consequently, the identification of these genes, pathways, and their respective functions could contribute to a better understanding of the genetics and mechanisms regulating mastitis and can be considered a starting point for future studies on bovine mastitis.

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Identification and Analysis of Key Genes Associated with Ulcerative Colitis by Integrated Bioinformatics Methods

10.21203/rs.3.rs-1019392/v1 ◽

2021 ◽

Author(s):

Xingyu Yu ◽

Jinjie Li ◽

Hongci Chen ◽

Xingmeng Chen ◽

Yu Xiang

Keyword(s):

Ulcerative Colitis ◽

Signaling Pathway ◽

Protein Interaction ◽

Chemokine Receptor ◽

Cytokine Receptor ◽

Receptor Type ◽

Receptor Interaction ◽

Potential Candidate ◽

Hub Genes

Abstract Background: Ulcerative colitis (UC) is a prevalent inflammatory bowel disease of the colonic mucosa. The exact mechanism of the disease still remains unclear. Here we tried to explore new biomarkers and potential therapeutic targets in UC through adopting integrated bioinformatics tools.Results: By performing DEGs analysis, 59 upregulated and 39 downregulated DEGs were successfully identified from GSE3365, respectively. And they were mainly enriched in the terms of Cytokine-cytokine receptor interaction,Viral protein interaction with cytokine and cytokine receptor,Pantothenate and CoA biosynthesis,IL-17 signaling pathway and Chemokine signaling pathway. Based on the data of protein–protein interaction (PPI), the top 10 hub genes were ranked, including Growth-regulated alpha protein (CXCL1), C-C motif chemokine 2 (CCL2), C-X-C chemokine receptor type 1 (CXCR1), Low affinity immunoglobulin gamma Fc region receptor III-B (FCGR3B), C-X-C chemokine receptor type 2 (CXCR2), Prostaglandin G/H synthase 2 (PTGS2), Triggering receptor expressed on myeloid cells 1 (TREM1), Interleukin-1 receptor type 1 (IL1R1), fMet-Leu-Phe receptor (FPR1), and Band 3 anion transport protein (SLC4A1).What’s more, the results of correlation analysis demonstrated that there was a positive correlation between the 10 hub DEGs.Conclusion: Ten DEGs were identified as potential candidate diagnostic biomarkers for patients with UC in present study. However, further experiments are needed to confirm the functional pathways and hub genes associated with UC.

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Analysis of Shared Genetic Regulatory Networks for Alzheimer’s Disease and Epilepsy

BioMed Research International ◽

10.1155/2021/6692974 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Xiao-Dan Wang ◽

Shuai Liu ◽

Hui Lu ◽

Yalin Guan ◽

Hao Wu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Association Studies ◽

Genetic Regulatory Networks ◽

Functional Enrichment ◽

Receptor Interaction ◽

Genome Wide Association Studies ◽

Hub Genes ◽

Gene Coexpression ◽

Shared Genetic

Alzheimer’s disease (AD) and epilepsy are neurological disorders that affect a large cohort of people worldwide. Although both of the two diseases could be influenced by genetic factors, the shared genetic mechanism underlying the pathogenesis of them is still unclear. In this study, we aimed to identify the shared genetic networks and corresponding hub genes for AD and epilepsy. Firstly, the gene coexpression modules (GCMs) were constructed by weighted gene coexpression network analysis (WGCNA), and 16 GCMs were identified. Through further integration of GCMs, genome-wide association studies (GWASs), and expression quantitative trait loci (eQTLs), 4 shared GCMs of AD and epilepsy were identified. Functional enrichment analysis was performed to analyze the shared biological processes of these GCMs and explore the functional overlaps between these two diseases. The results showed that the genes in shared GCMs were significantly enriched in nervous system-related pathways, such as Alzheimer’s disease and neuroactive ligand-receptor interaction pathways. Furthermore, the hub genes of AD- and epilepsy-associated GCMs were captured by weighted key driver analysis (wKDA), including TRPC1, C2ORF40, NR3C1, KIAA0368, MMT00043109, STEAP1, MSX1, KL, and CLIC6. The shared GCMs and hub genes might provide novel therapeutic targets for AD and epilepsy.

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Genomic Analysis, Progress and Future Perspectives in Dairy Cattle Selection: A Review

Animals ◽

10.3390/ani11030599 ◽

2021 ◽

Vol 11 (3) ◽

pp. 599

Author(s):

Miguel A. Gutierrez-Reinoso ◽

Pedro M. Aponte ◽

Manuel Garcia-Herreros

Keyword(s):

Dairy Cattle ◽

Production Efficiency ◽

Association Studies ◽

Phenotypic Traits ◽

Progeny Testing ◽

Genome Wide Association Studies ◽

Genetic Progress ◽

Breeding Programs ◽

Increased Risk ◽

Selection Of

Genomics comprises a set of current and valuable technologies implemented as selection tools in dairy cattle commercial breeding programs. The intensive progeny testing for production and reproductive traits based on genomic breeding values (GEBVs) has been crucial to increasing dairy cattle productivity. The knowledge of key genes and haplotypes, including their regulation mechanisms, as markers for productivity traits, may improve the strategies on the present and future for dairy cattle selection. Genome-wide association studies (GWAS) such as quantitative trait loci (QTL), single nucleotide polymorphisms (SNPs), or single-step genomic best linear unbiased prediction (ssGBLUP) methods have already been included in global dairy programs for the estimation of marker-assisted selection-derived effects. The increase in genetic progress based on genomic predicting accuracy has also contributed to the understanding of genetic effects in dairy cattle offspring. However, the crossing within inbred-lines critically increased homozygosis with accumulated negative effects of inbreeding like a decline in reproductive performance. Thus, inaccurate-biased estimations based on empirical-conventional models of dairy production systems face an increased risk of providing suboptimal results derived from errors in the selection of candidates of high genetic merit-based just on low-heritability phenotypic traits. This extends the generation intervals and increases costs due to the significant reduction of genetic gains. The remarkable progress of genomic prediction increases the accurate selection of superior candidates. The scope of the present review is to summarize and discuss the advances and challenges of genomic tools for dairy cattle selection for optimizing breeding programs and controlling negative inbreeding depression effects on productivity and consequently, achieving economic-effective advances in food production efficiency. Particular attention is given to the potential genomic selection-derived results to facilitate precision management on modern dairy farms, including an overview of novel genome editing methodologies as perspectives toward the future.

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Genetic Basis of Mastitis Resistance in Dairy Cattle – A Review / Podstawy Genetyczne Odporności Krów Mlecznych Na Zapalenie Wymienia – Artykuł Przeglądowy

Annals of Animal Science ◽

10.2478/aoas-2013-0043 ◽

2013 ◽

Vol 13 (4) ◽

pp. 663-673 ◽

Cited By ~ 17

Author(s):

Grażyna Sender ◽

Agnieszka Korwin-Kossakowska ◽

Adrianna Pawlik ◽

Karima Galal Abdel Hameed ◽

Jolanta Oprządek

Keyword(s):

Dairy Cattle ◽

Association Studies ◽

Genetic Resistance ◽

Clinical Mastitis ◽

Future Research ◽

Complex Nature ◽

Candidate Gene Approach ◽

Genome Wide Association Studies ◽

Polygenic Control ◽

Breeding Programmes

Abstract Mastitis is one of the most important mammary gland diseases impacting lactating animals. Resistance to this disease could be improved by breeding. There are several selection methods for mastitis resistance. To improve the natural genetic resistance of cows in succeeding generations, current breeding programmes use somatic cell count and clinical mastitis cases as resistance traits. However, these methods of selection have met with limited success. This is partly due to the complex nature of the disease. The limited progress in improving udder health by conventional selection procedures requires applying information on molecular markers of mastitis susceptibility in marker-assisted selection schemes. Mastitis is under polygenic control, so there are many genes that control this trait in many loci. This review briefly describes genome-wide association studies which have been carried out to identify quantitative trait loci associated with mastitis resistance in dairy cattle worldwide. It also characterizes the candidate gene approach focus on identifying genes that are strong candidates for the mastitis resistance trait. In the conclusion of the paper we focus our attention on future research which should be conducted in the field of the resistance to mastitis.

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A publicly available repository of ROH islands reveals signatures of selection in different livestock and pet species

Genetics Selection Evolution ◽

10.1186/s12711-020-00599-7 ◽

2021 ◽

Vol 53 (1) ◽

Author(s):

Wim Gorssen ◽

Roel Meyermans ◽

Steven Janssens ◽

Nadine Buys

Keyword(s):

Association Studies ◽

Genome Wide Association Studies ◽

Single Nucleotide ◽

Future Studies ◽

Snp Data ◽

Animal Populations ◽

Genome Wide ◽

Starting Point ◽

Different Populations ◽

Signatures Of Selection

Abstract Background Runs of homozygosity (ROH) have become the state-of-the-art method for analysis of inbreeding in animal populations. Moreover, ROH are suited to detect signatures of selection via ROH islands and are used in other applications, such as genomic prediction and genome-wide association studies (GWAS). Currently, a vast amount of single nucleotide polymorphism (SNP) data is available online, but most of these data have never been used for ROH analysis. Therefore, we performed a ROH analysis on large medium-density SNP datasets in eight animal species (cat, cattle, dog, goat, horse, pig, sheep and water buffalo; 442 different populations) and make these results publicly available. Results The results include an overview of ROH islands per population and a comparison of the incidence of these ROH islands among populations from the same species, which can assist researchers when studying other (livestock) populations or when looking for similar signatures of selection. We were able to confirm many known ROH islands, for example signatures of selection for the myostatin (MSTN) gene in sheep and horses. However, our results also included multiple other ROH islands, which are common to many populations and not identified to date (e.g. on chromosomes D4 and E2 in cats and on chromosome 6 in sheep). Conclusions We are confident that our repository of ROH islands is a valuable reference for future studies. The discovered ROH island regions represent a unique starting point for new studies or can be used as a reference for future studies. Furthermore, we encourage authors to add their population-specific ROH findings to our repository.

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RECAS9: Recombining wild species introgression via mitotic gene editing in barley

10.1101/2020.01.07.897280 ◽

2020 ◽

Author(s):

Shelly Lazar ◽

Manas Ranjan Prusty ◽

Khaled Bishara ◽

Amir Sherman ◽

Eyal Fridman

Keyword(s):

Wild Species ◽

Association Studies ◽

Digital Pcr ◽

Crop Wild Relatives ◽

Linkage Drag ◽

Genome Wide Association Studies ◽

Starting Point ◽

Rnp Complex ◽

Causal Genes ◽

The Individual

AbstractGenetic loci underlying variation in traits with agronomic importance or genetic risk factors in human diseases have been identified by linkage analysis and genome-wide association studies. However, narrowing down the mapping to the individual causal genes and variations within these is much more challenging, and so is the ability to break linkage drag between beneficial and unfavourable loci in crop breeding. We developed RECAS9 as a transgene-free approach for precisely targeting recombination events by delivering CRISPR/Cas9 ribonucleotide protein (RNP) complex into heterozygous mitotic cells for the barley (Hordeum vulgare) Heat3.1 locus. A wild species (H. spontaneum) introgression in this region carries the agronomical unfavourable tough rachis phenotype (non-brittle) allele linked with a circadian clock accelerating QTL near GIGANTEA gene. We delivered RNP, which was targeted between two single nucleotide polymorphism (SNPs), to mitotic calli cells by particle bombardment. We estimated recombination events by next generation sequencing (NGS) and droplet digital PCR (ddPCR). While NGS analysis grieved from confounding effects of PCR recombination, ddPCR analysis allowed us to associate RNP treatment on heterozygous individuals with significant increase of homologous directed repair (HDR) between cultivated and wild alleles, with recombination rate ranging between zero to 57%. These results show for the first time in plants a directed and transgene free mitotic recombination driven by Cas9 RNP, and provide a starting point for precise breeding and fine scale mapping of beneficial alleles from crop wild relatives.

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Abstract 144: Zebrafish Larvae: A Model System for Early Stage Atherosclerosis?

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.144 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Manoj K Bandaru ◽

Petter Ranefall ◽

Anastasia Emmanouilidou ◽

Tiffany Klingström ◽

Lingjie Tao ◽

...

Keyword(s):

Early Stage ◽

Association Studies ◽

Oxidized Ldl ◽

Control Diet ◽

High Energy ◽

Model System ◽

Genome Wide Association Studies ◽

Lipid Deposition ◽

Zebrafish Larvae ◽

Starting Point

Objectives: Published results show that overfeeding zebrafish larvae on a high-cholesterol diet (HCD) can result in hypercholesterolemia and sub-endothelial lipid deposition in macrophages and other cell types. However, results are so far based on small samples, and the atherogenic response has been heterogeneous. We aim to use zebrafish larvae for large-scale, CRISPR-Cas9-based genetic screens, using results from genome wide association studies for coronary heart disease as a starting point. Firstly however, we need to ensure the model system is appropriate and robust. Therefore, we examined the effect of a high-energy diet (HED) and HCD on vascular lipid deposition in a larger number of larvae (n=241). Methods: Starting at 5 days post fertilization (dpf), ~30 larvae/tank were fed 2x/day on: 1) 5 mg control diet (CD; n=33); 2) 15 mg control diet (HED; n=90); or 3) 15 mg control diet enriched with 4% cholesterol (HCD; n=94). At 14-17 dpf, larvae were soaked in monodansylpentane cadaverase - a lipid staining dye - for 45 min, before imaging the dorsal aorta and caudal vein with a Leica SP5 confocal microscope. We used a custom written script in Cell Profiler to quantify the surface area of lipid deposits in the vasculature. Results: Manual annotation of vascular lipid deposition in 30 images (10 randomly selected images per dietary condition) allowed us to calculate the sensitivity (36%) and specificity (71%) of the Cell Profiler script. Subsequent analyses showed that HED (p=0.004) and HCD (p=0.001) fed larvae have significantly more vascular lipid deposition than CD fed larvae after adjusting for age, batch and vessel length. There was no difference in vascular lipid deposition between HED and HCD fed larvae (p=0.11). Discussion and conclusion: Our results confirm that zebrafish larvae represent a promising model system for early-stage atherosclerosis. In addition, they show that enriching the diet with cholesterol is not required to prompt atherogenesis. Future directions: In the next few months, we will examine if overfeeding also triggers vascular infiltration by macrophages, neutrophils and oxidized LDL cholesterol, and if atherogenesis can be prevented or reduced by treating larvae with statins and/or ezetimibe, using our new, automated imaging setup.

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Genetic and Non-genetic Determinants of Cardiovascular Disease in South Asians

Current Diabetes Reviews ◽

10.2174/1573399817666210118103022 ◽

2021 ◽

Vol 17 ◽

Author(s):

Shiwali Goyal ◽

Dharambir K. Sanghera

Keyword(s):

Cardiovascular Disease ◽

Indian Subcontinent ◽

Association Studies ◽

South Asians ◽

Genome Wide Association Studies ◽

Cvd Risk ◽

Potential Implication ◽

Systematic Assessment ◽

Functional Studies ◽

Starting Point

: South Asians (SAs), people from the Indian subcontinent (e.g. India, Pakistan, Bangladesh, Sri Lanka, and Nepal) have a higher prevalence of cardiovascular disease (CVD) and suffer from a greater risk of CVD-associated mortality compared to other global populations. These problems are compounded by the alterations in lifestyles due to urbanization and changing cultural, social, economic, and political environment. Current methods of CV risk prediction are based on white populations that under-estimate the CVD risk in SAs. Prospective studies are required to obtain actual CVD morbidity/mortality rates so that comparisons between predicted CVD risk can be made with actual events. Overwhelming data support a strong influence of genetic factors. Genome-wide association studies (GWAS) serve as a starting point for future genetic and functional studies since the mechanisms of action by which these associated loci influence CVD is still unclear. It is difficult to predict the potential implication of these findings in clinical settings. This review provides a systematic assessment of the risk factors, genetics, and environmental causes of CV health disparity in SAs, and highlights progress made in clinical and genomics discoveries in the rapidly evolving field which has the potential to show clinical relevance in the near future.

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Anticancer Effects of Emodin on HepG2 Cell: Evidence from Bioinformatic Analysis

BioMed Research International ◽

10.1155/2019/3065818 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 3

Author(s):

Rui-sheng Zhou ◽

Xiong-Wen Wang ◽

Qin-feng Sun ◽

Zeng Jie Ye ◽

Jian-wei Liu ◽

...

Keyword(s):

Signaling Pathway ◽

Hepg2 Cells ◽

Molecular Mechanisms ◽

Mapk Signaling ◽

Ion Concentration ◽

Receptor Interaction ◽

Pathway Enrichment Analysis ◽

Mrna Levels ◽

Hub Genes ◽

Positive Regulation

Hepatocellular carcinoma (HCC) is a primary cause of cancer-related death in the world. Despite the fact that there are many methods to treat HCC, the 5-year survival rate of HCC is still at a low level. Emodin can inhibit the growth of HCC cells invitroand invivo. However, the gene regulation of emodin in HCC has not been well studied. In our research, RNA sequencing technology was used to identify the differentially expressed genes (DEGs) in HepG2 cells induced by emodin. A total of 859 DEGs were identified, including 712 downregulated genes and 147 upregulated genes in HepG2 cells treated with emodin. We used DAVID for function and pathway enrichment analysis. The protein-protein interaction (PPI) network was constructed using STRING, and Cytoscape was used for module analysis. The enriched functions and pathways of the DEGs include positive regulation of apoptotic process, structural molecule activity and lipopolysaccharide binding, protein digestion and absorption, ECM-receptor interaction, complement and coagulation cascades, and MAPK signaling pathway. 25 hub genes were identified and pathway analysis revealed that these genes were mainly enriched in neuropeptide signaling pathway, inflammatory response, and positive regulation of cytosolic calcium ion concentration. Survival analysis showed that LPAR6, C5, SSTR5, GPR68, and P2RY4 may be involved in the molecular mechanisms of emodin therapy for HCC. A quantitative real-time PCR (qRT-PCR) assay showed that the mRNA levels of LPAR6, C5, SSTR5, GPR68, and P2RY4 were significantly decreased in HepG2 cells treated with emodin. In conclusion, the identified DEGs and hub genes in the present study provide new clues for further researches on the molecular mechanisms of emodin.

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Confirmed effects of candidate variants for milk production, udder health, and udder morphology in dairy cattle

Genetics Selection Evolution ◽

10.1186/s12711-020-00575-1 ◽

2020 ◽

Vol 52 (1) ◽

Cited By ~ 1

Author(s):

Thierry Tribout ◽

Pascal Croiseau ◽

Rachel Lefebvre ◽

Anne Barbat ◽

Mekki Boussaha ◽

...

Keyword(s):

Dairy Cattle ◽

Candidate Genes ◽

Milk Production ◽

Association Studies ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Production Traits ◽

Milk Production Traits ◽

Udder Health ◽

Gwas Approach

Abstract Background Over the last years, genome-wide association studies (GWAS) based on imputed whole-genome sequences (WGS) have been used to detect quantitative trait loci (QTL) and highlight candidate genes for important traits. However, in general this approach does not allow to validate the effects of candidate mutations or determine if they are truly causative for the trait(s) in question. To address these questions, we applied a two-step, within-breed GWAS approach on 15 traits (5 linked with milk production, 2 with udder health, and 8 with udder morphology) in Montbéliarde (MON), Normande (NOR), and Holstein (HOL) cattle. We detected the most-promising candidate variants (CV) using imputed WGS of 2515 MON, 2203 NOR, and 6321 HOL bulls, and validated their effects in three younger populations of 23,926 MON, 9400 NOR, and 51,977 HOL cows. Results Bull sequence-based GWAS detected 84 QTL: 13, 10, and 30 for milk production traits; 3, 0, and 2 for somatic cell score (SCS); and 8, 2 and 16 for udder morphology traits, in MON, NOR, and HOL respectively. Five genomic regions with effects on milk production traits were shared among the three breeds whereas six (2 for production and 4 for udder morphology and health traits) had effects in two breeds. In 80 of these QTL, 855 CV were highlighted based on the significance of their effects and functional annotation. The subsequent GWAS on MON, NOR, and HOL cows validated 8, 9, and 23 QTL for production traits; 0, 0, and 1 for SCS; and 4, 1, and 8 for udder morphology traits, respectively. In 47 of the 54 confirmed QTL, the CV identified in bulls had more significant effects than single nucleotide polymorphisms (SNPs) from the standard 50K chip. The best CV for each validated QTL was located in a gene that was functionally related to production (36 QTL) or udder (9 QTL) traits. Conclusions Using this two-step GWAS approach, we identified and validated 54 QTL that included CV mostly located within functional candidate genes and explained up to 6.3% (udder traits) and 37% (production traits) of the genetic variance of economically important dairy traits. These CV are now included in the chip used to evaluate French dairy cattle and can be integrated into routine genomic evaluation.

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