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Prioritizing candidate genes post-GWAS using multiple sources of data for mastitis resistance in dairy cattle.

ABSTRACT: BACKGROUND:Improving resistance to mastitis, one of the costliest diseases in dairy production, has become an important objective in dairy cattle breeding. However, mastitis resistance is influenced by many genes involved in multiple processes, including the response to infection, inflammation, and post-infection healing. Low genetic heritability, environmental variations, and farm management differences further complicate the identification of links between genetic variants and mastitis resistance. Consequently, studies of the genetics of variation in mastitis resistance in dairy cattle lack agreement about the responsible genes. RESULTS:We associated 15,552,968 imputed whole-genome sequencing markers for 5147 Nordic Holstein cattle with mastitis resistance in a genome-wide association study (GWAS). Next, we augmented P-values for markers in genes in the associated regions using Gene Ontology terms, Kyoto Encyclopedia of Genes and Genomes pathway analysis, and mammalian phenotype database. To confirm results of gene-based analyses, we used gene expression data from E. coli-challenged cow udders. We identified 22 independent quantitative trait loci (QTL) that collectively explained 14% of the variance in breeding values for resistance to clinical mastitis (CM). Using association test statistics with multiple pieces of independent information on gene function and differential expression during bacterial infection, we suggested putative causal genes with biological relevance for 12 QTL affecting resistance to CM in dairy cattle. CONCLUSION:Combining information on the nearest positional genes, gene-based analyses, and differential gene expression data from RNA-seq, we identified putative causal genes (candidate genes with biological evidence) in QTL for mastitis resistance in Nordic Holstein cattle. The same strategy can be applied for other traits.

SUBMITTER: Cai Z

PROVIDER: S-EPMC6127918 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Prioritizing candidate genes post-GWAS using multiple sources of data for mastitis resistance in dairy cattle.

Cai Zexi Z Guldbrandtsen Bernt B Lund Mogens Sandø MS Sahana Goutam G

BMC genomics 20180906 1

<h4>Background</h4>Improving resistance to mastitis, one of the costliest diseases in dairy production, has become an important objective in dairy cattle breeding. However, mastitis resistance is influenced by many genes involved in multiple processes, including the response to infection, inflammation, and post-infection healing. Low genetic heritability, environmental variations, and farm management differences further complicate the identification of links between genetic variants and mastitis ...[more]

PMID: 30189836

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Project description:BackgroundBovine paratuberculosis is a contagious disease, caused by Mycobacterium avium subsp. paratuberculosis (MAP), with adverse effects on animal welfare and serious economic consequences. Published results on host genetic resistance to MAP are inconsistent, mainly because of difficulties in characterizing the infection status of cows. The objectives of this study were to identify quantitative trait loci (QTL) for resistance to MAP in Holstein and Normande cows with an accurately defined status for MAP.ResultsFrom MAP-infected herds, cows without clinical signs of disease were subjected to at least four repeated serum ELISA and fecal PCR tests over time to determine both infected and non-infected statuses. Clinical cases were confirmed using PCR. Only cows that had concordant results for all tests were included in further analyses. Positive and control cows were matched within herd according to their birth date to ensure a same level of exposure to MAP. Cows with accurate phenotypes, i.e. unaffected (control) or affected (clinical or non-clinical cases), were genotyped with the Illumina BovineSNP50 BeadChip. Genotypes were imputed to whole-genome sequences using the 1000 Bull Genomes reference population (run6). A genome-wide association study (GWAS) of MAP status of 1644 Holstein and 649 Normande cows, using either two (controls versus cases) or three classes of phenotype (controls, non-clinical and clinical cases), revealed three regions, on Bos taurus (BTA) chromosomes 12, 13, and 23, presenting significant effects in Holstein cows, while only one of those was identified in Normande cows (BTA23). The most significant effect was found on BTA13, in a short 8.5-kb region. Conditional analyses revealed that only one causal variant may be responsible for the effects observed on each chromosome with the ABCC4 (BTA12), CBFA2T2 (BTA13), and IER3 (BTA23) genes as good functional candidates.ConclusionsA sequence-based GWAS on cows for which resistance to MAP was accurately defined, was able to identify candidate variants located in genes that were functionally related to resistance to MAP; these explained up to 28% of the genetic variance of the trait. These results are very encouraging for efforts towards implementation of a breeding strategy aimed at improving resistance to paratuberculosis in Holstein cows.

Project description:BACKGROUND: One major problem in dairy cattle husbandry is the prevalence of udder infections. In today's breeding programmes, top priority is being given to making animal evaluation more cost-effective and reliable and less time-consuming. We proposed tumor necrosis factor ? (TNF-?), lactoferrin (LTF) and macrophage-expressed lysozyme (mLYZ) genes as potential DNA markers in the improvement of immunity to mastitis.This study included 588 Polish Holstein-Friesian cows kept on one farm located in the north-western region of Poland. All clinical cases of mastitis in the herd under study were recorded by a qualified veterinarian employed by the farm. The following indicators were applied to determine udder immunity to mastitis in the cows under study: morbidity rate (MR), duration of mastitis (DM) and extent of mastitis (EM). TNF-?, mLYZ and LTF genotypes were identified by real-time PCR method, using SimpleProbe technology. Due to the very low frequency of mLYZ allele T, the gene was excluded from further analysis.A statistical analysis of associations between TNF-? and LTF genes and immunity to mastitis were performed using three models: 1) a parity-averaged model including only additive effects of the genes; 2) a parity-averaged model including both additive and epistatic effects of the genes; and 3) a parity-specific model including only additive effects of the genes. RESULTS: With the first and second models it was revealed that the genes effects on the applied indicators of immunity to mastitis were non-significant whereas with the third one the effects were found to be statistically significant. Particularly noteworthy was the finding that the effects of TNF-? and LTF varied depending on age (parity). The alleles which were linked to high immunity to mastitis in lower parities appeared to be less favourable in higher parities. CONCLUSIONS: These interactions might be related to inflamm-ageing, that is an increased susceptibility to infection due to immune system deregulation that progresses with age. Such pattern of interactions makes it impossible to use the genes in question in marker-assisted selection aimed at reducing heritable susceptibility to mastitis. This is because the immune mechanisms behind resistance to infections proved to be too complex.

Project description:In our previous GWAS of Chinese and Nordic dairy cattle, genes CACNB2, SLC39A12, and ZEB1 locating on BTA 13 were suggested as candidate genes for reproduction. In this study, validation of these associations was performed in an independent population with records of nine reproductive traits. More importantly, functions of these genes in the reproductive process were verified by employing the expression data of ovarian follicles. The potential variants within the three genes were firstly detected in 68 Chinese Holstein bulls, and then screened in 1,588 Chinese Holstein cows using the KASP (Kompetitive allele-specific PCR) method. There were nine variants with polymorphisms in CACNB2, five in SLC39A12, and four in ZEB1, respectively, of which one SNP was in the upstream regulatory region, two in exon region, four in downstream regulatory region, and 11 SNPs in intronic regions. Amongst the 18 variants, g.33267056T/G in CACNB2 explained the largest phenotypic variance for age at first calving (0.011%), interval from first to last insemination (0.004%), and calving ease (0.002%), while g.32751518G/A in SLC39A12 contributed the most to stillbirth in heifers (0.038%). Two haplotype blocks were constructed for CACNB2 while one each for SLC39A12 and ZEB1, which were significantly associated with five reproductive traits, including age at the first service, age at the first calving, calving ease in heifers and cows, and the interval from calving to the first insemination. We then studied the profile of gene expression in granulosa cells isolated from four developmental stages of ovarian follicles from eight dairy cows. All three genes were differentially expressed between ovarian follicles with different sizes (p < 0.05), indicating their potential roles in the reproductive process of dairy cows. This study successfully demonstrated the associations of three BTA 13 genes CACNB2, SLC39A12, and ZEB1 with reproduction and further examined their expression levels in ovarian follicles directly. These findings can be beneficial for the ongoing genomic selection program for reproductive traits which have long been considered as traits that are difficult to achieve genetic improvement due to the lack of efficient genetic markers.

Project description:BACKGROUND:Mastitis is the most prevalent disease in dairy sheep with major economic, hygienic and welfare implications. The disease persists in all dairy sheep production systems despite the implementation of improved management practises. Selective breeding for enhanced mastitis resistance may provide the means to further control the disease. In the present study, we investigated the genetic architecture of four mastitis traits in dairy sheep. Individual animal records for clinical mastitis occurrence and three mastitis indicator traits (milk somatic cell count, total viable bacterial count in milk and the California mastitis test) were collected monthly throughout lactation for 609 ewes of the Greek Chios breed. All animals were genotyped with a custom-made 960-single nucleotide polymorphism (SNP) DNA array based on markers located in quantitative trait loci (QTL) regions for mastitis resistance previously detected in three other distinct dairy sheep populations. RESULTS:Heritable variation and strong positive genetic correlations were estimated for clinical mastitis occurrence and the three mastitis indicator traits. SNP markers significantly associated with these mastitis traits were confirmed on chromosomes 2, 3, 5, 16 and 19. We identified pathways, molecular interaction networks and functional gene clusters for mastitis resistance. Candidate genes within the detected regions were identified based upon analysis of an ovine transcriptional atlas and transcriptome data derived from milk somatic cells. Relevant candidate genes implicated in innate immunity included SOCS2, CTLA4, C6, C7, C9, PTGER4, DAB2, CARD6, OSMR, PLXNC1, IDH1, ICOS, FYB, and LYFR. CONCLUSIONS:The results confirmed the presence of animal genetic variability in mastitis resistance and identified genomic regions associated with specific mastitis traits in the Chios sheep. The conserved genetic architecture of mastitis resistance between distinct dairy sheep breeds suggests that across-breed selection programmes would be feasible.

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Prioritizing candidate genes post-GWAS using multiple sources of data for mastitis resistance in dairy cattle.

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Prioritizing candidate genes post-GWAS using multiple sources of data for mastitis resistance in dairy cattle.

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