Structural equation modeling for investigating multi-trait genetic architecture of udder health in dairy cattle

senior high school MY is known to increase risk of clinical mastitis, and consequently increase SCS, which is an index of mastitis. Mastitis, in turn, will reduce MY in the remaining part of suckling. such relationships have been described previously by a model with a recursive effect from SCS to MY providing evidence for the possible being of unfavorable effects between MY and SCS 26. In this cogitation, we explored the universe of putative dependencies among a set up of five phenotypes related to udder health, including not only MY and SCS but besides milk ph, LACT, and NCN, which are related to udder health status. The network structure identified by the HC Bayesian network algorithm was incorporated into a SEM-based GWAS model to decompose SNP effects into target effects on the trait and effects mediated by up-stream traits in the phenotypical net. average phenotypical values obtained for MY, LACT, ph and SCS were in line with previous results reported for Brown Swiss cattle breed 27, 28. Regarding NCN, this trait corresponds to the sum of whey proteins and non-protein N percentages ( i.e., complement of casein index to 100 % ). modal values obtained in this learn for NCN ( 21.96 ± 1.23 % ) are therefore coherent with values reported in the literature for casein index in Brown Swiss ( 76.76 ± 2.58 % ) 29. Genomic heritabilities estimated by the multi-trait Bayesian GBLUP for the investigate traits were in the range of genetic values obtained with univariate models 27, 30, 31, 32, except for milk ph, which showed higher values. The only statistically relevant genomic correlation was found between LACT ( an udder health indicator trait ) and NCN ( −0.280 ), which might support the guess that non-protein N in milk might be considered as an indicator of mammary gland inflammation. additionally, we previously found negative genic correlations between serum proteins ( albumins and globulins ) and lactose share 33. The application of the HC algorithm allowed us to infer the net social organization from a residual covariance matrix, after accounting for polygenic additive effects. New insights were provided on the relationships among traits related to udder health in dairy cattle. In particular, we found a putative mediation of LACT on SCS and NCN in our phenotypical network, which is supported by the magnitude of the path coefficients reflecting the military capability of the colony relationship. The relationships between lactose in milk and udder health or SCC have been widely investigated, and lactose share in the milk of mastitic animals was importantly below the average values of the healthy animals 34. Lactose is a β-galactoside consist of galactose and glucose residues, and it is the main carbohydrate in mammal breast milk. Galectins are a family of proteins that bind specifically to β-galactosides such as lactose and have regulative functions in the immune system. The interaction of lactose with detail galectin members seemed to largely determine its anti- or pro- incendiary effects 35. It is possible that the escape of lactose from milk to blood might have a chemotactic effect attracting macrophages and leukocytes from the blood to the mammary gland. This might besides explain the negative augury of the path coefficient ( −0.632 ). Monocyte and macrophages migrating to the excitement site secrete incendiary mediators, including proteinases such as plasminogen activators which can increase the horizontal surface of plasmin natural process in mastitic milk 36. This might besides support the function of LACT as an up-stream trait to NCN and the negative bless of the path coefficient ( −0.262 ). On the other bridge player, the intensity of edges between milk ph and the early traits in the network suggested this trait had a weak connectivity with MY, LACT and NCN. The only exception was the path between SCS and ph, which had potency values > 50 %. therefore, we used prior biological information to support the being of a relationship between these traits and infer its possible direction. It is well-recognized that milk ph increases with elevated SCC due to changes in milk ionic balance which results from the mammary tissue injury 23, 37. On the other hand, a potential colony kinship with guidance ph → SCS seemed to be much more difficult to envisage. however, the coefficient for this way ( λ43=0.057 ) was small, suggesting that the function of SCS in mediating SNP effects on milk ph is fringy.

By jointly applying MTM-GWAS and SEM-GWAS, we identified 6 indicative significant SNP for SCS and we quantified the contribution of MY and LACT acting as mediator traits to sum SNP effects. In detail, the contribution of the indirect path MY → LACT → SCS to total SNP effect on SCS was very minor while LACT revealed to be a relevant mediator trait affecting total SNP effects, specially for marker rs41569794. Interestingly, marker rs41569794 mapped on BTA4 at ~0.1 Mb from STEAP4, which is a metalloreductase involved in the control of systemic metabolic homeostatis by integrating incendiary and metabolic responses. This gene was among the top 10 genes with the greatest addition in formula in milk bodily cells after intra-mammary contagion with S. aureus in capricorn 38. The marker rs110736919 corresponded to an intron version of ADCY1. This gene codes for a calmodulin-sensitive adenylyl cyclase. According to GO annotations, ADCY1 seemed to have a function in respective processes such as rule of circadian rhythm, cellular answer to calcium ion and neuroinflammatory reaction. We did not find any association between this gene and mastitis or mammary gland inflammation. however, SNP within or close to ADCY1 have been associated to fertility traits in dairy cows 39, 40. The marker rs41615292 corresponded to an intergenic variant, which mapped close to INHBA ( ~0.6 Mb ). The INHBA is a member of the TGF-β superfamily 41, which has a character in apoptosis. The price induced by mastitis to the mammary tissue can be induced by apoptosis or necrosis 42. consequently, Fonseca et al. 43 found an increase in the formulation of this gene in bovine mammary gland after experimental contagion with Streptococcus agalactiae. The markers rs110854438 and rs110811284 mapped conclusion to ADCY1 ( ~40 Kb ) and at ~0.2 Mb from IGFBP3 and IGFBP1. It has been shown that lactoferrin specifically binds to extracellular IGFBP3 and plays a key function in the entry of IGFBP3 into mammary cells nucleus 44. Lactoferrin has a long-familiar function in the modulation of incendiary process since it prevents the release of cytokines from monocytes and regulates the proliferation and specialization of immune cells 45. therefore, it has been considered as a thoroughly index of mastitis in dairy cows similarly to SCC 46. last, the marker rs110490432 corresponded to an intergenic variant which mapped near ( at ~76 Kb ) to BTBD3. To our cognition, no association of this gene to immune reaction has been previously demonstrated in dairy cows.

Pathways enrichment analyses showed that variants associated to MY, LACT, SCS, ph, and NCN aggregated in versatile biological pathways, which were frequently shared among traits as further support for their intercorrelation. The secretion of milk depends on the natural process of respective membrane transport systems on mammary secretory cells 47. furthermore, Na+/H+ substitution and Na+/HCO3- cotransport is involved in the regulation of mammary cell ph 48. This might explain the overrepresentation of pathways connected with membrane ecstasy action for both MY and ph. Genes involved in the Wnt sign were associated to both SCS and NCN. Inflammatory epithelial cells were shown to induce changes in stromal fibroblast characteristics in bovine mammary gland with mastitis which are mediated by Wnt signal nerve pathway components 49. A net association between Wnt signaling and milk protein metamorphosis was not found. however, among the associated genes, there was GSKIP which is a minus regulator of GSK3β in the Wnt signaling nerve pathway. recently, it was reported that mTORC1 inhibition of GSK3β regulates the production of pro- and anti-inflammatory cytokines, which is in line with the interest of Wnt sinaling in the command of inflammation. however, mTOR signaling nerve pathway plays besides an crucial character in milk protein synthesis 50. regulation of signaling pathway for LACT might further support for its putative chemotactic action towards immune cells. This sketch represents the first application of SEM-GWAS in dairy cattle, in particular, to udder health traits. We showed that SEM is a elastic border on which allows to model the relationships among SNP and phenotypes including the contribution of potential mediator traits, which might be particularly utilitarian particularly in the case of highly interconnected phenotypes contributing to a final consequence through park or different pathways 51. SEM-GWAS might be therefore considered as an elongation of MTM-GWAS which accounts for the network social organization among phenotypes and is able to identify the contribution of steer and indirect effects on the sum SNP impression. caution must be used, however, when interpreting SEM as a causal model even if it is corroborated by the data, since causal pathways may be difficult to model in a multi‐trait framework in which many genes and interactions are involved 52. furthermore, it is acquit that omitting variables implicated in causal processes may distort views of the system 53. The identification of indirect effects can provide a better understanding of result mechanisms and aid in designing survival strategies and management decisions aimed at improving udder health in dairy cattle. Our results need to be validated on a larger population and using a database including repeated records along the suckling, together with records of clinical mastitis cases which might improve the accuracy for the detection of putative causal paths among the traits investigated .

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