Genome-wide association and systems genetic analyses of residual feed intake, daily feed consumption, backfat and weight gain in pigs.

BACKGROUND: Feed efficiency is one of the major components determining costs of animal production. Residual feed intake (RFI) is defined as the difference between the observed and the expected feed intake given a certain production. Residual feed intake 1 (RFI1) was calculated based on regression of individual daily feed intake (DFI) on initial test weight and average daily gain. Residual feed intake 2 (RFI2) was as RFI1 except it was also regressed with respect to backfat (BF). It has been shown to be a sensitive and accurate measure for feed efficiency in livestock but knowledge of the genomic regions and mechanisms affecting RFI in pigs is lacking. The study aimed to identify genetic markers and candidate genes for RFI and its component traits as well as pathways associated with RFI in Danish Duroc boars by genome-wide associations and systems genetic analyses. RESULTS: Phenotypic and genotypic records (using the Illumina Porcine SNP60 BeadChip) were available on 1,272 boars. Fifteen and 12 loci were significantly associated (p < 1.52 × 10-6) with RFI1 and RFI2, respectively. Among them, 10 SNPs were significantly associated with both RFI1 and RFI2 implying the existence of common mechanisms controlling the two RFI measures. Significant QTL regions for component traits of RFI (DFI and BF) were detected on pig chromosome (SSC) 1 (for DFI) and 2 for (BF). The SNPs within MAP3K5 and PEX7 on SSC 1, ENSSSCG00000022338 on SSC 9, and DSCAM on SSC 13 might be interesting markers for both RFI measures. Functional annotation of genes in 0.5 Mb size flanking significant SNPs indicated regulation of protein and lipid metabolic process, gap junction, inositol phosphate metabolism and insulin signaling pathway are significant biological processes and pathways for RFI, respectively. CONCLUSIONS: The study detected novel genetic variants and QTLs on SSC 1, 8, 9, 13 and 18 for RFI and indicated significant biological processes and metabolic pathways involved in RFI. The study also detected novel QTLs for component traits of RFI. These results improve our knowledge of the genetic architecture and potential biological pathways underlying RFI; which would be useful for further investigations of key candidate genes for RFI and for development of biomarkers.

Genome-wide association study reveals genetic architecture of eating behavior in pigs and its implications for humans obesity by comparative mapping.

This study was aimed at identifying genomic regions controlling feeding behavior in Danish Duroc boars and its potential implications for eating behavior in humans. Data regarding individual daily feed intake (DFI), total daily time spent in feeder (TPD), number of daily visits to feeder (NVD), average duration of each visit (TPV), mean feed intake per visit (FPV) and mean feed intake rate (FR) were available for 1130 boars. All boars were genotyped using the Illumina Porcine SNP60 BeadChip. The association analyses were performed using the GenABEL package in the R program. Sixteen SNPs were found to have moderate genome-wide significance (p<5E-05) and 76 SNPs had suggestive (p<5E-04) association with feeding behavior traits. MSI2 gene on chromosome (SSC) 14 was very strongly associated with NVD. Thirty-six SNPs were located in genome regions where QTLs have previously been reported for behavior and/or feed intake traits in pigs. The regions: 64-65 Mb on SSC 1, 124-130 Mb on SSC 8, 63-68 Mb on SSC 11, 32-39 Mb and 59-60 Mb on SSC 12 harbored several signifcant SNPs. Synapse genes (GABRR2, PPP1R9B, SYT1, GABRR1, CADPS2, DLGAP2 and GOPC), dephosphorylation genes (PPM1E, DAPP1, PTPN18, PTPRZ1, PTPN4, MTMR4 and RNGTT) and positive regulation of peptide secretion genes (GHRH, NNAT and TCF7L2) were highly significantly associated with feeding behavior traits. This is the first GWAS to identify genetic variants and biological mechanisms for eating behavior in pigs and these results are important for genetic improvement of pig feed efficiency. We have also conducted pig-human comparative gene mapping to reveal key genomic regions and/or genes on the human genome that may influence eating behavior in human beings and consequently affect the development of obesity and metabolic syndrome. This is the first translational genomics study of its kind to report potential candidate genes for eating behavior in humans.

The interactive effects of selenomethionine and methylmercury on their absorption, disposition, and elimination in juvenile white sturgeon.

Selenium (Se) and mercury (Hg) are prevalent pollutants of industrialized watersheds. However, when co-administered, Se has protective effects on organisms from Hg. The mechanism is not fully understood, but it is thought that Se reduces Hg availability, either by forming biologically inert complexes and/or associating with selenoproteins. Despite concerns with aquatic contaminations, relatively little information is available on the interaction in aquatic organisms. In the present study, the interactive effects of Se and Hg on their absorption, disposition, and elimination were examined in juvenile white sturgeon, a benthic fish species at high risk to exposures of both contaminants. Selenium and Hg were provided as L-selenomethionine (SeMet) and methylmercury (MeHg), respectively. Groups of 10 sturgeon were orally intubated with a single dose of either 0 (control), SeMet (500 µg Se/kg body weight; BW), MeHg (850 µg Hg/kg BW), or their combination (Se/Hg; 500 µg Se/kg and 850 µg Hg/kg BW). The blood was repeatedly sampled and urine collected from the fish, over a 48 h post intubation period. At 48 h, the fish were sacrificed for Se and Hg tissue concentration and distribution. The co-administration of SeMet and MeHg significantly (p<0.05) lowered blood concentrations of both Se and Hg and tissue Se concentrations. Similarly, assimilation of Se and Hg was also reduced significantly. The interaction has a more quantitative effect on Se metabolism because the reduction in the overall tissue Se is a consequence of reduced Se absorption at the gut and not from the metabolic effects after absorption. In contrast, given the pulse increase in blood Hg concentration, tissue redistribution, and increased urinary elimination, the interactive effect on tissue Hg concentration is likely to be post-absorption. Even in the absence of exogenous SeMet, Se and Hg co-accumulated in tissue at a Se:Hg molar ratio greater than 1. Thus, similar to mammals, maintaining at least a 1:1 molar ratio of Se and Hg is of great physiological importance in the white sturgeon. Interestingly, SeMet did not divert Hg from the brain. Allocation of Se from the kidneys may have occurred in order to maintain the high Se:Hg molar ratios in the brain of white sturgeon. In the current study, the combined use of kinetic analysis and that of the conventional approach of measuring tissue concentration changes provided a comprehensive understanding of the interactive effect of SeMet and MeHg on their respective metabolic processes in juvenile white sturgeon.

Absorption, distribution, and elimination of graded oral doses of methylmercury in juvenile white sturgeon.

Mercury (Hg) is toxic and is released into the environment from a wide variety of anthropogenic sources. Methylmercury (MeHg), a product of microbial methylation, enables rapid Hg bioaccumulation and biomagnification in the biota. Methylmercury is sequestered and made available to the rest of the biota through the benthic-detrital component leading to the high risk of exposure to benthic fish species, such as white sturgeon (Acipenser transmontanus). In the present study, a combined technique of stomach intubation, dorsal aorta cannulation, and urinary catheterization was utilized to characterize the absorption, distribution, and elimination of Hg in white sturgeon over a 48h exposure. Mercury, as methylmercury chloride, at either 0, 250, 500, or 1000 µg Hg/kg body weight, was orally intubated into white sturgeon, in groups of five. The blood was repeatedly sampled and urine collected from the fish over the 48h post intubation period, and at 48h, the fish were sacrificed for Hg tissue concentration and distribution determinations. The fractional rate of absorption (K), blood Hg concentration (µg/ml), tissue concentration (µg/g dry weight) and distribution (%), and urinary Hg elimination flux (µg/kg/h) are significantly different (p<0.05) among the MeHg doses. Complete blood uptake of Hg was observed in all MeHg treated fish by 12h. The maximal observed blood Hg concentration peaks are 0.56±0.02, 0.70±0.02, and 2.19±0.07 µg/ml (mean±SEM) for the 250, 500, and 1000 µgHg/kg body weight dose groups, respectively. Changes in blood Hg profiles can be described by a monomolecular function in all of the MeHg treated fish. The Hg concentration asymptote (A) and K are dose dependent. The relationship between A and the intubation dose, however, is nonlinear. Mercury levels in certain tissues are comparable to field data and longer-term study, indicating that the lower doses used in the current study are ecologically relevant for the species. Tissue Hg concentrations are in the following decreasing order: gastro-intestinal tract>kidney>spleen>gill>heart>liver>brain>white muscle and remaining whole body. At 48h, Hg was found to be preferentially distributed to metabolically active tissues. Digestibility is highest at the lowest MeHg dose. Measurable urinary Hg was observed in the fish treated with the highest MeHg dose, and a significant increase in the elimination flux was observed between 3 and 12h post intubation.

Selenocompounds in juvenile white sturgeon: evaluating blood, tissue, and urine selenium concentrations after a single oral dose.

Selenium (Se) is an essential micronutrient for all vertebrates, however, at environmental relevant levels, it is a potent toxin. In the San Francisco Bay-Delta, white sturgeon, an ancient Chondrostean fish of high ecological and economic value, is at risk to Se exposure. The present study is the first to examine the uptake, distribution, and excretion of various selenocompounds in white sturgeon. A combined technique of stomach intubation, dorsal aorta cannulation, and urinary catheterization was utilized, in this study, to characterize the short-term effects of Se in the forms of sodium-selenate (Selenate), sodium-selenite (Selenite), selenocystine (SeCys), l-selenomethionine (SeMet), Se-methylseleno-l-cysteine (MSeCys), and selenoyeast (SeYeast). An ecologically relevant dose of Se (∼500 µg/kg body weight) was intubated into groups of 5 juvenile white sturgeon. Blood and urine samples were repeatedly collected over the 48 h post intubation period and fish were sacrificed for Se tissue concentration and distribution at 48 h. The tissue concentration and distribution, blood concentrations, and urinary elimination of Se significantly differ (p ≤ 0.05) among forms. In general, organic selenocompounds maintain higher blood concentrations, with SeMeCys maintaining the highest area under the curve (66.3 ± 8.7 and 9.3 ± 1.0 µg h/ml) and maximum Se concentration in blood (2.3 ± 0.2 and 0.4 ± 0.2 µg/ml) in both the protein and non-protein bound fractions, respectively. Selenate, however, did not result in significant increase of Se concentration, compared with the control, in the protein-bound blood fraction. Regardless of source, Se is preferentially distributed into metabolically active tissues, with the SeMet treated fish achieving the highest concentration in most tissues. In contrast, Selenite has very similar blood concentrations and tissue distribution profile to SeCys and SeYeast. From blood and tissue Se concentrations, Selenate is not stored in blood, but taken up rapidly by the liver and white muscle. Urinary elimination of Se is form dependent and peaks between 3 and 12 h post intubation. A basic understanding of the overall Se absorption, distribution, and elimination is provided through monitoring tissue Se concentrations, however, conclusions regarding to the dynamics and the specific processes of Se metabolism can only be inferred, in the absence of kinetic information.

Selenocompounds in juvenile white sturgeon: estimating absorption, disposition, and elimination of selenium using Bayesian hierarchical modeling.

The biological function of selenium (Se) is determined by its form and concentration. Selenium is an essential micronutrient for all vertebrates, however, at environmental levels, it is a potent toxin. In the San Francisco Bay-Delta, Se pollution threatens top predatory fish, including white sturgeon. A multi-compartmental Bayesian hierarchical model was developed to estimate the fractional rates of absorption, disposition, and elimination of selenocompounds, in white sturgeon, from tissue measurements obtained in a previous study (Huang et al., 2012). This modeling methodology allows for a population based approach to estimate kinetic physiological parameters in white sturgeon. Briefly, thirty juvenile white sturgeon (five per treatment) were orally intubated with a control (no selenium) or a single dose of Se (500 µg Se/kg body weight) in the form of one inorganic (Selenite) or four organic selenocompounds: selenocystine (SeCys), l-selenomethionine (SeMet), Se-methylseleno-l-cysteine (MSeCys), or selenoyeast (SeYeast). Blood and urine Se were measured at intervals throughout the 48h post intubation period and eight tissues were sampled at 48 h. The model is composed of four state variables, conceptually the gut (Q1), blood (Q2), and tissue (Q3); and urine (Q0), all in units of µg Se. Six kinetics parameters were estimated: the fractional rates [1/h] of absorption, tissue disposition, tissue release, and urinary elimination (k12, k23, k32, and k20), the proportion of the absorbed dose eliminated through the urine (f20), and the distribution blood volume (V; percent body weight, BW). The parameter k12 was higher in sturgeon given the organic Se forms, in the descending order of MSeCys > SeMet > SeCys > Selenite > SeYeast. The parameters k23 and k32 followed similar patterns, and f20 was lowest in fish given MSeCys. Selenium form did not affect k20 or V. The parameter differences observed can be attributed to the different mechanisms of transmucosal transport, metabolic reduction, and storage of the Se forms, which, in general, appear to be similar to that in mammals. We have demonstrated that the Bayesian approach is a powerful tool for integrating quantitative information from a study with sparse blood and urinary measurements and tissue concentrations from a single time point, while providing a full characterization of parameter variability. The model permits the quantitative mechanistic interpretation and predictions of Se absorption, disposition, and elimination processes. Furthermore, the model represents a first step towards population based physiological toxicokinetic modeling of Se in white sturgeon.