The inhibition of 5-enolpyruvylshikimate-3-phosphate synthase as a model for development of novel antimicrobials

EPSP synthase (EPSPS) is an essential enzyme in the shikimate pathway, transferring the enolpyruvyl group of phosphoenolpyruvate to shikimate-3-phosphate to form 5-enolpyruvyl-3-shikimate phosphate and inorganic phosphate. This enzyme is composed of two domains, which are formed by three copies of βαβαββ-folding units; in between there are two crossover chain segments hinging the nearly topologically symmetrical domains together and allowing conformational changes necessary for substrate conversion. The reaction is ordered with shikimate-3-phosphate binding first, followed by phosphoenolpyruvate, and then by the subsequent release of phosphate and EPSP. N-[phosphomethyl]glycine (glyphosate) is the commercial inhibitor of this enzyme. Apparently, the binding of shikimate-3-phosphate is necessary for glyphosate binding, since it induces the closure of the two domains to form the active site in the interdomain cleft. However, it is somehow controversial whether binding of shikimate-3-phosphate alone is enough to induce the complete conversion to the closed state. The phosphoenolpyruvate binding site seems to be located mainly on the C-terminal domain, while the binding site of shikimate-3-phosphate is located primarily in the N-terminal domain residues. However, recent results demonstrate that the active site of the enzyme undergoes structural changes upon inhibitor binding on a scale that cannot be predicted by conventional computational methods. Studies of molecular docking based on the interaction of known EPSPS structures with (R)- phosphonate TI analogue reveal that more experimental data on the structure and dynamics of various EPSPS-ligand complexes are needed to more effectively apply structure-based drug design of this enzyme in the future. © 2007 Bentham Science Publishers Ltd.

Test-day model for milk yield of dairy buffaloes in colombia

The test-day model is the preferred method for genetic evaluations in dairy cattle. For this study, 28372 test-day records of 1220 lactations from 1997 to 2009 were used. The (co)variance components for milk in test-day were estimated using a Uni and multiple-traits repeated animal model with the Restricted Maximum Likelihood method (REML). The Contemporary Group (herd, year, and season of parity) and the age of parity (linear and quadratic) fixed effects, and the additive genetic, permanent environmental, and residual random effects were included in the model. The heritabilities ranged between 0.06 and 0.45 during lactation. The genetic correlations were greater than 0.93. In conclusion, the test-day model is appropriate for the genetic evaluation of dairy buffaloes in Colombia.

Genetic correlations between mature cow weight and productive and reproductive traits in Nellore cattle

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Frequency of multiple endocrine neoplasia type 1 in a group of patients with pituitary adenoma: genetic study and familial screening

The purpose of this study it was to evaluate the frequency of Multiple Endocrine Neoplasia type 1 (MEN1) in patients with pituitary adenoma and to perform genetic analysis and familial screening of those individuals afflicted with MEN1. 144 patients with pituitary adenoma at Botucatu Medical School, UNESP-Univ Estadual Paulista, were assessed retrospectively for MEN1 during the years of 2005-2011. The patients were evaluated for the presence of primary hyperparathyroidism (PHP) and enteropancreatic tumors. Genetic analysis was performed for the individuals with clinically diagnosed MEN1. Thirteen patients met the diagnostic criteria for MEN1, but three individuals belong to the same family and they were considered as a single MEN1 event, revealing 7.7 % frequency of MEN1 in this patient group. Genetic analysis showed MEN1 mutations in four index cases: IVS4+1 G>A, IVS3-6 C>T, c.1547insC and a new D180A mutation. One patient did not agree to participate in the genetic study and another one was referred for follow up in other hospital. Only polymorphisms were found in the other individuals, one of which was novel. We identified a high frequency of MEN1 in pituitary adenoma patients. Since PHP is one of the most common MEN1 tumor and patients are mostly asymptomatic, we suggest that all pituitary adenoma patients have their calcium profile analyzed. © 2013 Springer Science+Business Media New York.

Comparison of random regression models to estimate genetic parameters for milk production in Guzerat (Bos indicus) cows

Random regression models have been widely used to estimate genetic parameters that influence milk production in Bos taurus breeds, and more recently in B. indicus breeds. With the aim of finding appropriate random regression model to analyze milk yield, different parametric functions were compared, applied to 20,524 test-day milk yield records of 2816 first-lactation Guzerat (B. indicus) cows in Brazilian herds. The records were analyzed by random regression models whose random effects were additive genetic, permanent environmental and residual, and whose fixed effects were contemporary group, the covariable cow age at calving (linear and quadratic effects), and the herd lactation curve. The additive genetic and permanent environmental effects were modeled by the Wilmink function, a modified Wilmink function (with the second term divided by 100), a function that combined third-order Legendre polynomials with the last term of the Wilmink function, and the Ali and Schaeffer function. The residual variances were modeled by means of 1, 4, 6, or 10 heterogeneous classes, with the exception of the last term of the Wilmink function, for which there were 1, from 0.20 to 0.33. Genetic correlations between adjacent records were high values (0.83-0.99), but they declined when the interval between the test-day records increased, and were negative between the first and last records. The model employing the Ali and Schaeffer function with six residual variance classes was the most suitable for fitting the data. © FUNPEC-RP.

Phenotypic plasticity of composite beef cattle performance using reaction norms model with unknown covariate

The objective of the present study was to determine the presence of genotype by environment interaction (G × E) and to characterize the phenotypic plasticity of birth weight (BW), weaning weight (WW), postweaning weight gain (PWG) and yearling scrotal circumference (SC) in composite beef cattle using the reaction norms model with unknown covariate. The animals were born between 1995 and 2008 on 33 farms located throughout all Brazilian biomes between latitude -7 and -31, longitude -40 and -63. The contemporary group was chosen as the environmental descriptor, that is, the environmental covariate of the reaction norms. In general, higher estimates of direct heritability were observed in extreme favorable environments. The mean of direct heritability across the environmental gradient ranged from 0.05 to 0.51, 0.09 to 0.43, 0.01 to 0.43 and from 0.12 to 0.26 for BW, WW, PWG and SC, respectively. The variation in direct heritability observed indicates a different response to selection according to the environment in which the animals of the population are evaluated. The correlation between the level and slope of the reaction norm for BW and PWG was high, indicating that animals with higher average breeding values responded better to improvement in environmental conditions, a fact characterizing a scale of G × E. Low correlation between the intercept and slope was obtained for WW and SC, implying re-ranking of animals in different environments. Genetic variation exists in the sensitivity of animals to the environment, a fact that permits the selection of more plastic or robust genotypes in the population studied. Thus, the G × E is an important factor that should be considered in the genetic evaluation of the present population of composite beef cattle. © The Animal Consortium 2012.

Multiple-trait random regression models for the estimation of genetic parameters for milk, fat, and protein yield in buffaloes

In this study, genetic parameters for test-day milk, fat, and protein yield were estimated for the first lactation. The data analyzed consisted of 1,433 first lactations of Murrah buffaloes, daughters of 113 sires from 12 herds in the state of São Paulo, Brazil, with calvings from 1985 to 2007. Ten-month classes of lactation days were considered for the test-day yields. The (co)variance components for the 3 traits were estimated using the regression analyses by Bayesian inference applying an animal model by Gibbs sampling. The contemporary groups were defined as herd-year-month of the test day. In the model, the random effects were additive genetic, permanent environment, and residual. The fixed effects were contemporary group and number of milkings (1 or 2), the linear and quadratic effects of the covariable age of the buffalo at calving, as well as the mean lactation curve of the population, which was modeled by orthogonal Legendre polynomials of fourth order. The random effects for the traits studied were modeled by Legendre polynomials of third and fourth order for additive genetic and permanent environment, respectively, the residual variances were modeled considering 4 residual classes. The heritability estimates for the traits were moderate (from 0.21-0.38), with higher estimates in the intermediate lactation phase. The genetic correlation estimates within and among the traits varied from 0.05 to 0.99. The results indicate that the selection for any trait test day will result in an indirect genetic gain for milk, fat, and protein yield in all periods of the lactation curve. The accuracy associated with estimated breeding values obtained using multi-trait random regression was slightly higher (around 8%) compared with single-trait random regression. This difference may be because to the greater amount of information available per animal. © 2013 American Dairy Science Association.

Estimates of genetic parameters and eigenvector indices for milk production of Holstein cows

The objectives of the present study were to estimate genetic parameters of monthly test-day milk yield (TDMY) of the first lactation of Brazilian Holstein cows using random regression (RR), and to compare the genetic gains for milk production and persistency, derived from RR models, using eigenvector indices and selection indices that did not consider eigenvectors. The data set contained monthly TDMY of 3,543 first lactations of Brazilian Holstein cows calving between 1994 and 2011. The RR model included the fixed effect of the contemporary group (herd-month-year of test days), the covariate calving age (linear and quadratic effects), and a fourth-order regression on Legendre orthogonal polynomials of days in milk (DIM) to model the population-based mean curve. Additive genetic and nongenetic animal effects were fit as RR with 4 classes of residual variance random effect. Eigenvector indices based on the additive genetic RR covariance matrix were used to evaluate the genetic gains of milk yield and persistency compared with the traditional selection index (selection index based on breeding values of milk yield until 305 DIM). The heritability estimates for monthly TDMY ranged from 0.12 ± 0.04 to 0.31 ± 0.04. The estimates of additive genetic and nongenetic animal effects correlation were close to 1 at adjacent monthly TDMY, with a tendency to diminish as the time between DIM classes increased. The first eigenvector was related to the increase of the genetic response of the milk yield and the second eigenvector was related to the increase of the genetic gains of the persistency but it contributed to decrease the genetic gains for total milk yield. Therefore, using this eigenvector to improve persistency will not contribute to change the shape of genetic curve pattern. If the breeding goal is to improve milk production and persistency, complete sequential eigenvector indices (selection indices composite with all eigenvectors) could be used with higher economic values for persistency. However, if the breeding goal is to improve only milk yield, the traditional selection index is indicated. © 2013 American Dairy Science Association.

Genetic parameters for scrotal circumference, breeding soundness examination and sperm defects in young Nellore bulls

A total of 51,161 records of scrotal circumference measurements at 18 mo of age (SCI 8) and 17,648 records of sperm defects and breeding soundness of Nellore bulls (mean age of 22.5 mo), raised under extensive conditions, were analyzed to estimate coefficients of heritability and genetic correlations of morphological semen traits by Bayesian inference. The observed semen traits were classified as minor (MID). major (MAD), and total sperm defects (TD). The animals were classified according to breeding soundness as satisfactory and unsatisfactory potential breeders. The (co)variance components and breeding values were estimated by Gibbs sampling using the GIBBS2F90 program under an animal model that included contemporary group as fixed effect, age of animal as linear covariate, and direct additive genetic effects as random effects. Heritabilities of 0.40 ± 0.02, 0.16 ± 0.02, 0.04 ± 0.01, 0.15 ± 0.01, and 0.10 ± 0.01 were obtained for SCI8, MID, MAD, TD, and breeding soundness, respectively. The SC18 showed a positive and moderate correlation with breeding soundness (0.56 ± 0.04) and a negative and low correlation with MID (-0.23 ± 0.03), MAD (-0.16 ± 0.02), and TD (-0.24 ± 0.02). In conclusion, scrotal circumference showed the best response to selection among the traits studied and was favorably correlated with breeding soundness and sperm morphology in young Nellore bulls. © 2013 American Society of Animal Science. All rights reserved.

Cluster and meta-analyses of genetic parameters for feed intake traits in growing beef cattle

A data set based on 50 studies including feed intake and utilization traits was used to perform a meta-analysis to obtain pooled estimates using the variance between studies of genetic parameters for average daily gain (ADG); residual feed intake (RFI); metabolic body weight (MBW); feed conversion ratio (FCR); and daily dry matter intake (DMI) in beef cattle. The total data set included 128 heritability and 122 genetic correlation estimates published in the literature from 1961 to 2012. The meta-analysis was performed using a random effects model where the restricted maximum likelihood estimator was used to evaluate variances among clusters. Also, a meta-analysis using the method of cluster analysis was used to group the heritability estimates. Two clusters were obtained for each trait by different variables. It was observed, for all traits, that the heterogeneity of variance was significant between clusters and studies for genetic correlation estimates. The pooled estimates, adding the variance between clusters, for direct heritability estimates for ADG, DMI, RFI, MBW and FCR were 0.32 +/- 0.04, 0.39 +/- 0.03, 0.31 +/- 0.02, 0.31 +/- 0.03 and 0.26 +/- 0.03, respectively. Pooled genetic correlation estimates ranged from -0.15 to 0.67 among ADG, DMI, RFI, MBW and FCR. These pooled estimates of genetic parameters could be used to solve genetic prediction equations in populations where data is insufficient for variance component estimation. Cluster analysis is recommended as a statistical procedure to combine results from different studies to account for heterogeneity.

Genetic parameters for body weight in buffaloes (Bubalus bubalis) in Colombia using random regression models

The objective of this research was to estimate (co) variance functions and genetic parameters for body weight in Colombian buffalo populations using random regression models with Legendre polynomials. Data consisted of 34,738 weight records from birth to 900 days of age from 7815 buffaloes. Fixed effects in the model were contemporary group and parity order of the mother. Random effects were direct and maternal additive genetic, as well as animal and maternal permanent environmental effects. A cubic orthogonal Legendre polynomial was used to model the mean curve of the population. Eleven models with first to sixth order polynomials were used to describe additive genetic direct and maternal effects, and animal and maternal permanent environmental effects. The residual was modeled considering five variance classes. The best model included fourth and sixth order polynomials for direct additive genetic and animal permanent environmental effects, respectively, and third-order polynomials for maternal genetic and maternal permanent environmental effects. The direct heritability increased from birth until 120 days of age (0.32 +/- 0.05), decreasing thereafter until one year of age (0.18 +/- 0.04) and increased again, reaching 0.39 +/- 0.09, at the end of the evaluated period. The highest maternal heritability estimates (0.11 +/- 0.05), were obtained for weights around weaning age (weaning age range is between 8 and 9.5 months). Maternal genetic and maternal permanent environmental variances increased from birth until about one year of age, decreasing at later ages. Direct genetic correlations ranged from moderate (0.60 +/- 0.060) to high (0.99 +/- 0.001), maternal genetic correlations showed a similar range (0.41 +/- 0.401 and 0.99 +/- 0.003), and all of them decreased as time between weighings increased. Direct genetic correlations suggested that selecting buffalos for heavier weights at any age would increase weights from birth through 900 days of age. However, higher heritabilities for direct genetic weights effects after 600 days of age suggested that selection for these effects would be more effective if done during this age period. A greater response to selection for maternal ability would be expected if selection used maternal genetic predictions for weights near weaning. (C) 2013 Elsevier B.V. All rights reserved.

Genetic Correlation for Pre-Weaning and Post-Weaning Traits of Mediterranean Buffaloes from Brazil, Estimated By Bayesian Inference

The aim of this study was to estimate genetic, environmental and phenotypic correlation between birth weight (BW) and weight at 205 days age (W205), BW and weight at 365 days age (W365) and W205-W365, using Bayesian inference. The Brazilian Program for Genetic Improvement of Buffaloes provided the data that included 3,883 observations from Mediterranean breed buffaloes. With the purpose to estimate variance and covariance, bivariate analyses were performed using Gibbs sampler that is included in the MTGSAM software. The model for BW, W205 and W365 included additive direct and maternal genetic random effects, maternal environmental random effect and contemporary group as fixed effect. The convergence diagnosis was achieved using Geweke, a method that uses an algorithm implemented in R software through the package Bayesian Output Analysis. The calculated direct genetic correlations were 0.34 (BW-W205), 0.25 (BW-W365) and 0.74 (W205-W365). The environmental correlations were 0.12, 0.11 and 0.72 between BW-W205, BW-W365 and W205-W365, respectively. The phenotypic correlations were low for BW-W205 (0.01) and BW-W365 (0.04), differently than the obtained for W205-W365 with a value of 0.67. The results indicate that BW trait have low genetic, environmental and phenotypic association with the two others traits. The genetic correlation between W205 and W365 was high and suggests that the selection for weight at around 205 days could be beneficial to accelerate the genetic gain.

Genetic Parameters for Growth Traits of Mediterranean Buffaloes from Brazil, Estimated By Bayesian Inference

Quantitative analysis of growth genetic parameters is not available for many breeds of buffaloes making selection and breeding decisions an empirical process that lacks robustness. The objective of this study was to estimate heritability for birth weight (BW), weight at 205 days (W205) and 365 days (W365) of age using Bayesian inference. The Brazilian Program for Genetic Improvement of Buffaloes provided the data. For the traits BW, W205 and W365 of Brazilian Mediterranean buffaloes 5169, 3792 and 3883 observations have been employed for the analysis, respectively. In order to obtain the estimates of variance, univariate analyses were conducted using the Gibbs sampler included in the MTGSAM software. The model for BW, W205 and W365 included additive direct and maternal genetic random effects, random maternal permanent environmental effect and contemporary group that was treated as a fixed effect. The convergence diagnosis was performed employing Geweke, a method that uses an algorithm from the Bayesian Output Analysis package that was implemented using R software environment. The average values for weight traits were 37.6 +/- 4.7 kg for BW, 192.7 +/- 40.3 kg for W205 and 298.6 +/- 67.4 kg for W365. The heritability posterior distributions for direct and maternal effects were symmetric and close to those expected in a normal distribution. Direct heritability estimates obtained using the modes were 0.30 (BW), 0.52 (W205) and 0.54 (W365). The maternal heritability coefficient estimates were 0.31, 0.19 and 0.21 for BW, W205 and W365, respectively. Our data suggests that all growth traits and mainly W205 and W365, have clear potential for yield improvement through direct genetic selection.

A genetic linkage study in Brazil identifies a new locus for persistent developmental stuttering on chromosome 10

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Estimates of genetic parameters for total milk yield over multiple ages in Brazilian Murrah buffaloes using different models

The objective of this study was to estimate variance components and genetic parameters for accumulated 305-day milk yield (MY305) over multiple ages, from 24 to 120 months of age, applying random regression (RRM), repeatability (REP) and multi-trait (MT) models. A total of 4472 lactation records from 1882 buffaloes of the Murrah breed were utilized. The contemporary group (herd-year-calving season) and number of milkings (two levels) were considered as fixed effects in all models. For REP and RRM, additive genetic, permanent environmental and residual effects were included as random effects. MT considered the same random effects as did REP and RRM with the exception of permanent environmental effect. Residual variances were modeled by a step function with 1, 4, and 6 classes. The heritabilities estimated with RRM increased with age, ranging from 0.19 to 0.34, and were slightly higher than that obtained with the REP model. For the MT model, heritability estimates ranged from 0.20 (37 months of age) to 0.32 (94 months of age). The genetic correlation estimates for MY305 obtained by RRM (L23.res4) and MT models were very similar, and varied from 0.77 to 0.99 and from 0.77 to 0.99, respectively. The rank correlation between breeding values for MY305 at different ages predicted by REP, MT, and RRM were high. It seems that a linear and quadratic Legendre polynomial to model the additive genetic and animal permanent environmental effects, respectively, may be sufficient to explain more parsimoniously the changes in MY305 genetic variation with age.