AN ALTERNATIVE FOR MIXED MODEL ANALYSES OF LARGE, MESSY DATA SETS (MTDFREML)

Portable Fortran based programs (MTDFREML) were developed using a derivative-free algorithm to obtain REML estimates of (co)variance components. Computations are based on Henderson\u27s mixed model equations for multiple-trait models with missing observations on some traits and incorporation of relationships among relatives. Many fixed and random factors are allowed with number of levels dependent on computer memory. Data sets with more than 40,000 genetic effects have been analyzed. Options allow solving MME at convergence. Constraints are automatically imposed. Expectations, standard errors of contrasts of solutions for fixed effects and prediction error variances of solutions for random effects can be obtained. Dimensions can be changed to match data with computer capability. A Fortran compiler is necessary. No fee is charged but the University of Waterloo must certify a license has been obtained for sparse matrix subroutines (SPARSPAK) used in the program. As an example, birth weights of 4891 progeny of 389 sires nested within 12 breeds and of 2893 dams nested within 3 breeds of dam were analyzed to estimate components of variance due to sires and dams and to estimate differences among breeds of sires. For MTDFREML the analysis was trivial but for PROC MIXED the analysis was impossible unless dams were dropped from the model

EMPIRICAL ESTIMATES OF POWER FOR BINOMIAL DATA WITH MIXED MODELS

Observations on return to estrus from anestrus postpartum beef cows were used as the basis for a simulation study to develop a method to determine numbers of locations and animals per treatment per location to achieve a specified power of test. Estimates of among location and total variance were obtained by REML from the data set and then used to generate simulated data for the binomial trait. Each combination of several pre-determined factors was replicated 1000 times. Pre-determined factors were number of locations, number of animals per treatment per location, desired detectable difference due to treatment, alpha-probability level and ratio of among location to total variance. Two methods were used to test for treatment differences. In Method 1, simulated data were analyzed using a mixed model with the variance components used for the simulation based on estimates from the postpartum cow data. For Method 2, variance components were re-estimated from each replicate of the simulated data and used in the mixed model equations. The number of significant differences due to treatment was counted for the 1000 replicates. The fraction of replicates with significant differences is an empirical estimate of the power of the test. The comparison of power of test between the two methods indicates Method 2 may be preferable for empirical estimation of power of test

Estimates of parameters between direct and maternal genetic effects for weaning weight and direct genetic effects for carcass traits in crossbred cattle

Estimates of heritabilities and genetic correlations were obtained for weaning weight records of 23,681 crossbred steers and heifers and carcass records from 4,094 crossbred steers using animal models. Carcass traits included hot carcass weight; retail product percentage; fat percentage; bone percentage; ribeye area; adjusted fat thickness; marbling score, Warner- Bratzler shear force and kidney, pelvic and heart fat percentage. Weaning weight was modeled with fixed effects of age of dam, sex, breed combination, and birth year, with calendar birth day as a covariate and random direct and maternal genetic and maternal permanent environmental effects. The models for carcass traits included fixed effects of age of dam, line, and birth year, with covariates for weaning and slaughter ages and random direct and maternal effects. Direct and maternal heritabilities for weaning weight were 0.4 ± 0.02 and 0.19 ± 0.02, respectively. The estimate of direct-maternal genetic correlation for weaning weight was negative (−0.18 ± 0.08). Heritabilities for carcass traits of steers were moderate to high (0.34 to 0.60). Estimates of genetic correlations between direct genetic effects for weaning weight and carcass traits were small except with hot carcass weight (0.70), ribeye area (0.29), and adjusted fat thickness (0.26). The largest estimates of genetic correlations between maternal genetic effects for weaning weight and direct genetic effects for carcass traits were found for hot carcass weight (0.61), retail product percentage (−0.33), fat percentage (0.33), ribeye area (0.29), marbling score (0.28) and adjusted fat thickness (0.25), indicating that maternal effects for weaning weight may be correlated with genotype for propensity to fatten in steers

Estimates of parameters between direct and maternal genetic effects for weaning weight and direct genetic effects for carcass traits in crossbred cattle

Estimates of heritabilities and genetic correlations were obtained for weaning weight records of 23,681 crossbred steers and heifers and carcass records from 4,094 crossbred steers using animal models. Carcass traits included hot carcass weight; retail product percentage; fat percentage; bone percentage; ribeye area; adjusted fat thickness; marbling score, Warner- Bratzler shear force and kidney, pelvic and heart fat percentage. Weaning weight was modeled with fixed effects of age of dam, sex, breed combination, and birth year, with calendar birth day as a covariate and random direct and maternal genetic and maternal permanent environmental effects. The models for carcass traits included fixed effects of age of dam, line, and birth year, with covariates for weaning and slaughter ages and random direct and maternal effects. Direct and maternal heritabilities for weaning weight were 0.4 ± 0.02 and 0.19 ± 0.02, respectively. The estimate of direct-maternal genetic correlation for weaning weight was negative (−0.18 ± 0.08). Heritabilities for carcass traits of steers were moderate to high (0.34 to 0.60). Estimates of genetic correlations between direct genetic effects for weaning weight and carcass traits were small except with hot carcass weight (0.70), ribeye area (0.29), and adjusted fat thickness (0.26). The largest estimates of genetic correlations between maternal genetic effects for weaning weight and direct genetic effects for carcass traits were found for hot carcass weight (0.61), retail product percentage (−0.33), fat percentage (0.33), ribeye area (0.29), marbling score (0.28) and adjusted fat thickness (0.25), indicating that maternal effects for weaning weight may be correlated with genotype for propensity to fatten in steers

A Small Peptide Modeled after the NRAGE Repeat Domain Inhibits XIAP-TAB1-TAK1 Signaling for NF-κB Activation and Apoptosis in P19 Cells

In normal growth and development, apoptosis is necessary to shape the central nervous system and to eliminate excess neurons which are not required for innervation. In some diseases, however, apoptosis can be either overactive as in some neurodegenerative disorders or severely attenuated as in the spread of certain cancers. Bone morphogenetic proteins (BMPs) transmit signals for regulating cell growth, differentiation, and apoptosis. Responding to BMP receptors stimulated from BMP ligands, neurotrophin receptor-mediated MAGE homolog (NRAGE) binds and functions with the XIAP-TAK1-TAB1 complex to activate p38MAPK and induces apoptosis in cortical neural progenitors. NRAGE contains a unique repeat domain that is only found in human, mouse, and rat homologs that we theorize is pivotal in its BMP MAPK role. Previously, we showed that deletion of the repeat domain inhibits apoptosis, p38MAPK phosphorylation, and caspase-3 cleavage in P19 neural progenitor cells. We also showed that the XIAP-TAB1-TAK1 complex is dependent on NRAGE for IKK-α/β phosphorylation and NF-κB activation. XIAP is a major inhibitor of caspases, the main executioners of apoptosis. Although it has been shown previously that NRAGE binds to the RING domain of XIAP, it has not been determined which NRAGE domain binds to XIAP. Here, we used fluorescence resonance energy transfer (FRET) to determine that there is a strong likelihood of a direct interaction between NRAGE and XIAP occurring at NRAGE's unique repeat domain which we also attribute to be the domain responsible for downstream signaling of NF-κB and activating IKK subunits. From these results, we designed a small peptide modeled after the NRAGE repeat domain which we have determined inhibits NF-κB activation and apoptosis in P19 cells. These intriguing results illustrate that the paradigm of the NRAGE repeat domain may hold promising therapeutic strategies in developing pharmaceutical solutions for combating harmful diseases involving excessive downstream BMP signaling, including apoptosis

Genetic Parameters for Sex-Specific Traits in Beef Cattle

Data from 3,593 beef heifers and 4,079 of their steer paternal half-sibs were used to estimate genetic parameters of and among female growth and reproductive traits and male carcass traits. Estimates of heritability for adjusted 205-d weight, adjusted 365-d weight, age at puberty, calving rate, and calving difficulty measured on females were .16, .38, .47, .19, and .18, respectively; estimates for calving rate and calving difficulty were expressed on a normal scale. Estimates of heritability for hot carcass weight; retail product percentage; fat percentage; bone percentage; rib eye area; kidney, pelvic, and heart fat percentage; adjusted fat thickness; marbling score; Warner-Bratzler shear force; taste panel tenderness; taste panel juiciness; and taste panel flavor that were measured on steers at an average age of 447 d (weaning age = 185, days on feed = 262) were .50, .66, .58, .54, .61, .48, .66, .71, .26, .31, .00, and .04, respectively. Genetic correlations were positive for heifer weights with hot carcass weight, fat percentage, rib eye area, adjusted fat thickness, marbling score, and Warner-Bratzler shear force, and they were negative with retail product percentage and kidney, pelvic, and heart fat percentage of steers. Age at puberty was genetically correlated with taste panel tenderness but not with other carcass traits. Calving rate had positive genetic correlations with fat percentage, rib eye area, adjusted fat thickness, and taste panel flavor, and it had negative genetic correlations with retail product percentage; bone percentage; and kidney, pelvic, and heart fat percentage. Calving difficulty had favorable genetic correlations with hot carcass weight, retail product percentage, and measures of carcass tenderness, but it was unfavorably correlated with traits that involve carcass fatness. These results indicate that selection for some traits expressed in one sex of beef cattle may result in undesirable responses in traits expressed in the opposite sex