Genetic heterogeneity of residual variance - estimation of variance components using double hierarchical generalized linear models

Background

The sensitivity to microenvironmental changes varies among animals and may be under genetic control. It is essential to take this element into account when aiming at breeding robust farm animals. Here, linear mixed models with genetic effects in the residual variance part of the model can be used. Such models have previously been fitted using EM and MCMC algorithms.

Results

We propose the use of double hierarchical generalized linear models (DHGLM), where the squared residuals are assumed to be gamma distributed and the residual variance is fitted using a generalized linear model. The algorithm iterates between two sets of mixed model equations, one on the level of observations and one on the level of variances. The method was validated using simulations and also by re-analyzing a data set on pig litter size that was previously analyzed using a Bayesian approach. The pig litter size data contained 10,060 records from 4,149 sows. The DHGLM was implemented using the ASReml software and the algorithm converged within three minutes on a Linux server. The estimates were similar to those previously obtained using Bayesian methodology, especially the variance components in the residual variance part of the model.

Conclusions

We have shown that variance components in the residual variance part of a linear mixed model can be estimated using a DHGLM approach. The method enables analyses of animal models with large numbers of observations. An important future development of the DHGLM methodology is to include the genetic correlation between the random effects in the mean and residual variance parts of the model as a parameter of the DHGLM.     

Principal component and factor analytic models in international sire evaluation

Background

Interbull is a non-profit organization that provides internationally comparable breeding values for globalized dairy cattle breeding programmes. Due to different trait definitions and models for genetic evaluation between countries, each biological trait is treated as a different trait in each of the participating countries. This yields a genetic covariance matrix of dimension equal to the number of countries which typically involves high genetic correlations between countries. This gives rise to several problems such as over-parameterized models and increased sampling variances, if genetic (co)variance matrices are considered to be unstructured.

Methods

Principal component (PC) and factor analytic (FA) models allow highly parsimonious representations of the (co)variance matrix compared to the standard multi-trait model and have, therefore, attracted considerable interest for their potential to ease the burden of the estimation process for multiple-trait across country evaluation (MACE). This study evaluated the utility of PC and FA models to estimate variance components and to predict breeding values for MACE for protein yield. This was tested using a dataset comprising Holstein bull evaluations obtained in 2007 from 25 countries.

Results

In total, 19 principal components or nine factors were needed to explain the genetic variation in the test dataset. Estimates of the genetic parameters under the optimal fit were almost identical for the two approaches. Furthermore, the results were in a good agreement with those obtained from the full rank model and with those provided by Interbull. The estimation time was shortest for models fitting the optimal number of parameters and prolonged when under- or over-parameterized models were applied. Correlations between estimated breeding values (EBV) from the PC19 and PC25 were unity. With few exceptions, correlations between EBV obtained using FA and PC approaches under the optimal fit were ≥ 0.99. For both approaches, EBV correlations decreased when the optimal model and models fitting too few parameters were compared.

Conclusions

Genetic parameters from the PC and FA approaches were very similar when the optimal number of principal components or factors was fitted. Over-fitting increased estimation time and standard errors of the estimates but did not affect the estimates of genetic correlations or the predictions of breeding values, whereas fitting too few parameters affected bull rankings in different countries.     

Protocol for Birmingham Atrial Fibrillation Treatment of the Aged study (BAFTA): a randomised controlled trial of warfarin versus aspirin for stroke prevention in the management of atrial fibrillation in an elderly primary care population [ISRCTN89345269]

Background

Statins effectively lower blood cholesterol and the risk of cardiovascular death. Immunomodulatory actions, independent of their lipid-lowering effect, have also been ascribed to these compounds. Since macrophages participate in several vascular pathologies, we examined the effect of statin treatment on the survival and differentiation of primary human monocytes.

Methods

Peripheral blood mononuclear cells (PBMCs) from healthy individuals were cultured in the presence or absence of mevastatin. Apoptosis was monitored by annexin V / PI staining and flow cytometry. In parallel experiments, cultures were stimulated with LPS in the presence or absence of mevastatin and the release of IL-1β and IL-1Ra was measured by ELISA.

Results

Among PBMCs, mevastatin-treated monocytes were particularly susceptible to apoptosis, which occurred at doses >1 microM and was already maximal at 5 microM. However, even at the highest mevastatin dose used (10 microM), apoptosis occurred only after 24 h of culture, possibly reflecting a requirement for cell commitment to differentiation. After 72 h of treatment the vast majority (>50%) of monocytes were undergoing apoptosis. Stimulation with LPS revealed that mevastatin-treated monocytes retained the high IL-1β output characteristic of undifferentiated cells; conversely, IL-1Ra release was inhibited. Concurrent treatment with mevalonolactone prevented the induction of apoptosis and suppressed both IL-1β and IL-1Ra release in response to LPS, suggesting a rate-limiting role for HMG-CoA reductase in monocyte differentiation.

Conclusions

Our findings indicate that statins arrest the functional differentiation of monocytes into macrophages and steer these cells into apoptosis, suggesting a novel mechanism for the vasculoprotective properties of HMG-CoA reductase inhibitors.     

Do orthologous gene phylogenies really support tree-thinking?

Background  

Since Darwin's Origin of Species, reconstructing the Tree of Life has been a goal of evolutionists, and tree-thinking has become a major concept of evolutionary biology. Practically, building the Tree of Life has proven to be tedious. Too few morphological characters are useful for conducting conclusive phylogenetic analyses at the highest taxonomic level. Consequently, molecular sequences (genes, proteins, and genomes) likely constitute the only useful characters for constructing a phylogeny of all life. For this reason, tree-makers expect a lot from gene comparisons. The simultaneous study of the largest number of molecular markers possible is sometimes considered to be one of the best solutions in reconstructing the genealogy of organisms. This conclusion is a direct consequence of tree-thinking: if gene inheritance conforms to a tree-like model of evolution, sampling more of these molecules will provide enough phylogenetic signal to build the Tree of Life. The selection of congruent markers is thus a fundamental step in simultaneous analysis of many genes.     

Ouabain-insensitive salt and water movements in duck red cells. II. The role of chloride in the volume response

This paper describes the effect of external chloride on the typical swelling response induced in duck red cells by hypertonicity or norepinephrine. Lowering chloride inhibits swelling and produces concomitant changes in net movements of sodium and potassium in ouabain-treated cells, which resemble the effect of lowering external sodium or potassium. Inhibition is the same whether chloride is replaced with gluconate or with an osmotic equivalent of sucrose. Since changes in external chloride also cause predictable changes in cell chloride, pH, and water, these variables were systematically investigated by varying external pH along with chloride. Lowering pH to 6.60 does not abolish the response if external chloride levels are normal, although the cells are initially swollen due to the increased acidity. Cells deliberately preswollen in hypotonic solutions with appropriate ionic composition can also respond to norepinephrine by further swelling. These results rule out initial values of cell water, chloride, and pH as significant variables affecting the response. Initial values of the chloride equilibrium potential do have marked effect on the direction and rate of net water movement. If chloride is lowered by replacement with the permeant anion, acetate, E(Cl) is unchanged and a normal response to norepinephrine, which is inhibited by furosemide, is observed. Increasing internal sodium by the nystatin technique also inhibits the response. A theory is developed which depicts that the cotransport carrier proposed in the previous paper (W.F. Schmidt and T.J. McManus. 1977b. J. Gen. Physiol. 70:81-97) moves in response to the net electrochemical potential difference driving sodium and potassium across the membrane. Predictions of this theory fit the data for both cations and anions.     

Effects of context on judgements of odor intensities in humans

This study evaluated whether the intensity of previously smelled odors could unintentionally influence the subsequent judgement of odor intensity. The predicted context effect was based on the adaptation- level theory. Before and 25 min after either WEAK or STRONG biasing odor concentrations, 51 subjects were required to rate the intensity of 10 different odor concentrations of California Orange Oil. After the WEAK bias, subjects judged the odor intensity as being stronger than they did after the STRONG bias. Thus the intensity of odors smelled 25 min earlier can unintentionally influence subsequent odor intensity judgement. The findings are discussed in the light of two alternative explanations, namely, a central implicit memory process and a stimulus- level-based change at the peripheral level.      

Restriction-map variation with the yellow-achaete-scute region in five populations of Drosophila melanogaster

It has been proposed that the degree of recombination for a genomic region will affect the level of both nucleotide heterozygosity and the density of transposable elements. Both features of genomic diversity have been examined in a number of recent reports for regions undergoing relatively normal levels of recombination in Drosophila melanogaster. In this study the genomic variation associated with yellow-achaete- scute loci located at the tip of the X chromosome is examined by six- cutter restriction mapping. In this region, as usual for regions adjacent to telomeres, crossing-over is dramatically reduced, and published studies of visible mutants indicate extremely little restriction-map variation. Eight six-cutter restriction endonucleases were used to locate sequence variation in 14- and 16.5-kb regions in 109 lines sampled from North America, Africa, and Europe. The overall level of heterozygosity is estimated as 0.29%. Nine large insertions, all presumed to be transposable elements, were observed. Base-pair heterozygosity appears to be reduced compared with regions having normal levels of recombination. The estimated heterozygosity is much higher than reported in earlier studies of restriction-map variation among visible mutations in the complex. The incidence of large insertions is not elevated compared with that in other regions of the genome. This suggests that asymmetric synapsis and exchange is not an important mechanism for the elimination of transposable elements.      

Fuzzy classification of phantom parent groups in an animal model

Background

Genetic evaluation models often include genetic groups to account for unequal genetic level of animals with unknown parentage. The definition of phantom parent groups usually includes a time component (e.g. years). Combining several time periods to ensure sufficiently large groups may create problems since all phantom parents in a group are considered contemporaries.

Methods

To avoid the downside of such distinct classification, a fuzzy logic approach is suggested. A phantom parent can be assigned to several genetic groups, with proportions between zero and one that sum to one. Rules were presented for assigning coefficients to the inverse of the relationship matrix for fuzzy-classified genetic groups. This approach was illustrated with simulated data from ten generations of mass selection. Observations and pedigree records were randomly deleted. Phantom parent groups were defined on the basis of gender and generation number. In one scenario, uncertainty about generation of birth was simulated for some animals with unknown parents. In the distinct classification, one of the two possible generations of birth was randomly chosen to assign phantom parents to genetic groups for animals with simulated uncertainty, whereas the phantom parents were assigned to both possible genetic groups in the fuzzy classification.

Results

The empirical prediction error variance (PEV) was somewhat lower for fuzzy-classified genetic groups. The ranking of animals with unknown parents was more correct and less variable across replicates in comparison with distinct genetic groups. In another scenario, each phantom parent was assigned to three groups, one pertaining to its gender, and two pertaining to the first and last generation, with proportion depending on the (true) generation of birth. Due to the lower number of groups, the empirical PEV of breeding values was smaller when genetic groups were fuzzy-classified.

Conclusion

Fuzzy-classification provides the potential to describe the genetic level of unknown parents in a more parsimonious and structured manner, and thereby increases the precision of predicted breeding values.