"Conversion" of epistatic into additive genetic variance in finite populations and possible impact on long-term selection response.

The role of epistasis in understanding the genetic architecture and variation of quantitative traits and its role, if any, in artificial selection and livestock improvement more generally has a long and sometimes controversial history. Its presence has been clearly demonstrated in, for example, laboratory experiments, but the amount of variation it contributes is likely to be small in outbred populations. In a finite population, although additive x additive epistatic variance is lost by genetic drift, it also contributes by conversion to additive variance through drift sampling and therefore has a potential indirect role in medium and long-term selection response, with superficial similarity to and hard to distinguish from mutation. Whilst predictions of response require knowledge of genetic parameters, an infinitesimal model provides some analytic results. Otherwise there is little quantitative information relevant to animal populations on which to judge this potential role of epistasis and reach firm conclusions.

Expected influence of linkage disequilibrium on genetic variance caused by dominance and epistasis on quantitative traits.

Linkage disequilibrium (LD) influences the genetic variation in a quantitative trait contributed by two or more loci, with positive LD increasing the variance. The magnitude of LD also affects the relative magnitude of dominance and epistatic variation. We quantify the extent of the non-additive variance expected within populations, deriving analytical expressions for simple models and using numerical simulation in finite population more generally. As LD generates non-independence among loci, a simple partition into additive, dominance and epistatic components is not possible, so we merely distinguish between additive and non-additive components based on comparing covariances among close relatives, such as full sibs, half sibs and offspring-parent. As tight linkage is needed to yield substantial LD in outbred populations, we ignore recombination in the generation used to estimate components and it is analogous to a multi-allelic model. The expected magnitude of the non-additive variance is generally increased but not greatly so by the LD in outbred populations. Thus, as found in previous studies for unlinked loci, independent of the type and strength of gene interaction, the epistatic variance contributes little to the total.

Variation in actual relationship among descendants of inbred individuals.

In previous analyses, the variation in actual, or realized, relationship has been derived as a function of map length of chromosomes and type of relationship, the variation being greater the shorter the total chromosome length and the coefficient of variation being greater the more distant the relationship. Here, the results are extended to allow for the relatives' ancestor being inbred. Inbreeding of a parent reduces variation in actual relationship among its offspring, by an amount that depends on the inbreeding level and the type of mating that led to that level. For descendants of full-sibs, the variation is reduced in later generations, but for descendants of half-sibs, it is increased.

Genome-wide association analysis and genetic architecture of egg weight and egg uniformity in layer chickens.

The pioneering work by Professor Soller et al., among others, on the use of genetic markers to analyze quantitative traits has provided opportunities to discover their genetic architecture in livestock by identifying quantitative trait loci (QTL). The recent availability of high-density single nucleotide polymorphism (SNP) panels has advanced such studies by capitalizing on population-wide linkage disequilibrium at positions across the genome. In this study, genomic prediction model Bayes-B was used to identify genomic regions associated with the mean and standard deviation of egg weight at three ages in a commercial brown egg layer line. A total of 24,425 segregating SNPs were evaluated simultaneously using over 2900 genotyped individuals or families. The corresponding phenotypic records were represented as individual measurements or family means from full-sib progeny. A novel approach using the posterior distribution of window variances from the Monte Carlo Markov Chain samples was used to describe genetic architecture and to make statistical inferences about regions with the largest effects. A QTL region on chromosome 4 was found to explain a large proportion of the genetic variance for the mean (30%) and standard deviation (up to 16%) of the weight of eggs laid at specific ages. Additional regions with smaller effects on chromosomes 2, 5, 6, 8, 20, 23, 28 and Z showed suggestive associations with mean egg weight and a region on chromosome 13 with the standard deviation of egg weight at 26-28 weeks of age. The genetic architecture of the analyzed traits was characterized by a limited number of genes or genomic regions with large effects and many regions with small polygenic effects. The region on chromosome 4 can be used to improve both the mean and standard deviation of egg weight by marker-assisted selection.

Twenty-five years of selection for improved leg health in purebred broiler lines and underlying genetic parameters.

Leg health is an important component of broiler welfare and the economics of broiler production. This study presents the development of leg health in 3 purebred commercial broiler lines during 25 yr of selection and investigates the genetic background of leg health traits in current populations of these lines. The leg health traits were deformities of the long bones (LD) and crooked toes (CT), recorded since 1985, and tibial dyschondroplasia (TD) and hock burn (HB), recorded since 1990. The prevalence of CT and HB decreased mainly in the first decade (range among lines -1.2 to -2.3% and -1.3 to -1.5% per year, respectively), after which it stabilized at low levels. The prevalence of LD and TD decreased by -0.6 to -0.9% and -0.4 to -1.2% per year, respectively. Genetic parameters were estimated using data from 4 recent generations. The BW ranged from 2.0 to 2.4 kg at 5 wk of age; the prevalences of LD, CT, TD, and HB from 8.6 to 12.9%, 0.6 to 2.6%, 4.6 to 8.0%, and 4.0 to 12.2%, respectively. Estimates of heritability were 0.04 to 0.07 for LD, 0.01 to 0.10 for CT, 0.10 to 0.27 for TD, and 0.06 to 0.09 for HB (all SE ≤0.01). Estimates of the genetic correlations between LD and CT were 0.11 to 0.43 (all SE ≤0.09), between these traits and HB were negligible, and of TD with LD, CT, and HB were -0.26 to 0.16 (all SE ≤0.11). Estimates of genetic correlations between the leg health traits and BW were lowly to moderately unfavorable, ranging from 0.09 to 0.37 (all SE ≤0.06). The differences between the lines suggest that strategies for simultaneous improvement of all traits tailored for each line individually have been effective. This research demonstrates the long-term effectiveness of selection for improving leg health in broilers and highlights that, despite somewhat unfavorable genetic correlations with BW, these traits can be improved simultaneously in a balanced breeding program.

Genetic parameters of foot-pad dermatitis and body weight in purebred broiler lines in 2 contrasting environments.

The aims of this study were to investigate the genetic background of foot-pad dermatitis (FPD) in 4 different broiler lines reared in 2 contrasting environments (pedigree or sib-test) and to evaluate the performance of simultaneous genetic selection for improved FPD and BW. Data were available for 4 generations from 4 broiler lines, bred with varying intensities of selection for growth. The average BW ranged from 1.7 to 2.4 kg at 5 wk of age. In the pedigree environment, the prevalence of FPD ranged from 14 to 37%, with 3 to 9% being severely affected; in the sib-test environment, these values were correspondingly 45 to 79% and 35 to 70%. Both traits showed re-ranking of the 4 lines in terms of phenotype across the 2 environments, indicating the existence of a genotype-by-environment interaction. In both environments, females showed higher prevalences of FPD than males. In line with their higher prevalence, heritabilities of FPD in the sib-test environment ranged from 0.22 to 0.32, compared with 0.18 to 0.24 for FPD in the pedigree environment (all SE ≤0.02). Estimates of the genetic correlation between FPD in the pedigree and in the sib-test environments were high (0.78-0.82), which suggests that selection against FPD in a highly biosecure environment can improve the genetic merit for birds reared under commercial conditions. Estimates of the genetic associations between FPD and BW were small and varied in sign. Predicted responses to selection showed a yearly reduction in average score of -3.4 to -7.5% for FPD in the pedigree environment and -0.5 to -6.6% for FPD in the sib-test environment, while maintaining improvement of BW of 2.6 to 3.2% and 2.6 to 3.8% of the average BW per year, respectively. This research indicates that balanced genetic selection for both BW and FPD in contrasting environments is an effective strategy to reduce the genetic disposition to develop FPD in broilers.

Genetic parameters of egg defects and egg quality in layer chickens.

Genetic parameters were estimated for egg defects, egg production, and egg quality traits. Eggs from 11,738 purebred brown-egg laying hens were classified as salable or as having one of the following defects: bloody, broken, calcium deposit, dirty, double yolk, misshapen, pee-wee, shell-less, and soft shelled. Egg quality included albumen height, egg weight, yolk weight, and puncture score. Body weight, age at sexual maturity, and egg production were also recorded. Heritability estimates of liability to defects using a threshold animal model were less than 0.1 for bloody and dirty; between 0.1 and 0.2 for pee-wee, broken, misshapen, soft shelled, and shell-less; and above 0.2 for calcium deposit and double yolk. Quality and production traits were more heritable, with estimates ranging from 0.29 (puncture score) to 0.74 (egg weight). High-producing hens had a lower frequency of egg defects. High egg weight and BW were associated with an increased frequency of double yolks, and to a lesser extent, with more shell quality defects. Estimates of genetic correlations among defect traits that were related to shell quality were positive and moderate to strong (0.24-0.73), suggesting that these could be grouped into one category or selection could be based on the trait with the highest heritability or that is easiest to measure. Selection against defective eggs would be more efficient by including egg defect traits in the selection criterion, along with egg production rate of salable eggs and egg quality traits.

Variation in actual relationship as a consequence of Mendelian sampling and linkage.

Although the expected relationship or proportion of genome shared by pairs of relatives can be obtained from their pedigrees, the actual quantities deviate as a consequence of Mendelian sampling and depend on the number of chromosomes and map length. Formulae have been published previously for the variance of actual relationship for a number of specific types of relatives but no general formula for non-inbred individuals is available. We provide here a unified framework that enables the variances for distant relatives to be easily computed, showing, for example, how the variance of sharing for great grandparent-great grandchild, great uncle-great nephew, half uncle-nephew and first cousins differ, even though they have the same expected relationship. Results are extended in order to include differences in map length between sexes, no recombination in males and sex linkage. We derive the magnitude of skew in the proportion shared, showing the skew becomes increasingly large the more distant the relationship. The results obtained for variation in actual relationship apply directly to the variation in actual inbreeding as both are functions of genomic coancestry, and we show how to partition the variation in actual inbreeding between and within families. Although the variance of actual relationship falls as individuals become more distant, its coefficient of variation rises, and so, exacerbated by the skewness, it becomes increasingly difficult to distinguish different pedigree relationships from the actual fraction of the genome shared.

Can more be learned from selection experiments of value in animal breeding programmes? Or is it time for an obituary?

Selection experiments in laboratory animals and livestock have provided a wealth of information on genetic parameters of quantitative traits and on the effectiveness of selection in the short and long term on both directly selected and correlated traits. They have stimulated developments in theory and tests of it, and extreme selected lines continue to be source material for biological study. Some of the main questions and findings are briefly reviewed. Yet much of successful animal breeding practice has been based essentially on statistical methods, assuming where necessary the infinitesimal model, and new developments such as genomic selection are similarly not based on selection experiments. Information on the genetic architecture of quantitative traits is provided by selection experiments, but new methods for deeper studies of the biology are available. I discuss the future role for selection experiments in view of changes in funding streams and technology and conclude that there is little case for starting new experiments, but retention of existing long-term lines is desirable and DNA should be collected from all lines on a continuing basis.

Genetic heterogeneity of variance in production traits of laying hens.

Genetic parameters for mean and for environmental variation in egg weight, body weight, age at first egg, and egg production were estimated in eight layer lines. The data were recorded from years 1999-2007, with on average of 6500 birds per line. An iterative mean-variance REML method was applied with a sire-plus-dam model for mean, a sire model for variance, and a fixed effect of hatch within generation for both mean and variance. The estimated heritability of environmental variation averaged about 5% for body weight, 3% for egg weight, and 11% for age at first egg, but was inconsistent among the lines for egg production (0-15%). Correlations between means and variances were slightly positive for body weight, egg weight, and age at first egg; and strongly negative for egg production. Age at first egg had the highest heritability of environmental variation; and favourable correlations with egg production and with variation in other production traits indicate that reducing variation in this trait may have potential benefits for the breeding industry.

Contributions of genetic and environmental components to changes in phenotypic variation between generations.

We evaluate the extent to which changes in phenotypic variation among generations of populations kept in the same environment are due to changes in genetic (V(A)) or in environmental (V(E)) variance. Data were available on body weight of adult poultry on a total of 89186 birds (mainly females) from six generations of each of seven lines of layers. There was substantial heterogeneity of variation between generations, shown to be in both V(A) and V(E) components. Based on the Akaike information criterion (AIC), the best fit was with both components changing, and a better fit was obtained if V(A)/V(E) (i.e. heritability) or V(E), rather than V(A), was assumed constant. In analyses of quantitative genetic data spanning environmental groups, attention should be paid to whether and how the variance components change among groups before undertaking detailed variance partition that may be sensitive to such changes.

Inheritance of hatchability in broiler chickens and its relationship to egg quality traits.

The first objective of this study on broiler breeders was to investigate the genetic basis of variability in hatchability over age using a longitudinal model. Weekly percentage hatch of fertile and hatch of set eggs were available for 23,250 dams mated to 3,106 sires of the same age between the 28th and 54th week of life. Hatch of set was very highly correlated with fertility and showed a similar pattern through lay. There was a genetic contribution of the dam but not the sire to hatch of fertile; its heritability was about 6% from peak lay onward but lower earlier. The second objective was to investigate the relationship between hatchability and internal and external egg quality traits measured at 48 wk of age. These traits, specific gravity, weight loss, egg weight, and Haugh units, had moderate to high heritabilities, 0.53, 0.38, 0.65, and 0.38, respectively. Parameters of the genetic trend in weekly hatchability (mean and persistency) were significantly correlated with these egg quality traits, suggesting that in a bulk mating situation in which individual recording of hatchability is not possible, these quality traits could provide some indication on the trend in flock hatchability.

Genetic variability in residual variation of body weight and conformation scores in broiler chickens.

The aim of the study was to estimate genetic variance in residual variation of BW and body conformation scores of 34-d-old male and female broiler chickens. The data set included performance records of 52,349 female and 49,001 male birds. Two models were used: an iterative mean-variance restricted maximum likelihood sire plus dam model and a Bayesian sire plus dam model, in each case with heterogeneity in residual variances across sire families. They gave similar results. Estimates of heritability for BW in females and males were, respectively, 0.25 and 0.21, and for conformation score were 0.24 and 0.15, and genetic correlations for the same trait between sexes were high. Estimates of genetic correlations between means and variances were positive for both sexes and both traits. Estimates of the heritability of residual variation were low, between 0.023 and 0.038 for both traits, but genetic CV were substantial (between 0.25 and 0.40), indicating the possibility of improving uniformity of BW and conformation by means of selection.

Introduction. Evolutionary dynamics of wild populations: the use of long-term pedigree data.

Studies of populations in the wild can provide unique insights into the forces driving evolutionary dynamics. This themed issue of Proc. R. Soc. B focuses on new developments in long-term analyses of animal populations where pedigree information has been collected. These address fundamental questions in evolutionary biology concerning the genetic basis of phenotypic diversity, patterns of natural and sexual selection, the occurrence of inbreeding and inbreeding depression, and speciation. Contributions include the analysis of evolutionary responses to climate change, exploration of the genetic basis of senescence, the exploitation of advances in molecular genetic technology, and reviews of developments in quantitative genetic methodology. We discuss here common themes, specific problems and pointers for future research.

Prediction of breeding values and selection responses with genetic heterogeneity of environmental variance.

There is empirical evidence that genotypes differ not only in mean, but also in environmental variance of the traits they affect. Genetic heterogeneity of environmental variance may indicate genetic differences in environmental sensitivity. The aim of this study was to develop a general framework for prediction of breeding values and selection responses in mean and environmental variance with genetic heterogeneity of environmental variance. Both means and environmental variances were treated as heritable traits. Breeding values and selection responses were predicted with little bias using linear, quadratic, and cubic regression on individual phenotype or using linear regression on the mean and within-family variance of a group of relatives. A measure of heritability was proposed for environmental variance to standardize results in the literature and to facilitate comparisons to "conventional" traits. Genetic heterogeneity of environmental variance can be considered as a trait with a low heritability. Although a large amount of information is necessary to accurately estimate breeding values for environmental variance, response in environmental variance can be substantial, even with mass selection. The methods developed allow use of the well-known selection index framework to evaluate breeding strategies and effects of natural selection that simultaneously change the mean and the variance.

Enhanced channelling of sulphate through a rapidly exchangeable sulphate pool in response to stimulated glycosaminoglycan synthesis in pancreatic epithelial cells.

The ability of cells to decorate glycosaminoglycans (GAGs) with sulphate in highly specific patterns is important to extracellular matrix biogenesis and placing appropriate glycosulphated ligands on the cell surface. We have examined sulphate metabolism in two pancreatic duct epithelial cell lines - PANC-1 and CFPAC-1 (derived from a cystic fibrosis patient) with a view to understanding how pancreatic cells utilise intracellular sulphate. [35S]Sulphate uptake was rapid and reached near steady state levels within 10 min. However, the intracellular specific activity of [35S]sulphate for PANC-1 and CFPAC-1 reached only 35 and 10%, respectively, of the medium specific activity at 10 min. Therefore, sulphate appears to reside within two compartments; a rapidly exchangeable sulphate pool (RESP) and a slowly exchangeable sulphate pool (SESP). Reducing chloride in the medium, increased the specific activity of [35S]sulphate within cells and increased the size of the inorganic sulphate pool, suggesting that the RESP was enlarged. Sulphate pools were not different in size between the two cell lines in physiological NaCl. Increasing the size of the sulphate pool had no effect on [35S]sulphate:[3H]glucosamine ratios incorporated into glycosaminoglycans (GAGs); however, stimulating the synthesis of GAGs with 4-methylumbelliferyl-beta-d-xyloside, stably elevated [35S]:[3H] ratios. This was due to higher [35S]sulphate incorporation. [35S]Cysteine contributed less than 0.1% of the cells' sulphate requirements. We conclude that in the face of elevated demand for sulphate, pancreatic cells appear to channel a greater proportion through the RESP.

Water permeability of asymmetric planar lipid bilayers: leaflets of different composition offer independent and additive resistances to permeation.

To understand how plasma membranes may limit water flux, we have modeled the apical membrane of MDCK type 1 cells. Previous experiments demonstrated that liposomes designed to mimic the inner and outer leaflet of this membrane exhibited 18-fold lower water permeation for outer leaflet lipids than inner leaflet lipids (Hill, W.G., and M.L. Zeidel. 2000. J. Biol. Chem. 275:30176-30185), confirming that the outer leaflet is the primary barrier to permeation. If leaflets in a bilayer resist permeation independently, the following equation estimates single leaflet permeabilities: 1/P(AB) = 1/P(A) + 1/P(B) (Eq. l), where P(AB) is the permeability of a bilayer composed of leaflets A and B, P(A) is the permeability of leaflet A, and P(B) is the permeability of leaflet B. Using for the MDCK leaflet-specific liposomes gives an estimated value for the osmotic water permeability (P(f)) of 4.6 x 10(-4) cm/s (at 25 degrees C) that correlated well with experimentally measured values in intact cells. We have now constructed both symmetric and asymmetric planar lipid bilayers that model the MDCK apical membrane. Water permeability across these bilayers was monitored in the immediate membrane vicinity using a Na+-sensitive scanning microelectrode and an osmotic gradient induced by addition of urea. The near-membrane concentration distribution of solute was used to calculate the velocity of water flow (Pohl, P., S.M. Saparov, and Y.N. Antonenko. 1997. Biophys. J. 72:1711-1718). At 36 degrees C, P(f) was 3.44 +/- 0.35 x 10(-3) cm/s for symmetrical inner leaflet membranes and 3.40 +/- 0.34 x 10(-4) cm/s for symmetrical exofacial membranes. From, the estimated permeability of an asymmetric membrane is 6.2 x 10(-4) cm/s. Water permeability measured for the asymmetric planar bilayer was 6.7 +/- 0.7 x 10(-4) cm/s, which is within 10% of the calculated value. Direct experimental measurement of P(f) for an asymmetric planar membrane confirms that leaflets in a bilayer offer independent and additive resistances to water permeation and validates the use of.

Role of leaflet asymmetry in the permeability of model biological membranes to protons, solutes, and gases.

Bilayer asymmetry in the apical membrane may be important to the barrier function exhibited by epithelia in the stomach, kidney, and bladder. Previously, we showed that reduced fluidity of a single bilayer leaflet reduced water permeability of the bilayer, and in this study we examine the effect of bilayer asymmetry on permeation of nonelectrolytes, gases, and protons. Bilayer asymmetry was induced in dipalmitoylphosphatidylcholine liposomes by rigidifying the outer leaflet with the rare earth metal, praseodymium (Pr3+). Rigidification was demonstrated by fluorescence anisotropy over a range of temperatures from 24 to 50 degrees C. Pr3+-treatment reduced membrane fluidity at temperatures above 40 degrees C (the phase-transition temperature). Increased fluidity exhibited by dipalmitoylphosphatidylcholine liposomes at 40 degrees C occurred at temperatures 1-3 degrees C higher in Pr3+-treated liposomes, and for both control and Pr3+-treated liposomes permeability coefficients were approximately two orders of magnitude higher at 48 degrees than at 24 degrees C. Reduced fluidity of one leaflet correlated with significantly reduced permeabilities to urea, glycerol, formamide, acetamide, and NH3. Proton permeability of dipalmitoylphosphatidylcholine liposomes was only fourfold higher at 48 degrees than at 24 degrees C, indicating a weak dependence on membrane fluidity, and this increase was abolished by Pr3+. CO2 permeability was unaffected by temperature. We conclude: (a) that decreasing membrane fluidity in a single leaflet is sufficient to reduce overall membrane permeability to solutes and NH3, suggesting that leaflets in a bilayer offer independent resistances to permeation, (b) bilayer asymmetry is a mechanism by which barrier epithelia can reduce permeability, and (c) CO(2) permeation through membranes occurs by a mechanism that is not dependent on fluidity.

A note on effective population size with overlapping generations.

A simple derivation is given for a formula obtained previously for the effective size of random-mating populations with overlapping generations. The effective population size is the same as that for a population with discrete generations having the same variance of lifetime family size and the same number of individuals entering the population per generation.