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The importance of variance modelling is now widely known for the analysis of microarray data. In particular the power and accuracy of statistical tests for differential gene expressions are highly dependent on variance modelling. The aim of this paper is to use a structural model on the variances, which includes a condition effect and a random gene effect, and to propose a simple estimation procedure for these parameters by working on the empirical variances. The proposed variance model was compared with various methods on both real and simulated data. It proved to be more powerful than the gene-by-gene analysis and more robust to the number of false positives than the homogeneous variance model. It performed well compared with recently proposed approaches such as SAM and VarMixt even for a small number of replicates, and performed similarly to Limma. The main advantage of the structural model is that, thanks to the use of a linear mixed model on the logarithm of the variances, various factors of variation can easily be incorporated in the model, which is not the case for previously proposed empirical Bayes methods. It is also very fast to compute and is adapted to the comparison of more than two conditions.
Multiple-trait analyses have been shown to improve the detection of quantitative trait loci (QTLs) with multiple effects. Here we applied a multiple-trait approach on obesity- and growth-related traits that were surveyed in 275 F2 mice generated from an intercross between the high body weight selected line NMRI8 and DBA/2 as lean control. The parental lines differed 2·5-fold in body weight at the age of 6 weeks. Within the F2 population, the correlations between body weight and weights of abdominal fat weight, muscle, liver and kidney at the age of 6 weeks were about 0·8. A least squares multiple-trait QTL analysis was performed on these data to understand more precisely the cause of the genetic correlation between body weight, body composition traits and weights of inner organs. Regions on Chr 1, 2, 7 and 14 for body weights at different early ages and regions on Chr 1, 2, 4, 7, 14, 17 and 19 for organ weights at 6 weeks were found to have significant multiple effects at the genome-wide level.
Whether there are different genes involved in response to different environmental signals and how these genes interact to determine the final expression of the trait are of fundamental importance in agricultural and biological research. We present a statistical framework for mapping environment-induced genes (or quantitative trait loci, QTLs) of major effects on the expression of a trait that respond to changing environments. This framework is constructed with a maximum-likelihood-based mixture model, in which the mean and covariance structure of environment-induced responses is modelled. The means for responses to continuous environmental states, referred to as reaction norms, are approximated for different QTL genotypes by mathematical equations that were derived from fundamental biological principles or based on statistical goodness-of-fit to observational data. The residual covariance between different environmental states was modelled by autoregressive processes. Such an approach to studying the genetic control of reaction norms can be expected to be advantageous over traditional mapping approaches in which no biological principles and statistical structures are considered. We demonstrate the analytical procedure and power of this approach by modelling the photosynthetic rate process as a function of temperature and light irradiance. Our approach allows for testing how a QTL affects the reaction norm of photosynthetic rate to a specific environment and whether there exist different QTLs to mediate photosynthetic responses to temperature and light irradiance, respectively.
Public health genetics is a new discipline. It brings together the insights of genetic and molecular science as a means of preventing disease and of protecting and improving the health of the population. Its scope is wide, and requires an understanding of genetics, epidemiology, public health, the principles of ethics, law and the social sciences and much else besides.
At the core of public health genetics is the notion that genes, like the classic environmental factors that have been shown over many decades to be causally implicated in disease, are themselves important determinants of health; and that they play as important a role as exposures to physical and biological agents or to social and structural factors such as poverty and unemployment. But, as with environmental determinants, genes act not on their own but in combination with other factors. Every gene interacts with others in the genome and with a host of external exposures to produce the full range of human characteristics. The complexities of these relationships mean that, while genetic factors are at work in all diseases, no single genetic variant (except in the case of relatively rare ‘genetic diseases’, discussed further below) will be predictive of when or whether disease will strike, or of its severity.
The health and social policy issues that form much of the practice of public health genetics are equally complex, including legal and regulatory frameworks in genetic testing; science funding and policy; consent, confidentiality and data protection; the pharmaceutical and biotechnology industries; the patenting of genes and genetic sequences; and the education and training of health professionals and of the public in the implications of genetic science.
Inappropriate floors in pig pens and slippery floor conditions may cause leg problems that reduce animal welfare. Therefore the objectives of the present study were to characterise the walk of pigs on dry concrete solid floor, to evaluate whether pigs modify their gait according to floor condition, and to suggest a coefficient of friction (COF) that ensures safe walking on solid concrete floors for pigs. Kinematic (50 Hz video recordings in the sagittal plane) and kinetic (1 KHz force plate measuring three perpendicular ground reaction forces) data were collected from four strides of both the fore- and hindlimbs of 30 healthy pigs walking on dry, greasy and wet concrete floor with 10 pigs on each floor condition. The COF of the floor conditions were tested in a drag-test. The results from the gait analysis showed that the pigs adapted their gait to potentially slippery floors by lowering their walking speed and reducing their peak utilised COF on greasy and wet (contaminated) floors compared with dry floors. Moreover, the pigs shortened their progression length and prolonged their stance phase duration on greasy floor compared with dry and wet floors. Thus the greasy floor appeared the most slippery condition to the pigs, whereas the wet floor was intermediate to the other two conditions. The pigs walked with a four-beat gait, and the limbs differed biomechanically, as the forelimbs carried more load, received higher peak vertical forces and had longer lasting stance phases than did the hindlimbs. The utilised COF from the gait analysis indicated that a high floor COF (>0.63) is needed to prevent pigs from slipping and thus to ensure safe walking on dry concrete floors.
In Chapter 4 we have discussed a variety of potential applications of genetic science in the treatment and prevention of disease. Many of these applications are still at the research stage; at present, the application of genetics in health services is largely confined to services for individuals and families affected by – or at risk of – relatively rare Mendelian diseases, chromosomal disorders, syndromes or congenital abnormalities. In this chapter we first review these services and then outline some of the challenges for service development that are likely to emerge in the coming decades as research on the genetic contribution to common disease begins to bear fruit.
It is important to keep in mind that, although individually rare, Mendelian diseases and chromosomal disorders collectively account for a significant burden of mortality and morbidity, especially in children. The genetic cause of around 1800 single-gene or chromosomal disorders is now known, and the number continues to grow rapidly. As knowledge has grown about single-gene causes of common disease such as breast cancer, increasing numbers of individuals have identified themselves as potentially at risk on the basis of their family history, and sought advice from genetics specialists. The workload of clinical geneticists, laboratory geneticists and genetic counsellors has grown at a rapid rate. It is vital, therefore, that funding for clinical genetics services is protected and that provision is made for the introduction of validated new tests and technologies as they become available, to improve services for patients.
Maize silage-based diets with three dietary crude protein (CP) supplements were offered to 96 finishing cattle of contrasting breed (Holstein Friesian (HF) v. Simmental × HF (SHF)) and gender (bull v. steer) housed in two types of feeding system (group fed v. individually fed). The three protein supplements differed either in CP or protein degradability (degradable (LUDP) v. rumen undegradable (HUDP)) and provided CP concentrations of 142 (Con), 175 (LUDP) and 179 (HUDP) g/kg dry matter (DM) respectively, with ratios of degradable to undegradable of 3.0, 1.4 and 0.9:1 for diets Con, LUDP and HUDP, respectively. DM intakes were marginally higher (P = 0.102) for LUDP when compared with Con and HUDP. Rates of daily live-weight gain (DLWG) were higher (P = 0.005) in LUDP and HUDP when compared with Con. HF had higher DM intakes than SHF although this did not result in any improvement in HF DLWG. Bulls had significantly better DM intakes, DLWG and feed conversion efficiency than steers. Conformation scores were better in SHF than HF (P < 0.001) and fat scores lower in bulls than steers (P < 0.001). There was a number of first order interactions established between dietary treatment, breed, gender and housing system with respect to rates of gain and carcass fat scores.
Birth weight plays a central role in lamb survival and growth, and the knowledge of its genetic determinism has become essential in worldwide selection programmes. Within this context, within-litter birth weight variation (BWV) has been suggested as an attractive trait to homogenise litters in prolific species, although it has not been analysed in sheep. The objective of this study was to ascertain whether maternal additive genetic variance exists for BWV in Ripollesa ewes, and to study its genetic, permanent environmental and residual relationships with litter weight (LW) and litter size (LS) at birth. Data were recorded in the Ripollesa experimental flock of the Universitat Autònoma of Barcelona, between 1986 and 2005, and included 1 662 litters from 380 ewes, with 712 records of BWV and 1 530 records of LW. Traits were analysed with a multivariate animal model solved through Bayesian methodologies, and with a threshold characterisation of LS. Additionally, the effect of BWV on lamb survival was studied. Additive genetic variance was observed for BWV (h2 = 0.061), as well as for LW (h2 = 0.200) and LS (h2 = 0.141). Nevertheless, genetic correlations among those traits were not substantial (BWV and LW = 0.151; BWV and LS = − 0.219; LW and LS = − 0.320) and suffered from a high degree of uncertainly, with the null correlation included within the highest posterior interval at 95%. Within-litter birth weight variation and LS showed a negative and large permanent environmental correlation ( − 0.872), and LW and LS were negatively correlated due to residual ( − 0.762) and permanent environmental ( − 0.449) random sources of variation. Within-litter birth weight variation influenced lamb mortality during the first 7 days of life (P < 0.05), increasing and decreasing survivability in heavier and lighter littermates, respectively. Nevertheless, stillbirths and lambs died after the 1st week of life were not affected by BWV (P>0.05). The low heritability found indicates that slow genetic progress may be expected from selecting for BWV. Close to zero genetic correlations suggest that this selection will probably not affect LS and LW, although some significant permanent and residual correlations must be taken into account. Further studies are needed to understand better the genetic architecture among these three reproductive traits.
Previously, feeding fish oil (FO) and sunflower seeds to dairy cows resulted in the greatest increases in the concentrations of vaccenic acid (VA, t11 C18:1) and conjugated linoleic acid (CLA) in milk fat. The objective of this study was to evaluate the effects of forage level in diets containing FO and sunflower oil (SFO) on the production of trans C18:1 and CLA by mixed ruminal microbes. A dual-flow continuous culture system consisting of three fermenters was used in a 3 × 3 Latin-square design. Treatments consisted of (1) 75:25 forage:concentrate (HF); (2) 50:50 forage:concentrate (MF); and (3) 25:75 forage:concentrate (LF). FO and SFO were added to each diet at 1 and 2 g/100 g dry matter (DM), respectively. The forage source was alfalfa pellets. During 10-day incubations, fermenters were fed treatment diets three times daily (140 g/day, divided equally between three feedings) as TMR diet. Effluents from the last 3 days of incubation were collected and composited for analysis. The concentration of trans C18:1 (17.20, 26.60, and 36.08 mg/g DM overflow for HF, MF, and LF treatments, respectively) increased while CLA (2.53, 2.35, and 0.81 mg/g DM overflow) decreased in a linear manner ( P < 0.05) as dietary forage level decreased. As dietary forage levels decreased, the concentrations of t10 C18:1 (0.0, 10.5, 33.5 mg/g DM) in effluent increased ( P < 0.05) and t10c12 CLA (0.08, 0.12, 0.35 mg/g DM) tended to increases ( P < 0.09) linearly. The concentrations of VA (14.7, 13.9, 0.0 mg/g DM) and c9t11 CLA (1.78, 1.52, 0.03 mg/g DM) in effluent decreased in a linear manner ( P < 0.05) as dietary forage levels decreased. Decreasing dietary forage levels resulted in t10 C18:1 and t10c12 CLA replacing VA and c9t11 CLA, respectively, in fermenters fed FO and SFO.
Practitioners of public health genetics need a working knowledge of the basic principles of genetic science, including not just the classical rules of inheritance but also how the genetic ‘programme’ is played out in the functions of cells, tissues and whole organisms. They also need an understanding of how genetic changes may be related to the development and progression of disease. The first part of this chapter is devoted to laying the groundwork in genetic science and medical genetics.
In this chapter we also introduce some of the basic features of deoxyribonucleic acid (DNA) technology, which has enabled scientists to study and manipulate the genetic material. The development of this technology has been the driving force behind the human genome project, which has now delivered a complete ‘reference sequence’ for the human genome and is rapidly moving forward in the task of assigning functions to genes and their products. It is the explosion of information arising from the human genome project, and from the ‘post-genomic’ sciences such as proteomics, functional genomics, comparative genomics and bioinformatics, that is providing the raw material and the impetus for the development of new approaches to the diagnosis, treatment and prevention of disease. These new opportunities for genetics in medicine will be discussed in Chapter 4.
Basic molecular genetics
In most organisms, the genetic material in each cell is the chemical DNA. The DNA molecule acts as a code to specify the synthesis of different proteins, which are responsible for carrying out the functions of the cell.
In a stochastic simulation study the effect of simultaneously changing the model for prediction of breeding values and changing the breeding goal was studied. A population of 100 000 cows with registrations on seven traits was simulated in two steps. In the first step of 15 years the population was selected for production and mastitis occurrence using a univariate model for prediction of breeding values for production and a trivariate model using information on mastitis treatments, udder depth and somatic cell score for prediction of breeding values for mastitis occurrence. In the second step six different scenarios were set up and simulated for 15 years combining two different breeding goals and three different models for prediction of breeding values in 20 replicates. Breeding goal 1 had relative economic value per genetic standard deviation on production (19.4) and mastitis occurrence ( − 50) whereas breeding goal 2 had a economic value on production (19.4), udder depth (4.2), mastitis occurrence ( − 50), non return rate (13.0) and days open ( − 16.75). Model 1 was a model similar to the one used in the first 15 years. Model 2 was an approximate multitrait model where solutions for fixed effects from a model corresponding to model 1 were subtracted from the phenotypes and a multitrait model with an overall mean, a year effect, an additive genetic and a residual effect were applied. Model 3 was a full multitrait model. Average genetic trends for total merit and each individual trait over 20 replicates were compared for each scenario. With the number of replicates the genetic responses using model 2 and 3 were not significant different. With a broad breeding goal using, model 2 or model 3 gave a significantly higher response in total merit than using model 1. Using a narrow breeding goal there was no significant difference between models used for prediction of breeding values. Results showed that with a breeding goal with a lot of emphasis on low heritable traits with a high economic value using a multitrait methodology for prediction of breeding values will redistribute the genetic progress in the total merit index. More gain will come from the low heritable traits in the breeding goal and less from traits with higher heritability. With a broad breeding goal and exploiting the available information in the data the inbreeding coefficient increased though not significantly.
This work was designed to study the effects of carcass maturity on meat quality characteristics and intramuscular connective tissue of beef semitendinosus muscle from Chinese native Yellow steers. Chemical determinations, histological and mechanical measurements were performed on the raw and cooked meat at 4 days post mortem. In raw meat, intramuscular fat, collagen solubility, mechanical strength and transition temperature of intramuscular connective tissue increased (P < 0.05) with carcass maturity before body maturation, whilst moisture, total collagen, fibre diameter decreased after body maturation. Warner-Bratzlar shear force (WBSF) of cooked meat increased with maturity before body maturation due to the muscle atrophy, and thus the decline of moisture content and the increase of cooking losses. After body maturation, the increase of WBSF was neutralised by the increase of intramuscular fat, the decrease of total collagen and the elongation of sarcomere length.
The molecular basis and control of the biochemical and biophysical properties of skeletal muscle, regarded as muscle phenotype, are examined in terms of fibre number, fibre size and fibre types. A host of external factors or stimuli, such as ligand binding and contractile activity, are transduced in muscle into signalling pathways that lead to protein modifications and changes in gene expression which ultimately result in the establishment of the specified phenotype. In skeletal muscle, the key signalling cascades include the Ras-extracellular signal regulated kinase-mitogen activated protein kinase (Erk-MAPK), the phosphatidylinositol 3′-kinase (PI3K)-Akt1, p38 MAPK, and calcineurin pathways. The molecular effects of external factors on these pathways revealed complex interactions and functional overlap. A major challenge in the manipulation of muscle of farm animals lies in the identification of regulatory and target genes that could effect defined and desirable changes in muscle quality and quantity. To this end, recent advances in functional genomics that involve the use of micro-array technology and proteomics are increasingly breaking new ground in furthering our understanding of the molecular determinants of muscle phenotype.
Effects of synchronising the availability of amino acids and glucose within a day on protein and energy metabolism were studied in growing pigs. Ten pigs of on average 54 (s.e. 1.0) kg live weight were assigned to each of two dietary treatments (synchronous v. asynchronous nutrient supply) in a change-over design. On the synchronous treatment (SYN), pigs received two balanced meals: one at 0800 h and one at 1600 h. On the asynchronous treatment (ASYN), pigs received virtually all protein at 0800 h and all carbohydrates at 1600 h. The dietary supply of ingredients and nutrients to pigs was similar for both treatments. Pigs were housed individually in respiration chambers. Faecal apparent nutrient digestibility was determined and nitrogen and energy balances were measured. Faecal apparent digestibility of energy, organic matter and non-starch polysaccharides was higher ( P < 0.05) for SYN than for ASYN. The efficiency of utilisation of digestible protein with protein gain was higher ( P = 0.001) for SYN (56.7%) than for ASYN (47.1%). The substantial decrease ( P < 0.05) in respiratory quotient and 13C enrichment of the expired CO2 after the morning meal indicated higher amino acid oxidation for ASYN than for SYN. Heat production and energy retention as fat were not affected by nutrient synchrony. In conclusion, an asynchronous availability of glucose and amino acids within a day increases amino acid oxidation, resulting in a substantial reduction in protein utilisation but with virtually no effect on fat retention.
In Chapters 2 and 3 we have discussed the relationship between genes and disease. We have also outlined the approaches that are being used to discover and quantify associations between specific genetic variants and disease risk, and to understand how genetic risk is modulated by environmental and lifestyle factors.
Although our knowledge of the genetic determinants of disease is incomplete, applications of genetics in medical practice are already in existence or are being developed. Within the specialist service of medical genetics in the UK, consultant clinical geneticists and genetic counsellors see individuals and families who are affected by, or at high risk of, conditions that may have a genetic basis. Genetics professionals attempt to assess whether the condition is, for example, a known disease caused by a single-gene lesion or chromosomal abnormality. They may suggest tests to aid diagnosis. In addition, they may give advice about a variety of issues including genetic risk to other family members, and reproductive options. Specialist genetic services, and related services within the healthcare system, are discussed in more detail in Chapter 5.
Many applications of genetics in health care, both actual and potential, rely on technology designed to test for the presence of specific genetic variants. We begin this chapter with a discussion of genetic testing and its uses in the diagnosis of disease and estimation of disease risk. We then move on to consider broader applications of genetics in the two major component areas of health care: disease prevention and disease management.
It is a privilege to introduce this new book on public health genetics. Advances in genetic research have created unprecedented tools for understanding human health. The new knowledge arising from this research has the potential to transform disease prevention and management, and public health genetics is a new field poised to harness the insights of this knowledge for the benefit of population health.
To accomplish the task, public health genetics must take a comprehensive approach. It must bring together traditional public health principles, a meaningful evaluation of the combined effects of genetics and environment on health, and attention to the social implications of genetic risk information. Integration of knowledge across a broad array of subject areas will be needed, to support appropriate public policy, health services, mechanisms for communication and stakeholder engagement, and education and training programmes.
This important effort will require the participation of professionals from diverse disciplines. All will have essential expertise to offer the emerging field of public health genetics, yet many will have had little exposure to the full range of issues it must address. Working together will require a common language, based on the underlying science, principles, and goals. For everyone who wishes to participate in the exciting new venture of public health genetics, this book is the right place to start.