The first step towards genetic selection for host tolerance to infectious pathogens: Obtaining the tolerance phenotype through group estimates

Reliable phenotypes are paramount for meaningful quantification of genetic variation and for estimating individual breeding values on which genetic selection is based. In this paper we assert that genetic improvement of host tolerance to disease, although desirable, may be first of all handicapped by the ability to obtain unbiased tolerance estimates at a phenotypic level. In contrast to resistance, which can be inferred by appropriate measures of within host pathogen burden, tolerance is more difficult to quantify as it refers to change in performance with respect to changes in pathogen burden. For this reason, tolerance phenotypes have only been specified at the level of a group of individuals, where such phenotypes can be estimated using regression analysis. However, few studies have raised the potential bias in these estimates resulting from confounding effects between resistance and tolerance. Using a simulation approach, we demonstrate (i) how these group tolerance estimates depend on within group variation and co-variation in resistance, tolerance and vigour (performance in a pathogen free environment); and (ii) how tolerance estimates are affected by changes in pathogen virulence over the time course of infection and by the timing of measurements. We found that in order to obtain reliable group tolerance estimates, it is important to account for individual variation in vigour, if present, and that all individuals are at the same stage of infection when measurements are taken. The latter requirement makes estimation of tolerance based on cross-sectional field data challenging, as individuals become infected at different time points and the individual onset of infection is unknown. Repeated individual measurements of within host pathogen burden and performance would not only be valuable for inferring the infection status of individuals in field conditions but would also provide tolerance estimates that capture the entire time course of infection

Optimal experimental designs for estimating genetic and non-genetic effects underlying infectious disease transmission

BACKGROUND: The spread of infectious diseases in populations is controlled by the susceptibility (propensity to acquire infection), infectivity (propensity to transmit infection), and recoverability (propensity to recover/die) of individuals. Estimating genetic risk factors for these three underlying host epidemiological traits can help reduce disease spread through genetic control strategies. Previous studies have identified important ‘disease resistance single nucleotide polymorphisms (SNPs)’, but how these affect the underlying traits is an unresolved question. Recent advances in computational statistics make it now possible to estimate the effects of SNPs on host traits from epidemic data (e.g. infection and/or recovery times of individuals or diagnostic test results). However, little is known about how to effectively design disease transmission experiments or field studies to maximise the precision with which these effects can be estimated. RESULTS: In this paper, we develop and validate analytical expressions for the precision of the estimates of SNP effects on the three above host traits for a disease transmission experiment with one or more non-interacting contact groups. Maximising these expressions leads to three distinct ‘experimental’ designs, each specifying a different set of ideal SNP genotype compositions across groups: (a) appropriate for a single contact-group, (b) a multi-group design termed “pure”, and (c) a multi-group design termed “mixed”, where ‘pure’ and ‘mixed’ refer to groupings that consist of individuals with uniformly the same or different SNP genotypes, respectively. Precision estimates for susceptibility and recoverability were found to be less sensitive to the experimental design than estimates for infectivity. Whereas the analytical expressions suggest that the multi-group pure and mixed designs estimate SNP effects with similar precision, the mixed design is preferred because it uses information from naturally-occurring rather than artificial infections. The same design principles apply to estimates of the epidemiological impact of other categorical fixed effects, such as breed, line, family, sex, or vaccination status. Estimation of SNP effect precisions from a given experimental setup is implemented in an online software tool SIRE-PC. CONCLUSIONS: Methodology was developed to aid the design of disease transmission experiments for estimating the effect of individual SNPs and other categorical variables that underlie host susceptibility, infectivity and recoverability. Designs that maximize the precision of estimates were derived. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12711-022-00747-1

Uses and Implications of Field Disease Data for Livestock Genomic and Genetics Studies

This paper identifies issues associated with field disease data and their implications on the interpretation of estimated genetic parameters and experimental designs. The main focus is on concepts relating to the impacts of diagnostic test properties and exposure to infection, and how exposure to infection is intricately related to within-herd epidemic dynamics. The following are raised challenges: (i) to more fully understand and describe the dynamic impacts of disease epidemics on genetic interpretations; (ii) to develop statistical methods to jointly estimate epidemiological and genetic parameters from complex epidemiological data; (iii) to develop and explore optimal experimental designs for case-control studies, exploiting field disease data. Solving these problems would add insight to both disease genetic and epidemiological studies, as well as enabling us to better select animals for increased disease resistance

Novel methods for quantifying individual host response to infectious pathogens for genetic analyses

Here we propose two novel approaches for describing and quantifying the response of individual hosts to pathogen challenge in terms of infection severity and impact on host performance. The first approach is a direct extension of the methodology for estimating group tolerance – the change in performance with respect to changes in pathogen burden in a host population – to the level of individuals. The second approach aims to capturethe dynamic aspects of individual resistance and tolerance over the entire time course of infections. In contrast to the first approach, which provides a means to disentangle host resistance from tolerance, the second approach considers the combined effects of host resistance and tolerance. Both approaches provide new individual phenotypes for subsequent genetic analyses and come with specific data requirements. Consideration of individual tolerance also highlights some of the assumptions hidden within the concept of group tolerance, indicating where care needs to be taken in trait definition and measurement

Implications of Conflicting Associations of the Prion Protein (PrP) Gene with Scrapie Susceptibility and Fitness on the Persistence of Scrapie

Existing mathematical models for scrapie dynamics in sheep populations assume that the PrP gene is only associated with scrapie susceptibility and with no other fitness related traits. This assumption contrasts recent findings of PrP gene associations with post-natal lamb survival in scrapie free Scottish Blackface populations. Lambs with scrapie resistant genotypes were found to have significantly lower survival rates than those with susceptible genotypes. The present study aimed to investigate how these conflicting PrP gene associations may affect the dynamic patterns of PrP haplotype frequencies and disease prevalence.A deterministic mathematical model was developed to explore how the associations between PrP genotype and both scrapie susceptibility and postnatal lamb mortality affect the prevalence of scrapie and the associated change in PrP gene frequencies in a closed flock of sheep. The model incorporates empirical evidence on epidemiological and biological characteristics of scrapie and on mortality rates induced by causes other than scrapie. The model results indicate that unfavorable associations of the scrapie resistant PrP haplotypes with post-natal lamb mortality, if sufficiently strong, can increase scrapie prevalence during an epidemic, and result in scrapie persisting in the population. The range of model parameters, for which such effects were observed, is realistic but relatively narrow.The results of the present model suggest that for most parameter combinations an unfavourable association between PrP genotype and post-natal lamb mortality does not greatly alter the dynamics of scrapie and, hence, would not have an adverse impact on a breeding programme. There were, however, a range of scenarios, narrow, but realistic, in which such an unfavourable association resulted in an increased prevalence and in the persistence of infection. Consequently, associations between PrP genotypes and fitness traits should be taken into account when designing future models and breeding programmes