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biotechnology

biotechnology

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05/28/2013

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Rev. sci. tech. Off. int. Epiz., 2005,24 (1), 343-353
Use of molecular markers to enhance resistance
of livestock to disease: a global approach
J.P. Gibson(1) & S.C. Bishop(2)

(1) The Institute for Genetics and Bioinformatics, University of New England, Armidale, NSW 2351, Australia
and The International Livestock Research Institute, P.O. Box 30709 Nairobi, Kenya
(2) Roslin Institute (Edinburgh), Midlothian, EH25 9PS, Scotland, United Kingdom

Summary

The improvement and utilisation of host genetic resistance to disease is an attractive option as a component of livestock disease control in a wide range of situations. This paper reviews the situations where genetic resistance of the host is likely to be a useful component of disease control and provides a framework for deciding whether genetic improvement of resistance is likely to be worthwhile. Discussion is focused on low-input production systems in the developing world, where disease resistance is particularly important. The authors propose an integrated strategy for the use of molecular markers in assessing genetic diversity and in utilising and improving host genetic resistance to disease. The integrated approach assures that there is value in the molecular genetic information whether or not it proves useful in genetic selection, a feature that should prove attractive to funding and executing agencies.

Keywords

Conservation \u2013 Disease resistance \u2013 Disease tolerance \u2013 Genetic diversity \u2013 Genetic epidemiology \u2013 Genetic improvement \u2013 Marker-assisted introgression \u2013 Marker-assisted selection \u2013 Molecular markers \u2013 Quantitative trait loci.

Introduction

Disease resistance is a particularly important attribute of livestock in low-input livestock production systems in the developing world (5). Resistance to infectious diseases is often the critical determinant of the sustainability of such systems, and improving resistance is perceived as a primary target for genetic improvement programmes. This paper considers the value of host genetic variation in resistance for the control of livestock infectious disease, and the authors address the speci\ufb01c question of how molecular genetic markers can play a role in the utilisation and genetic improvement of host genetic resistance. An integrated strategy is then proposed and developed for the use of molecular markers that generates multiple bene\ufb01ts that might prove attractive for application in various situations in the developing world.

Utilising and improving genetic
resistance to disease
The role of genetic resistance to disease
in livestock production: key issues
The control of infectious disease of livestock is currently
achieved by a number of mechanisms, including:

\u2013 chemical intervention, such as anthelmintics for nematode parasite control, acaricides for tick control and antibiotics for the control of many bacterial diseases

\u2013 vaccination
\u2013 sanitation and disinfection
\u2013 culling, isolation and control of the movements of
animal and/or animal products.

Disease control or management using host genetic resistance (i.e. exploiting genetic variation in disease resistance amongst hosts) is increasingly recognised as a key component of effective disease control, complementing or sometimes replacing existing strategies.

Breeders and agricultural industries in the developed world have a variety of incentives to genetically improve host resistance to disease. Host resistance to disease is a low-cost and usually sustainable approach to disease control. Increasingly, other measures are failing as parasites evolve to resist chemical or vaccine control measures. Important examples include the evolution of resistance to anthelmintics by nematodes in all major sheep-producing countries, the evolution of resistance to antibiotics by bacteria, and the evolution of resistance to vaccines by the virus causing Marek\u2019s disease. Also, legislative changes in many countries are increasingly restricting the use of antibiotics and other therapeutics in animal production systems. There are also examples of governments dictating breeding strategies to farmers, such as the programme to limit clinical expression of scrapie in sheep \ufb02ocks in Western Europe, using selection for prion protein (PrP) genotypes associated with resistance to scrapie. (It remains to be seen whether the PrP alleles said to be associated with resistance to scrapie in sheep confer complete or partial resistance, or perhaps confer delayed onset of clinical signs of disease.)

In the developing world, the majority of poor farmers face all the pressures experienced in more developed regions but either cannot afford or do not have access to therapeutic and vaccine control. In their systems, the genetically controlled resistance of the host is a critical component of effective disease control.

A major question that will be addressed below is: what are the bene\ufb01ts of improving disease resistance? The bene\ufb01ts of improved disease resistance differ from the bene\ufb01ts of improved production traits, because animals may infect each other either directly or indirectly. Hence, the expression of disease status in individual animals is not independent of expression in other animals. Consequently, animal breeders need to widen their perspective to include the dynamics of disease and ask the question: what impact will changing host genotype have upon disease dynamics within the population as a whole?

Setting priorities for genetic improvement

There are many potential target diseases for genetic improvement. Indeed, there are many more diseases than can ever feasibly be addressed. Before embarking on a genetic improvement programme it is important to demonstrate that:

\u2013 a disease is being targeted for which genetic improvement is an effective, low-risk method of disease control

\u2013 there is suf\ufb01cient genetic variation for disease resistance between or within breeds to allow effective genetic improvement

\u2013 there will be clear economic and social bene\ufb01ts resulting from the genetic improvement of resistance, allowing for the option of using other methods of disease control (which might be used as an alternative too, or in conjunction with, the use of host resistance).

Evidence for genetic variation in disease resistance

Before assessing the evidence for genetic variation in disease resistance, it is necessary to de\ufb01ne what is meant by disease and disease resistance. Disease is often used to describe two distinct concepts: infection and disease itself. For the purpose of this paper, infection is de\ufb01ned as the colonisation of a host animal by a parasite, where \u2018parasite\u2019 is a general term to describe an organism with a dependence upon a host. Parasites will include viruses, bacteria and protozoa (pathogens or microparasites), as well as helminths, \ufb02ies and ticks (macroparasites). Disease describes the side effects of infection by a parasite. Disease may take several forms \u2013 acute, sub-acute, chronic and sub-clinical \u2013 which may or may not be debilitating. An individual host may be infected by a parasite, but suffer little or no harm. This is known as tolerance. In contrast, resistance is the ability of the individual host to resist infection or control the parasite lifecycle.

For almost every disease that has been intensively and carefully investigated, evidence has been found for host genetic variation in either resistance or tolerance. However, it is often not clear whether the observed genetic variation is for resistance to infection, tolerance of infection or a combination of both. Bishop (2) and Gibson (11) give partial summaries of more than 50 diseases for which there is documented or strong anecdotal evidence of genetic variation in host resistance or tolerance among the major domestic livestock species. Well-known examples include Marek\u2019s disease in chickens, F4 and F18 Escherichia coli infections in pigs, and nematode infections, mastitis, dermatophilosis, trypanosomosis and theileriosis in ruminants. In most cases, there are breeding programmes that aim to select animals for enhanced resistance (or tolerance) to these diseases, and in the case of bovine dermatophilosis this has been spectacularly successful (19).

The distinction between resistance and tolerance becomes important when considering the impact of selecting for disease resistance, as described in the next section. In general terms, when genetic improvement is made in host resistance to infection, there will be an impact on the transmission of infection. Conversely, genetic improvement of tolerance may reduce clinical signs of disease, but may not reduce transmission of infection to other animals.

Rev. sci. tech. Off. int. Epiz.,24(1)
344
Assessing the bene\ufb01ts of selecting for disease
resistance: the concept of genetic epidemiology

The consequences of genetic change in the resistance of a population of animals to an infectious disease depend upon the transmission pathways of infection (6, 7). Typical pathways are shown in simpli\ufb01ed form in Figure 1. Not all pathways are relevant to all diseases, and some of the pathways may be considerably more complex than shown here. For example, pathwayc may involve intermediate hosts.

In diseases that arise from a reservoir of infection outside the host population of interest, the transmission of infection from this reservoir may be \u2018continuous\u2019 or sporadic. Once infection is in the host population it may follow several transmission pathways. Typically, but not exclusively, viral or bacterial infections will be transmitted by direct animal-to-animal contact along pathwayb, whereas macroparasitic (for example, nematode or arthropod) infections will be transmitted via some external host, vector or reservoir. There are many diseases where pathwaya is important and continuous, and pathwaysb andc are non-existent or trivial in terms of the impact of the disease. Examples include trypanosomosis and mastitis caused by environmental contamination. Diseases where pathwayb is critical, with sporadic infection from the reservoir (pathwaya), include most viral diseases affecting livestock. Pathwaysa andc are critical for nematode infections in ruminants, where there is a continuous \ufb02ow of infection between the host population and the reservoir, which in this case is the pasture.

The consequences of these infection pathways have been explored by Bishop and Stear (3, 4) for the case of nematode infections in sheep, and by MacKenzie and Bishop (16, 17, 18) for viral infections in pigs. Reducing transmission of infection along pathwaysa andc will lead to so-called Type III epidemiological effects, in which a virtuous cycle of reduction in infection and disease consequence can be achieved (7). Reducing transmission along pathwayb will lead to Type II epidemiological effects (7), in which the outcome of the reduction of transmission is a reduction in the frequency and/or severity of epidemics.

These considerations indicate that the outcomes of selection should be measured at the population level, rather than the individual animal level. Moreover, the outcomes are very non-linear and depend upon the starting point. For example, a moderate improvement in animal resistance to viral disease might either solve the disease problem or make no impact at all, depending on the nature of the disease and the initial level of resistance of the host. A useful parameter for summarising this concept is the reproductive ratio, R0, which is de\ufb01ned as the average number of secondary cases of infection resulting from one primary case introduced into a population of susceptible individuals. For example, if the primary animal infects \ufb01ve other animals, then R0is 5. As examples, scrapie probably has an R0 only a little above 1.0, whereas foot and mouth disease (FMD) usually has a much higher R0, well in excess of 10. R0has direct application in terms of defining genetically resistant populations of animals. In the case of genes that determine complete resistance, then the number of resistant animals that the population as a whole must contain is a simple function of R0, as the requirement is simply to reduce R0 below 1.0. These concepts are explored by Bishop and MacKenzie (6).

Genetic improvement which results in a reduction in the clinical signs of disease \u2013 that is, improved tolerance of infection \u2013 will be effective in reducing the incidence or the impact of disease in the target population. However, it may not decrease the prevalence of the pathogen. Hence, the disease incidence in other populations in the same environment will not be affected. In worst-case scenarios, the presence of infection in the environment may be masked by the absence of symptoms in the carriers of the pathogen.

Suitability of, and risks associated with, genetic
improvement of disease resistance

Arguments developed from genetic-epidemiological concepts assist in the choice of suitable target diseases. For example, it is unlikely that breeding for resistance to FMD would be a viable strategy for the livestock industries in the United Kingdom (UK), even if it were possible. Because FMD has a high R0, it would be necessary to have a high proportion of animals that were completely resistant to the disease before the population as a whole would be protected (i.e. before R0 is reduced below 1.0). This could take many decades to achieve. In the meantime, any epidemic (from which the population wouldnot be protected) would result in large-scale slaughter of animals under the current UK disease control strategy. In this example, current disease control strategies override genetic approaches.

For a zoonotic disease, it would be unwise to breed animals
for apparent resistance if this apparent resistance were in fact
Rev. sci. tech. Off. int. Epiz.,24(1)
345
Reservoir
Host population
ac
b

Fig. 1
Summary of different pathways of infection (a, band c) for
diseases in domestic livestock

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