Genetic resistance to parasitic infection

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1 Rev. sci. tech. Off. int. Epiz., 1998,17 (1), Genetic resistance to parasitic infection M.J.Stear ( 1 ), & D. Wakelin( 2) (1) Department of Veterinary Clinical Studies, University of Glasgow Veterinary School, Bearsden Road, Glasgow GB1 1QH, United Kingdom (2) Department of Life Science, School of Biological Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom Summary The ability of animals to resist infections with parasites is genetically determined and therefore variable between individuals or breeds of a given host species. Such variation may involve innate (non-immunological) and acquired (immunologically mediated) resistance mechanisms, and is determined by both major histocompatibility complex (MHC)-linked and non-mhc genes. Resistance is inherited as a dominant trait, with heritability often exceeding 0.3. Genetic variation can be exploited to improve the capacity of domestic animals to resist parasitic infection. Methods to achieve this exploitation are discussed in relation to gastrointestinal nematode infections in sheep Keywords Disease resistance - Genetic markers - Genetics - Immunity - Laboratory models - Nematodes - Parasites - Selection - Sheep. Introduction The fact that members of a given species (both plants and animals) are not all equally susceptible to infectious diseases is commonly acknowledged. Some individuals show considerably more resistance than others and may survive exposure to infections which prove lethal to, or cause serious disease in, other individuals. One of the best known examples in animals is the resistance of individual rabbits to the virus responsible for myxomatosis (33). The human species is equally familiar with variation in susceptibility to disease. Evidence that domestic animals show variation in the ability to resist infection with protozoan and helminth (worm) parasites has been documented since the beginning of the 20th century, and anecdotal knowledge of variation almost certainly originates from earlier periods. Such variation in response is now known to occur both within and between breeds of cattle, chickens, goats, pigs and sheep (43). Systematic analysis of variation in resistance to parasites began in the 1950s and has now become a major area of research (64,66). The work has illuminated many aspects of the innate and acquired immune response to parasites, has contributed to fundamental insights into immunological mechanisms and has provided the basis for alternative approaches to the control of parasitic infections in domestic animals. The genetic basis of variation in resistance is evident from observations on breed differences, from the results of selective breeding experiments and from laboratory studies. An enhanced capacity to resist infection is clearly inherited and can be passed from parent to offspring, usually as a dominant trait (64). Genetically determined variation in resistance to parasites has been demonstrated in humans, in domestic stock, in wild animal populations and in laboratory rodents. Such variation has been described in infections involving all categories of parasite: protozoans, helminths and arthropods. As far as domestic animals are concerned, the best documented examples are those concerning coccidian parasites in chickens (9), trypanosomes in catle (18), gastrointestinal (GI) nematodes in sheep (31, 54) and tick infestations in cattle (16). This review will focus primarily on variation in responses to GI nematode parasites, and will deal first with some general principles of resistance, and will then discuss how genetic variation may be exploited to improve resistance to infection in domestic stock. Approaches to studying genetic resistance Genetic resistance to parasites can be studied at a number of levels. In domestic animals, resistance may be evident clinically. For example, when animals are kept in environments known to carry the infective stages of a parasite, variation between individuals may be seen in different patterns of disease, in time to recovery or in differential mortality. Variation at this level may reflect differences in the

2 144 Rev. sci. tech. Off. int. Epiz., 17 (1) abilities of animals to control infection - resistance - or to tolerate the physiological disturbances caused by infection - resilience (7). Variation which relates more clearly to resistance as such may be determined in a quantitative manner if the numbers of parasite stages present can be counted, in blood (e.g., trypanosomes), in faeces (e.g., protozoan cysts or helminth eggs) or at post-mortem examination. Clearly there are many variables, such as age, sex and nutritional or reproductive state, which may contribute to observed variations in resistance under field conditions and therefore more defined studies should be carried out preferably under experimental conditions, where potential variables can be minimised. However, such studies on domestic animals can be logistically complex and expensive. An alternative is to use laboratory animals for fundamental studies on the genetic and immunological bases of variation in resistance and susceptibility (63). Animals such as mice are ideal for these experiments: mice are available as genetically defined strains and are relatively inexpensive, and consequently can be used in large numbers. An additional advantage is that the immunological characteristics of mice are known in great detail and a wide variety of reagents is available both to define the responses and to manipulate those responses experimentally. Resistance and susceptibility The distinction between resilience and resistance has already been mentioned. The term 'resistance' requires further definition. Animals may be termed 'resistant' to a given infection if, after entry into the body, the parasite: - fails to establish an infection - establishes an infection but then fails to complete development - establishes and develops infection but is then controlled or eliminated by the host. In the first case, resistance often has a purely physiological basis, in that the host fails to provide an environment which is suitable for the parasite. This type of resistance can be termed natural' or 'non-specific' resistance (48) and is the basis of host insusceptibility. By definition, the host is susceptible when the parasite can establish an infection, but innate mechanisms of resistance (e.g., acute inflammatory mechanisms) may then operate to prevent further development. The host may be termed 'fully susceptible' when the parasite can develop, reproduce and continue to survive. Susceptibility of this kind characterises natural host-parasite relationships, i.e., those in which the parasite is adapted to the physical and biochemical environment of that particular host species. The resistance which develops to control such infections can be termed 'acquired resistance' and is heavily dependent on the adaptive immune response: in other words, such resistance is antigenspecific in origin and its expression involves immunological mechanisms such as antibodies, T lymphocytes and immunemediated inflammatory responses (49). Genetic control of variation in resistance The biological mechanisms which underlie innate and acquired resistance to parasites are of course regulated by the sequential operation of genes, and resistance is therefore, by definition, always genetically determined. However, the term 'genetic resistance' is usually applied to instances where particular individuals or breeds show significantly enhanced levels of resistance compared with the mean response of the population. In almost all cases, many genes are involved in the control of resistance (i.e., control is polygenic) and variation between individuals is quantitative in nature, following a continuous distribution curve. However, qualitative variation is also known. This may arise because of mutations which delete critical components of the resistance mechanisms. Extreme examples are the mutations which result in deficiencies of particular lymphocyte populations (for example, the nude mutation in rodents, the primary T- and B-cell deficiencies in humans, the severe combined immune deficiency (SCID) mutations in humans and rodents) or inflammatory cells (for example, chronic granulomatous disease). Such deficiencies drastically reduce the ability to develop resistance to a wide variety of infections and would be lethal in nature. Qualitative variation may also arise because of a failure adequately to present specific antigens to T cells, which is the initial step in all adaptive immune responses to parasites. This can occur because the individual concerned lacks the correct major histocompatibility complex (MHC) molecules necessary for antigen presentation. This variation is antigen-specific in its expression and influences resistance to specific pathogens whilst not affecting other responses. There are relatively few clear-cut examples of MHC-linked failure of resistance to parasites resulting in qualitative differences in resistance (30), although MHC genes can clearly be associated with significant variation in ability to resist infection and may therefore prove to be useful markers for selection, as described by Beh and Maddox and by the authors later in this paper (2). MHC-linked effects can be seen clearly in experimental systems where the confounding effects of other genes can be removed. By using MHC-congenic mice (strains of mice which share all non-mhc genes and differ only at the MHC loci), marked MHC-linked differences in resistance can be shown. This has been demonstrated using a number of GI nematodes in mice, e.g., Heligmosomoides polygyrus (3), Trichinella spiralis (69) or Trichuris muris (21). Qualitative variation involving non-mhc (or background) genes may also be seen in otherwise normal hosts because a crucial component necessary for the development of responses to

3 Rev. sci. tech. Off. int. Epiz., 17 (1) 145 particular parasites is absent or ineffective. Perhaps the best example is the operation of the natural resistance-associated macrophage protein (Nramp) gene in mice, which regulates innate macrophage resistance to intracellular pathogens (8). For example, in the absence of the resistance allele, the initial replication of the protozoan Leishmania donovani is unchecked. Mice which carry the appropriate MHC alleles can subsequently control infection immunologically, whereas those which lack these alleles suffer overwhelming infection. The Nramp gene also regulates the intracellular development of a number of bacteria (1). Background gene-controlled qualitative variation in response to GI nematodes has been described, but the genes concerned have yet to be defined or identified. Two examples can be cited. In some strains of mice, certain individuals are fully susceptible to the nematode T. muris and fail to develop the strong resistance seen in the majority (60). Some individual sheep may carry genes which confer a qualitatively greater resistance to Haemonchus contortus than is seen in the rest of the population (27). There are many examples in which background genes are known to control quantitative variation in resistance to GI nematodes, and biologically these may well be the most important determinants of responses to infection. Unfortunately, none has been defined so far, either positionally or functionally. Such genetic variation is well documented in sheep (27, 54), both when responses of different breeds are compared and when individuals within a breed are compared. Variation is reflected in the responses to infection as well as to vaccination (17) and can be quantified by a variety of parasitological, immunological and pathological parameters. Animals which show greater resistance develop smaller worm burdens, pass fewer eggs in their faeces, expel worms earlier and more effectively, suffer less pathology and respond better to vaccination. Greater resistance to GI nematode infection is often associated with greater antibody responses, higher levels of T-cell proliferation and increased inflammatory responses, particularly those involving eosinophils and mast cells (20). There is much debate about whether these associations are causal correlates of enhanced resistance or are irrelevant, and merely reflect a greater level of overall responsiveness, thereby playing no direct role in controlling infection. The nature of the complications associated with large animal experimentation means that some of these questions are difficult to resolve, but valuable pointers can be obtained from the experimental work which has been carried out with mouse models in inbred strains of mice. Genetic resistance in laboratory models In the three most intensively studied mouse models of GI nematode infection (H. polygyrus, T. spiralis and T. muris), resistance is most often quantified by determining the numbers of worms present in the intestine after given periods of time and by measuring female worm fecundity in terms of numbers of eggs or larvae produced. Enhanced resistance, seen in mice carrying a high-responder genotype, is associated with an accelerated expulsion of worms and reduced fecundity. In the case of H. polygyrus (which, like the major GI worms of sheep, is a trichostrongyle nematode), all strains of mice allow the parasite to reach sexual maturity and to reproduce. Some strains (high responders) then expel the worms, others (low responders) retain infections for many months (47). T. spiralis infections mature in all strains of mice, but survival in the intestine is relatively short. However, the duration of survival is markedly strain-dependent (61). T. muris, although a natural parasite of the wild mouse, fails to mature in most strains of laboratory mice and is expelled. A few strains, however, are unable to expel the worms and these strains retain mature infections for many weeks (21). A number of general statements can be made about genetic aspects of resistance in these models, as follows: - the level of resistance expressed is genetically determined and inherited in Fl crosses between resistant and susceptible parents as a dominant characteristic - the number of genes which influence resistance appears to be relatively small - background (non-mhc) genes exert the strongest influence on levels of resistance - on a low-responder genetic background, MHC-linked genes may exert a significant influence on levels of resistance - in two of the models (H. polygyrus and T. muris), selective breeding experiments have shown that lines with distinct response phenotypes (resistant and susceptible) can be separated relatively easily (25, 26). In all three experimental models, variation in genetic resistance is based primarily on variation in the expression of acquired immune responses. The responses concerned are T lymphocyte-dependent and are mediated by cytokines released by CD4 + T helper cells. The pattern of cytokines associated with resistance is, in each case, that released by the T helper 2 subset (cytokines such as interleukin-4 [IL-4], IL-5, IL-9 and IL-13); T helper 1 cytokines promote susceptibility. These cytokines regulate a number of characteristic immune and inflammatory responses - production of the antibody classes IgGl (immunoglobulin), IgE and IgA, and increased eosinophilia and mastocytosis - and the responses usually correlate positively with enhanced resistance (23). However, the causal basis of these correlations is far from clear. For example, data from the T. spiralis system show that genetically resistant (high-responder) strains of mice mount more rapid T-cell responses than low responders (15) and show higher levels of eosinophilia and mastocytosis (65), whereas susceptible mice can produce more IgGl and IgE antibodies (44). Studies in which particular inflammatory cell populations are depleted, and work with genetically modified (mutant, knockout and transgenic) mice, suggest that only

4 146 Rev. sci. tech. Off. int. Epiz., 17 (1) mastocytosis is causally correlated with resistance, and that eosinophilia is irrelevant (28); the role played by antibodies is unclear. Antibody can probably play a much more important role in resistance to H. polygyrus and T. muris. The value of these laboratory models is that they provide guidelines for focused analysis of data from experiments with target animals such as cattle and sheep. For example, as in the mouse models, genetic resistance to GI nematodes in sheep is associated (but not necessarily correlated) with T-celldependent inflammatory responses such as eosinophilia and mastocytosis (20); genetic resistance to H. contortus in sheep is immunologically based (25) and this immunity is CD4 T-cell-dependent (26); and depletion of the T helper 1 cytokine interferon gamma enhances resistance to Trichostrongylus colubriformis (34). In two of the mouse models (H. polygyrus and T. muris), a subtle interplay is observed between the genotype of the host, the immune system and immunomodulatory influences exerted by the worm. Adult H. polygyrus are strongly immunosuppressive and can prevent the expression of protective immunity. In mouse strains with a low-responder genotype, this immunosuppression is responsible for the prolonged infections: mice with a high-responder genotype appear able to overcome the immunomodulatory influence (59). In the case of T. muris, mice with low-responder genotypes appear unable to eliminate the parasite before it reaches a developmental stage at which immunomodulatory factors are released (22). Resistance here requires expression of responses controlled by cytokines from the T helper 2 (Th2) subset of CD4 + lymphocytes, and is associated with both T-cell activity and the production of immunoglobulin isotypes controlled by Th2 cytokines. Immunomodulation polarises the Th response to the Thl subset and the cytokines released by these cells effectively disable the protective response, allowing the parasite to persist. Separation of mice into resistant and susceptible phenotypes is seen in genetically heterogeneous strains of mice (17)- a situation which more closely resembles that of domestic animals in the field - and in inbred mice with certain combinations of background and MHC genes (22). Interestingly, there is a further layer of complexity in this system. Response phenotype is determined by the genotype of both the host and the parasite (4). Mice which express a low-responder phenotype with one isolate of T. muris may express a high-responder phenotype with a different isolate and vice versa. The genetic variability in the populations of GI nematodes which affect domestic stock is well known, and such variation can add a complicating factor to the identification and prediction of resistance. host. The challenge for animal breeders is to determine the best methods of using this variation to minimise infection and the effects of infection. This review will concentrate on cattle and sheep. However, the principles are generally applicable. The best methods for exploiting the genetic variation will depend on the traits which the breeder wishes to improve and on the relative importance of variation among and within breeds for these traits. The choice of traits for improvement In most commercial farms, the main aim is to maximise the return on the investment of money and labour. The best strategy to maximise the economic return will vary between countries. For example, farmers in much of Australia breed sheep to improve wool production, while in the United Kingdom, growth rate and carcass composition are more important, especially for farmers who keep hill breeds such as the Scottish Blackface. In contrast, East African smallholders seek large cattle, goats or sheep for slaughter to celebrate religious festivals. Clearly, the type of animal which is desired will vary between countries. The justification for including nematode resistance in a breeding programme is threefold. Firstly, nematode infections can be a major constraint on productivity. For example, Coop et al. estimated that lambs infected with Ostertagia circumcincta grew approximately one-third more slowly than uninfected contemporaries (12) and only one-third of this loss was recovered by anthelmintic treatment (11). There is also some indication that animals infected with nematodes may have carcasses of poorer quality (12). However, the genetic relationships between resistance and productivity are more contentious. There is a strong favourable genetic correlation between decreased numbers of nematode eggs in the faeces and increased growth rate in Scottish Blackface lambs (5). Research performed in Australia on Merino sheep has shown essentially no relationship between resistance and productivity (71), while there are moderately unfavourable associations between resistance and productivity in dual-purpose sheep in New Zealand (38). The contrasting results could be a consequence of differences in the way the sheep are kept, the breeds of sheep studied or the species of parasites. A study of cattle in Australia (36) found that the genetic correlations were more favourable in the wet than in the dry season, presumably due to seasonal differences in the intensity of nematode infection. Exploiting genetic variation As the preceding section has made clear, there is considerable variation among animals in resistance to nematode infection, and much of this variation is due to genetic variation in the The second justification is that there is increasing demand by consumers for meat products which are free of drug residues. Relatively resistant animals require less frequent treatment with anthelmintics (38). The resistant animals excrete fewer nematode eggs and there is a lower infection rate (6), so even the relatively susceptible animals will require fewer

5 Rev. sci. tech. Off. int. Epiz., 17(1) 147 treatments. The benefits will vary from farm to farm and depend upon the stocking rate, the quality of food available and the pre-existing state of pasture contamination. The third justification is that profitable and humane sheep and cattle farming in much of the world requires routine and regular anthelmintic treatment. Farming in these areas is threatened by the evolution of anthelmintic resistance in nematode populations. Therefore, breeding sheep which can survive and thrive without treatment is a desirable insurance against potential catastrophe. Some farmers in South Africa, for example, no longer keep sheep because the parasites on their farms have a high level of resistance to all available anthelmintics. The value of this justification is difficult to quantify precisely. A related consideration is that, even in the absence of resistance to anthelmintic drugs, animals which require fewer treatments are easier to manage and drug resistance will probably evolve more slowly in the parasite populations of such animals. Identifying animals with increased resistance to infection with nematodes A number of traits can be used to identify animals with increased resistance to infection. These include the concentration of nematode eggs in the faeces, the packed red blood cell volume, the extent of eosinophilia in the peripheral blood, the concentration of antiparasite antibodies, the concentration of fructosamine and the growth rate of the animal. The faecal egg count is the trait most widely used to monitor nematode resistance. Somewhat surprisingly, the heritabilities of egg counts following deliberate infection are similar to those of egg counts following natural infection. In both cases, most estimates for a single count range from 0.2 to 0.4 (5, 38, 70, 71). The heritability is the ratio of the additive genetic variation to the total variation and indicates the likely response to selection. The additive genetic variation represents the sum of the average effects of all the relevant genes. Therefore, there is little justification for using deliberate infections, except in situations where the parasite challenge varies widely from year to year due to changes in weather conditions. Three factors which do influence the heritability of faecal egg counts are the age and exposure of the animals studied, the precision of the egg count and the number of samples examined. Resistance to nematode infection is probably an acquired, and not an innate, response. Thus, for natural, predominantly 0. circumcincta infection, the heritability increases from essentially zero at one and two months of age to 0.33 at six months of age (5, 58). This is due to a combination of age and exposure, but the precise contribution of each component is unknown. The egg count actually made on a sample is only an estimate of the true egg count. The true egg count is not known, but the extent of measurement variation can be estimated from the repeatability (55) or from a repeated measures design (5, 56). This variation can be quite high, even without taking variation among faecal samples or faecal preparations into account, but variation can be reduced by counting more eggs. The measurement variation is a major component of the total variation. Consequently, reducing this component increases the relative contribution of all the other components and this increases the heritability. Similarly, taking repeated samples from the same animals also increases the heritability (53); the lower the repeatability, the greater the associated increase. With very few exceptions, the genetic value of other traits as markers of resistance to nematodes is unknown. The exceptions include, firstly, packed red cell volume following infection with H. contortus (71). This is a valuable marker for blood-sucking parasites, but has no value for infection with other nematodes. The value of this trait is also compromised in some areas where H. contortus exists, such as East Africa, because of the presence of trypanosomosis, which also depresses packed red cell volumes. Secondly, the concentration of antiparasite antibody is routinely used in New Zealand to assist in the identification of resistant sheep (19). Studies performed in Scotland of lambs infected with 0. circumcincta suggest that IgA is the important antibody and fourth-stage larvae are the important stage of the parasite life-cycle (51, 55). Both the amount (55) and specificity of* antibody (35) appear to be important. The third marker is weight gain in Scottish Blackface lambs (5). The genetic correlation between growth rate and egg count is so strong (-0.8) that selecting sheep for growth rate automatically selects for decreased egg counts. However, this work is based on sheep from only one farm and more extensive work on other breeds and other farms is necessary. Further work on additional markers is currently being performed at several locations. Genetic markers of resistance to infection Identifying the genes which code for resistance to nematode infection could increase the accuracy of identifying genetically superior animals and could enable the ranking of animals with different histories of exposure to infection. Research in several species of hosts has demonstrated that genes in or around the MHC are associated with resistance to nematode infection (42, 50, 52, 53, 56, 62). The influence of these genes can be difficult to estimate but may be quite strong (32). For example, six-month-old Scottish Blackface lambs with the G2 allele of the DRB1 locus have egg counts over 50 times lower

6 148 Rev. sci. tech. Off. int. Epiz., 17 (1) than lambs without this allele. This locus alone accounts for two-fifths of the genetic variation in faecal egg counts. A corollary of the strong effect of these MHC genes is that additional genes at other loci may be difficult to detect. The additional genes are unlikely to explain as much variation as the MHC and their influence will be weaker. Many genes which influence immune responses to nematodes are likely to be very polymorphic. Any serious search for genes in outbred populations will require large numbers of animals to ensure that rare but potentially important alleles are included in the study population. The problem is even more acute with linkage analyses or genome-wide screens, because these analyses need a significant number of sires to allow for polymorphism and a large number of offspring from each sire to detect relatively small effects. Creation of a selection index The most appropriate way to combine information on the different traits in a selective breeding scheme is to construct a selection index (10, 41). The necessary information includes details of the traits one wishes to improve (the selection objective) and the economic value of these traits. The economic value is the additional financial benefit which will be derived from an improvement in the trait. Details on the traits which are actually going to be measured (the selection criteria) are also needed. For example, the selection objective might be increased growth rate and reduced mass of nematodes. The selection criterion might be average daily weight gain from birth to six months of age and faecal egg counts at four, five and six months of age in naturally infected sheep given anthelmintics at five months of age. The major difficulty in constructing a selection index which includes nematode resistance is placing an economic value on the trait. As mentioned above, the advantages of nematode resistance are undoubtedly important but are difficult to estimate with precision. Variation between breeds A large number of studies have demonstrated significant differences in susceptibility to nematode infection among breeds of cattle and sheep (13, 14, 39, 40, 45, 46, 68). In general, resistant breeds come from areas with substantial exposure to natural infection and the superior resistance of such breeds may have arisen through natural selection. Geneticists have often stressed that when a trait under genetic control is examined, apparent differences between breeds could be due to genetic variation within each breed (41). For example, if the majority of the animals from breed A come from a resistant sire while those in breed B come from a variety of sires, then breed A will appear superior to breed B, regardless of the true difference between the breeds. This does not mean that all parasitological trials in outbred animals which have fewer than several hundred individuals in each group are worthless, but differences between breeds should be interpreted with caution until the results can be confirmed in independent studies. Among breed comparisons for resistance to H. contortus, the Red Maasai is consistently superior to other breeds from East Africa, and the Gulf Coast native from Louisiana and Florida is more resistant than other breeds in the United States of America (USA). Similarly, the Hampshire Down seems more susceptible than other breeds originating in Great Britain (67). To date, there are no confirmed reports of breed differences for other species of nematodes, such as 0. circumcincta and T. colubriformis. Exploiting breed differences in resistance to nematodes If one breed is markedly superior to all competing breeds in the selection objective, then this breed should be used. If this breed is not already widespread, then the policy is called breed substitution, which is a rapid, simple and sustainable solution appropriate for many countries. For example, in many Western countries, the Holstein-Friesian has replaced more traditional dairy breeds. The Red Maasai in East Africa is not only more resistant to nematodes but is more productive under moderate to severe challenge with H. contortus. This breed is the population of choice for farmers in East Africa with animals suffering from haemonchosis. Two misconceptions prevent the widespread use of superior, indigenous breeds in much of sub-saharan Africa. Many authors believe that larger animals are more productive and that because disease-resistant breeds are often small, there must be a trade-off between disease resistance and productivity. This argument confuses variation between groups with variation within groups. Nematode infections increase protein requirements (57). Large, grazing animals with fast growth rates may not be able to obtain sufficient protein to meet the increased demands during infection and they suffer disproportionately (67). However, within each group, the less severely infected animals are more productive. A second misconception assumes that those farmers and smallholders who keep susceptible animals do so because these animals meet the socio-economic requirements of the farmers most efficiently. However, even countries such as Australia, which has a highly efficient agricultural sector, have found that encouraging farmers to use obviously superior animals is a time-consuming and difficult task. For example, cattle which are a cross between Bos taurus and B. indicus perform much better in the Northern Territory and Queensland than straightbred animals, yet there was a long and bitter campaign before these crosses were widely

7 Rev. sci. tech. Off. int. Epiz., 17 (1) 149 adopted. In poor countries, farmers have less access to the results of research, extension services are underfunded and breed societies do not exist to promote the indigenous breeds. Consequently, without investment in advertising, there may be little chance of some breeds being used widely, even though these breeds may be largely superior. Two other methods of exploiting generic variation between breeds are systematic cross-breeding and the creation of a composite population (41). The optimal cross-breeding strategy cannot be determined unless there is a considerable amount of information on the performance of various breeds and the resulting crosses, in particular the amount of heterosis in the traits constituting the selection criterion. A considerable amount of research has been conducted on cattle in Australia (24), but unfortunately very little research has been performed on sheep, apart from one experiment in the coastal areas of Kenya which is examining Red Maasai and Dorper sheep (R.L. Baker, personal communication). Several composite cattle populations have been created for the hot, drought-prone areas of the southern USA and northern Australia, including the Droughtmaster and the Belmont Red. These animals are claimed to be more heat-tolerant and better able to withstand tropical diseases, including nematode infections. There is nothing similar in sheep apart from the Dorper, which is a composite of the Dorset Horn and the Persian breed. The Persian breed is the same as the Blackheaded Somali breed, and neither the Dorper nor the Blackheaded Somali include a particularly high level of resistance to nematodes among their undoubted attributes. There may even be a commercial opportunity for any breeder bold enough to create a composite sheep breed adapted to the harsh conditions of East and Central Africa. Exploitation of variation within breeds The best way to use genetic variation within a breed is to set up a selective breeding scheme. Breeding for resistance to nematodes is no different, in principle, than breeding for any other trait. Breeders who already select sheep for improved production could incorporate nematode resistance into the selection programme. The success of a breeding programme will depend upon several factors, including the intensity of selection, the genetic make-up of the breeding animals, the accuracy of selection methods, the age of the parents and the size of the population. Intensity of selection The smaller the proportion of animals selected to be parents, the greater the rate of progress will be. If the top 10% of animals are used for breeding, there will be better progress than if the parents are chosen from the top 50%. The intensity of selection may be constrained by the need to avoid inbreeding. Genetic make-up of the breeding animals Populations or traits with a wide genetic variation will give faster genetic progress. In most populations examined, there is considerable variation in resistance to nematodes. For example, the offspring of some Scottish Blackface sires have over 40 times fewer nematode eggs in their faeces than the offspring of other sires. Accuracy of selecting the best animals for breeding The accuracy of the selection process can be increased by taking additional samples and by taking samples from animals at a time when the heritability of the desired traits is highest. Another method of increasing the accuracy is to use information from relatives (10), and there are several computer programmes now available which will do this using best linear unbiased prediction methodology (29, 37). Average age of the parents when the lambs are born The younger the sheep are bred, the faster progress will be made. Population size A large population has more animals to select from and avoids the loss of desirable genes due to chance. Larger populations also diminish the risks of inbreeding. The population size can be considerably enhanced if several farms work together. The response to selection will probably be even greater than that predicted by quantitative genetic theory. Selection will produce a virtuous circle with positive feedback. The selected sheep will produce fewer eggs and there will be less pasture contamination. Fewer infective larvae are likely to be ingested and these larvae, when mature, will produce fewer eggs than comparable larvae in unselected sheep, and so on. Using a realistic model, Bishop and Stear predicted that the epidemiological effect would be even more important than the genetic effect, at least in the early stages of selection (6). Conclusion There is considerable variation in resistance to nematode infection among animals and much of this variation is genetic in origin. Understanding the genetic and immunological basis of resistance to parasitic infection is necessary for a comprehensive explanation of resistance to disease. In addition, this variation can be used to produce animals which are better able to survive and thrive in the presence of nematode infection. The best methods for exploiting the genetic variation depend upon the relative importance of variation within and among breeds.

8 150 Rev. sci. tech. Off. int. Epiz., 17 (1) Résistance génétique aux maladies parasitaires M.J. Stear&D. Wakelin Résumé L'aptitude des animaux à résister aux maladies parasitaires est liée à des facteurs génétiques; aussi varie-t-elle d'un animal ou d'une race à l'autre au sein d'une espèce hôte donnée. Cette variabilité, qui peut s'expliquer par des mécanismes de résistance innée (non immunitaires) et acquise (immunitaire), est déterminée par des gènes liés, ou non, au complexe majeur d'histocompatibilité (CMH). La résistance se transmet comme un caractère dominant, avec une héritabilité souvent supérieure à 0,3. La variabilité génétique peut être exploitée pour améliorer la capacité des animaux domestiques à résister aux maladies parasitaires. Les auteurs discutent les méthodes permettant d'y parvenir en prenant comme modèle le parasitisme des ovins par des nematodes gastro-intestinaux. Mots-clés Génétique - Immunité - Marqueurs génétiques - Modèles de laboratoire - Nematodes - Ovins - Parasites - Résistance aux maladies - Sélection. Resistencia genética a las enfermedades parasitarias M.J. Stear&D. Wakelin Resumen La capacidad de los animales para resistir a las enfermedades parasitarias viene determinada genéticamente, y varia por lo tanto entre los distintos individuos o razas de una especie huésped concreta. Esta variación puede guardar relación con mecanismos de resistencia innata (no inmunológica) o adquirida (mediada por el sistema inmunológico), y su control depende de genes tanto ligados como no ligados al complejo mayor de histocompatibilidad (major histocompatibility complex, MHC). La resistencia es un rasgo hereditario dominante, con una heredabilidad a menudo superior a 0,3. Es posible utilizar la variación genética para mejorar la capacidad de los animales domésticos para hacer frente a las enfermedades parasitarias. Los autores examinan algunos métodos en este sentido referidos a las infecciones gastrointestinales de la oveja causadas por nemátodos. Palabras clave Genética - Inmunidad - Marcadores genéticos - Modelos de laboratorio - Nemátodos - Oveja - Parásitos - Resistencia a la enfermedad - Selección.

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