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Rev. sci. tech. Off. int. Epiz. 1 9 9 8 , 1 7 (1), 302-314 Biological principles of heredity of and resistance to disease P. Horin Institute of Animal Breeding and Genetics, Faculty of Veterinary Medicine, University of Veterinary and Pharmaceutical Sciences, Palackeho 1/3, CZ 612 42 Brno, Czech Republic Summary U n d e r s t a n d i n g t h e biological principles of d i s e a s e h e r e d i t y a n d r e s i s t a n c e to d i s e a s e is a p r e r e q u i s i t e for t h e i n c o r p o r a t i o n of t h e s e f a c t o r s into multi-trait b r e e d i n g p r o g r a m m e s . M u t a t i o n s r e p r e s e n t a n e v o l u t i o n a r y a s p e c t of disease. T h e a u t h o r r e v i e w s p a t t e r n s of M e n d e l i a n i n h e r i t a n c e a n d possible c a u s e s of n o n - M e n d e l i a n i n h e r i t a n c e , s u c h a s m u l t i f a c t o r i a l i n h e r i t a n c e , e x p a n s i o n of trinucleotide repeats, mitochondrial inheritance and genomic imprinting, in relation t o d i s e a s e s of d o m e s t i c a n i m a l s . H o s t - p a t h o g e n i n t e r a c t i o n s underlie g e n e t i c variability in r e s i s t a n c e to d i s e a s e . I n f e c t i o u s p a t h o g e n s e n d o w e d with a high potential for e v o l u t i o n a r y c h a n g e use this potential t o e v a d e v a r i o u s host d e f e n c e m e c h a n i s m s . This i n t e r a c t i o n m a y h a v e a c o m p e t i t i v e or c o - e v o l u t i o n a r y c h a r a c t e r . T h e host i m m u n e s y s t e m c o p e s w i t h t h e variability of p a t h o g e n s by using t h e potential of g e n e t i c diversity of l y m p h o c y t e s in i m m u n o g l o b u l i n , T-cell r e c e p t o r and m a j o r h i s t o c o m p a t i b i l i t y c o m p l e x g e n e s . Possible m e c h a n i s m s for m a i n t e n a n c e of this diversity a r e d i s c u s s e d in t h e c o n t e x t of s e l e c t i o n f o r disease resistance. Keywords Disease heredity - Disease resistance - Domestic animals - Genetics - Host-pathogen interaction - M a j o r histocompatibility complex. Health traits as selection criteria in breeding programmes the evolutionary aspects of inherited disease as well as of Health is a prerequisite for optimal animal production. Losses due to disease are equivalent to 1 0 % - 2 0 % of total production costs. Genetic variability was found to influence different animal diseases many years ago ( 2 8 ) . Hereditary diseases caused by germ-line mutations, birth defects, often with complex origins (including germ-line and/or somatic mutations), chromosome aberrations and resistance to environmental pathogens are the main manifestations of genetic variability as an impediment to animal health. The genes which influence animal health are the focus of interest of gene-mapping projects ( 2 0 ) . Since selection is an evolutionary process, the incorporation of health criteria into breeding programmes must be based on an understanding of Heredity of disease resistance to disease. Mutations as a source of genetic variability represent the evolutionary aspect of disease ( 5 6 ) . From a long-term perspective, the effects of mutations are considered as advantageous, enabling the living organisms to adapt to changing environmental conditions and to evolve. In organisms such as viruses, bacteria or uni- and multicellular eukaryotic parasites, which have a short generation time and the capacity to produce high numbers of offspring, these evolutionary and adaptive aspects of mutations prevail. From the short-term perspective of an individual life-span or a few generations, mutations are considered as DNA damage with 303 Rev. sci. tech. Off. int. Epiz., 17 ( 1 | deleterious effects. In humans and in the breeding of domestic birds and mammals, it is this aspect of mutations which prevails. The genetics of disease and resistance to disease are thus based on different aspects of mutations. The eukaryotic genome Three main types of sequence in the eukaryotic genome are potentially subject to mutations that will subsequently cause disease. Single-copy genes Single-copy genes exist, together with their corresponding regulatory sequences, in one copy within the genome. These are the major type of structural genes. Their products may be different structural or regulatory proteins or RNA molecules. The polymorphism of these genes is based on the existence of alleles which differ in nucleotide sequences, produced by different types of point mutations, which are mostly nucleotide substitutions. Repetitive sequences The eukaryotic genome contains a number o f repeated sequences. The repeating unit may vary from a single nucleotide up to a whole gene (e.g., genes for ribosomal RNA [rRNA]). These repeated sequences are located at multiple sites (loci) in the genomes as dispersed copies or may be arranged into tandem repeats. Loci differ in the core sequence repeated. Their polymorphism consists of different numbers of repeats of the unit sequence among different individuals. These variants behave as Mendelian alleles. Microsatellites' are simple tandem repeat units, usually two to four nucleotides long, that are repeated many (up to 1 0 0 ) times. 'Minisatellites' are longer and possess a lower number of repeats. Some of the repetitive sequences may have a special function in the genomes, e.g., in the telomeres ( 7 1 ) : the function of others remains unknown. Extranuclear genes The mitochondrial genome is represented by circular DNA containing genes encoding components of the electron transport system as well as genes for transfer RNA (tRNA) and rRNA. Mitochondria have their own proteosynthetic machinery and use a modified genetic code for the synthesis of their proteins. Each cell contains large numbers of mitochondria with between two and ten identical molecules of mitochondrial DNA (mtDNA). There is no recombination between mitochondrial genes. These genes are of special importance due to their role in basic metabolic processes. Cytoplasmic effects on economically important traits, which may be attributed to mitochondrial inheritance, were observed in cattle (22). modes of disease inheritance may be distinguished: Mendelian and non-Mendelian (complex) inheritance (52). Mendelian inheritance of disease In this mode of inheritance, the disease behaves as a Mendelian trait through consecutive generations. The majority of hereditary diseases are phenotypically variable between, and also within, families. Genetic background, interactions with other genes, non-allelic heterogeneity and instability of some genetic material are considered to be major genetic factors influencing the phenotypic variation. Monogeneic diseases may be due to a single mutation or to a group of diverse mutations within the same gene, which may result in different or identical phenotypes. A spectrum of diverse phenotypes may be caused by multiple allelic variation in a single locus. Some traits were shown to be influenced by a single major gene and by polygenic variation (e.g., ryanodine receptor gene in pigs, Booroola gene in sheep). Polygenic/multifactorial diseases are an extreme example without any apparent contribution from a single gene ( 6 3 ) : The phenotype, as a product of the individual development, may also be influenced during its realisation in ontogenesis (72). Mutations of several genes leading to monogeneic diseases of domestic animals have been characterised at the DNA level. In other cases, the Mendelian inheritance pattern remains merely a descriptive term. The mode of inheritance is determined by the nature of interaction between the alleles involved (dominant, recessive, incompletely dominant). The ratio may also be influenced by the lethal character of the mutation involved. In animal breeding practice it is often difficult, if not impossible, to infer the mode of inheritance from held data (17). Monogeneic autosomal recessive inheritance The diseased phenotype is caused by the occurrence of two recessive mutant alleles in a single autosomal gene. Both sexes are affected with an equal probability. Unaffected parents may produce affected offspring. Consanguinity increases the probability of the appearance of affected recessive homozygous offspring, especially in rare disorders. The identification of unaffected carriers (heterozygotes) of selected diseases is one objective of the majority of breeding programmes. Molecular mechanisms of recessiveness usually result from a lack of a gene product (enzyme, receptor or other type of molecule), or the cause is unknown. The recessive homozygous genotype is sometimes lethal, which leads to a change in the F 2 generation to 2 carriers: 1 noncarrier (all unaffected). Dominance and recessiveness may be relative to the methods used to determine the phenotype. Monogeneic autosomal dominant inheritance Patterns of disease inheritance Different types of mutations in different sorts of genes lead to a variety of patterns of inheritance of the resulting disease. Two The diseased phenotype is caused by the occurrence of at least one dominant allele in a single autosomal gene. Both sexes are affected with an equal probability. Unaffected parents may produce only unaffected offspring. Affected heterozygous 304 parents may produce unaffected (recessive homozygous) offspring. This pattern of inheritance is rather rare. The molecular mechanisms of dominance remain largely unknown, although several different mechanisms have been postulated (57). M o n o g e n e i c a u t o s o m a l , incompletely d o m i n a n t inheritance In some diseases, a difference between dominant homozygotes and heterozygotes may be detected, often depending on the sensitivity of the methods used. This difference may involve a differential lethality (as is the case with achondroplasia in cattle). M o n o g e n e i c gonosomal recessive i n h e r i t a n c e (X-linked inheritance) If the mutant gene is located in the sex chromosomes, the inheritance pattern displays the characteristic features of a sex-linked trait. In domestic species, the disease genes identified so far have been located on the non-homologous part of the chromosome X. The pattern of inheritance is characterised by the existence of affected males (hemizygous for the condition), no male-to-male transmission, two genetic types of unaffected females (one of which transmits the condition to her sons through the X chromosome carrying the mutant allele), and a low probability of occurrence of an affected (homozygous recessive) female. Theoretically, gonosomal dominant and two-gene models for disease inheritance exist as well. However, no economically important disease of domestic animals has been identified unequivocally to fit such models. Non-Mendelian (complex) inheritance of disease Many inherited diseases and defects do not show regular Mendelian inheritance and their behaviour in genealogies is rather unpredictable. This situation may have been caused by a number of factors, which may result in different impacts on animal breeding. Rev. sci. tech. Off. int. Epiz., 17 (1) disease, or in heavily affected animals. The intermediate stages of the phenotypic expression may be explained by many different combinations of putative genotypes and environmental factors. Based on these characteristics, a large proportion of affected animals which vary in the degree of expression of the disease may be detected in the population. More severely affected parents tend to have more severely affected offspring, though transmission over generations is irregular. The concept of multifactorial inheritance is of practical importance in animal breeding. Various animal breeds have been bred for specific traits which may lead to an unintentional increase in predisposition to certain pathological conditions (for example, hip joint angle leading to hip dysplasia in German shepherd dogs, an extremely short head leading to upper respiratory defects in Persian cats, meat production as a cause of skeletal and muscular disorders in pigs). The concept of multifactorial inheritance thus indicates the limits of actual variability which may be used for the improvement of production traits without compromising animal health. Statistical analyses of quantitative variation of the disease phenotypes are based on an infinitesimal genetic model that assumes a large number of independent loci with small effects. This model is suitable for description and for prediction of response to artificial selection, but is unrealistic. The actual theory of polygenes is based on a concept of allelic series of mutants at fewer loci. For many traits, approximately ten loci may account for a major part of the variation observed. The mutants vary in their effect on the phenotype and its stability (53). The threshold model, which is formal, may be resolved by identification of the individual major genes involved. In mice and humans, major genes have been identified for some multifactorial disorders. This approach helps to elucidate the complex nature of these disorders and to understand the underlying pathogenetic mechanisms (21). Multifactorial (threshold) i n h e r i t a n c e The formal concept of threshold inheritance of disease is based on a continuous quantitative variation of genetic predisposition (liability) caused by segregation of more than one gene, which interacts with environmental factors and results in two phenotypes: 'affected' if a threshold value separating the two phenotypes is reached, or 'unaffected' if the action of genotype and environment remains below the threshold. The affected phenotype usually displays quantitative variation as well. Often, a group of different pathological states is considered as a single unit due to the lack of knowledge of the aetiology and pathogenesis of each. The threshold may be reached by different combinations of genetic and environmental factors, thus leading to a variety of more susceptible or more resistant genotypes. The correlation between the genotype and the phenotype is strong in the extremes, i.e., in animals completely free from any signs of the Congenital (birth) defects are an important category of health disorders of livestock with possible genetic aetiology. Since these defects are a heterogeneous group of pathophysiological states caused by many different factors, their mode of inheritance often remains undetermined. The defects may occur as idiopathic (i.e., solitary) or as part of complex syndromes. In pigs, a species suitable for segregation analyses, the inheritance patterns could not be clarified in many birth defects of practical importance, such as cryptorchidism, atresia ani, scrotal hernia and hermaphroditism. Recent genetic analyses showed that a majority of these defects fitted a bigeneic or polygenic model (65). Expansion of t r i n u c l e o t i d e r e p e a t s Not only mutations in single-copy genes lead to a disease. Certain triple repeats, present in every animal species studied 305 Rev. sci tech. Off. int. Epiz., 17(1) so far, were found to be unstable in humans. Mutations in such unstable trinucleotide repeats result in an increase in the number of copies of the same trinucleotide sequence or, less frequently, in its contraction. This type of mutation, termed 'dynamic mutation' ( 3 9 ) , has been shown to cause serious inherited human disorders ( 6 0 ) . Dynamic mutations are characterised by a non-Mendelian inheritance. Each trinucleotide repeat displays a normal range of numbers of repeats within which the polymorphic alleles are stable and are inherited in a Mendelian way. A pre-mutational non-symptomatic stage (transitional alleles) and a stage with a fully developed symptomatology, due to a copy number increased beyond a threshold, may be distinguished. Clinical anticipation, i.e., an earlier onset of the disease through successive generations, may be observed, and this is probably due to the progressive accumulation of numbers of repeats. The severity of disease increases in accordance with the increase in the number of repeats. There is probably more than one mechanism of pathogenesis ( 2 6 ) . No inherited disease of this type has been identified in domestic animals so far, and no naturally occurring animal equivalent of dynamic mutation is known. The mouse homologues of the corresponding human genes have shorter length repeats and lower polymorphism (64). An artificial animal model, SCA1 transgenic mouse, has been developed ( 2 6 ) . The potential importance of this type of mutation for livestock remains undetermined. Mitochondrial inheritance In humans, several diseases due to mutations in mitochondrial genes have been identified. Large-scale DNA rearrangements and/or point mutations in tRNA or rRNA genes, or in protein-coding genes, lead to different disorders (24). The numbers of mutant mtDNA may vary in the different cells and tissues within an individual. The resulting diseases are maternally inherited: males do not transmit the disease to their offspring. All offspring may be affected, although this is not always the case, and males and females are usually affected equally. High variability in disease manifestation may be observed. Animal mitochondrial genes display a high substitution rate. Within vertebrates, the gene arrangement is well conserved ( 3 6 ) . However, no disease with an established mitochondrial inheritance pattern has been identified in livestock so far. Epigenetic i n h e r i t a n c e a n d polar o v e r d o m i n a n c e Non-Mendelian inheritance may result not only from mutations of the gene(s) involved, but also from epigenetic phenomena. A potentially Mendelian inheritance of some genes may be altered by genomic imprinting. Genomic imprinting is the differential expression of genetic material depending on whether the material was inherited from the male or from the female parent ( 2 5 ) . In inherited diseases, this means that specific gene(s) has/have a different phenotypic (clinical manifestation) effect depending on whether they have been transmitted through the male or female parent. The Mendelian rule of equivalency of each parental allele thus does not apply in this case. In each generation, a new genomic mark is made. As a result of its epigenetic nature, genomic imprinting may influence different types of mutations: point mutations, chromosome abnormalities or trinucleotide repeats (42). Inheritance of several human diseases has been shown to be influenced by genomic imprinting (35). Recently, the callipyge locus in sheep causing muscular hypertrophy in the hindquarters was characterised by a form of nonMendelian inheritance termed 'polar overdominance'. The callipyge phenotype is manifested only in heterozygotes which have inherited the mutated callipyge allele from their father (6). The pattern of inheritance observed could be explained by genomic imprinting. A breeding strategy of establishing paternal callipyge (CLPG/CLPG) lines which would produce 1 0 0 % callipyge offspring with normal ewes, despite their normal phenotype, has been suggested (7). Mendelian cytogenetics Current classifications of genetic disorders involve chromo somal defects. Chromosome aberrations may produce different clinical manifestations in humans and animals, including embryonic mortality, spontaneous abortions, multiple congenital anomalies and other manifestations. Some of the chromosome aberrations may be associated with Mendelian disorders in humans ( 6 6 ) . In cattle, the robertsonian translocation 1/29, which impairs fertility in heterozygous cows, is inherited through fertile sires (38). In some countries breeding bulls are examined for the presence of this translocation in their karyotypes. Phenomena complicating selection against inherited diseases A direct practical application of the theoretical knowledge of patterns of disease inheritance may be hampered by several phenomena, including penetrance of disease, expressivity, the heterogeneity of inherited disease, phenocopies and pleiotropy. P e n e t r a n c e of d i s e a s e Penetrance of disease is a statistical concept that indicates the probability that animals of a special genotype express the affected phenotype ( 3 1 ) . This is then expressed as a proportion (%) of affected animals out of all diseased genotypes. There may be various genetic and non-genetic causes of incomplete penetrance. For example, different environmental factors may interfere with the manifestation of the disease, an individual may die for other reasons before the onset of the disease under consideration or methods of determining the phenotype may be too insensitive. Involvement of other genes (i.e., a more complicated case than the monogeneic model of inheritance) may produce this situation as well. A false penetrance may be caused by genetic heterogeneity of the disease. Existence of incomplete penetrance leads to complications in determining the mode of inheritance and to mistakes in the determination of individual genotypes. 306 Expressivity Expressivity means that the degree of phenotypic presentation of the disease in an individual varies quantitatively and/or qualitatively (e.g., bovine hereditary syndactyly). Thus, the same genotype may differ in its expression of a disease. The mechanisms for this variation remain unknown. The differential symptomatology may be due to differences in individual development. In general, the shorter the pathogenetic path from the genetic defect to its phenotypic manifestation, the less the variability. Heterogeneity of inherited disease Heterogeneity of inherited disease means that the same disease may be caused by different mutations in different individuals. Consequently, modes of inheritance will differ in different families. Different mutations of the same or, more often, of different genes contributing to the genetic detetmination of the normal trait may be involved. Phenocopies Phenocopies are diseases or defects which are identical to those caused by germ-line mutations but which are not inherited (e.g., arthrogryposis in catde). These phenocopies thus mimic a phenotype caused by a specific genotype and cannot be distinguished from the hereditary forms by clinical examination. There is common pathogenesis, although the aetiology (germ-line mutation versus foetal somatic mutation or non-mutational, environmental teratogenic effects) differs. Pleiotropy Pleiotropy means that a given locus may have more than one phenotypic effect. The identity of genes coding for two different phenotypic effects is not necessarily immediately apparent. Due to the effects described, a straightforward diagnosis of inherited disease based on previous experience may be difficult. A confirmation of hereditary nature and of the mode of inheritance may be required in cases of a new occurrence of known hereditary diseases. Importance of the patterns of inheritance for breeding programmes Knowledge of the mode of inheritance of a disease is a prerequisite for incorporation of health traits into breeding programmes. In monogeneic diseases, different approaches leading to the elimination of sires suspected of carrying undesirable alleles may be used, for example, progeny-testing (often combined with superovulation and embryo transfer), detection by use of markers or direct detection of the mutant allele by molecular genetic techniques. In the case of multifactorial inheritance of undesirable traits, the measures adopted are usually based either on identification of the most liable individuals according to their phenotype or on offspring analysis. A majority of congenital defects are caused during pregnancy by environmental teratogens, such as different chemicals, viral infections or plant toxins ( 3 7 ) . Hereditary cases often display a multifactorial inheritance. Thus, breeding Rev. sci. tech. Off. int. Epiz.. 17 (1) programmes must integrate different types of disease inheritance as well as environmental factors. In addition, economic considerations are important for introducing a control measure into the breeding programme. Biological basis of heredity of resistance to disease Genetic variability in the reaction to different pathogenic stimuli has been described repeatedly. As observed, resistance and susceptibility to disease are of a quantitative nature and are rarely absolute. In many cases, resistance/susceptibility represents a complex phenotype influenced by a variety of environmental factors. Improvement in disease resistance by artificial selection has been demonstrated in experimental work as well as in domestic animal species (40). Conventional selection for disease resistance results mostly in quantitative improvement in resistance without major changes in the mechanisms ( 1 9 ) . Disease resistance traits fulfil the criteria used for incorporation of a trait into a breeding programme (58). Low heritability, the effects of age and sex, heterogeneity of disease traits and correlations with resistance to other diseases and production traits are the major limiting disadvantages of conventional breeding methods (40). In livestock, selection for disease resistance implies an artificial re-shaping of the genetic structure of a population and/or of an individual. Some of the changes induced by artificial selection have even been compared to speciation, as illustrated by differences between modern broiler and layer chickens and between dairy and beef cattle. The changes may be considered as a continuation of human influence on the evolution of farm animals ( 1 9 ) . Therefore, selection for disease resistance, in order to be functional and efficient, must follow the rules operating in naturally evolving populations. This is always a complex process, resulting from both synergetic and. antagonistic interactions of artificial and natural selection, involving multiple factors. In animals left under natural conditions, the status of actual disease resistance is the result of a selection pressure of multiple pathogens (19). In animal breeding, there is often a tendency to emphasise one currently important, but nonetheless singular, aspect of the complex phenomenon of disease resistance. Formal genetics of disease resistance Disease resistance may be formally classified according to several criteria. Species-specific disease resistance describes inter-species variability in resistance to different types of diseases. For the practical purposes of animal breeding, investigations into the mechanisms of this type of resistance might be useful. Rev. sci. tech. Off. int. Epiz., 17 (1) Breed-specific resistance has been observed in different species. Resistant pure breeds or crossbred animals are used in different parts of the world under extreme conditions of temperature, parasite load, etc. Their use results from inherent limitations of selection between breeds and/or of crossbreeding. Individual disease resistance manifested by individual variability within species and within breeds is the most important type with regard to breeding programmes, and enables the use of selection for disease resistance within breeds. General and specific resistance to disease represents another classification of disease resistance. General resistance is the ability to cope with unfavourable environmental factors in general, and is relatively independent of the causative factor. Such resistance is determined by the cumulative effects of many genes and is influenced by environmental factors. A variety of different mechanisms mediated by structural, physiological and other traits may underlie the phenotype. Animal breeders take this capacity into consideration under the name of constitution. Formally, general resistance is of a multifactorial nature and behaves as a quantitative trait with low heritability. Specific resistance is resistance to a specific pathogen which may differ in nature (infectious, physical, nutritional, etc.). The degree of specificity may vary from a viral strain or bacterial serovar to a large group of pathogens, such as intracellular infectious pathogens. Formally, the inheritance is often monogeneic. The mechanisms and the corresponding genes involved may be extremely variable. The formal genetic terminology is merely descriptive. Efficient incorporation into breeding programmes requires an understanding of the underlying biological principles. The evolutionary approach to disease and to artificial selection, as an important aspect of the breeding policy, is particularly useful in the case of disease resistance. Evolutionary principles of resistance to infectious disease: genetics of host-pathogen interaction As one of many different pathogenic factors, infection represents a substantial cause of economic loss in animal production. Resistance to infectious diseases is not only an economically important problem, but also a model situation in which evolutionary interaction between two living organisms occurs. The interaction is based upon a confrontation of the survival strategy of the pathogens and that of the host. Often, interaction may acquire the character of co-evolution rather than competition. The genetics of the host-pathogen interaction thus provide information on the evolutionary mechanisms of the process of selection for disease resistance. 307 Strategy of pathogens Infectious pathogens are considered as organisms adapted to multiplication within a host as part of their strategy of survival and persistence. The art of survival of living pathogens is based on their high reproduction capacity, resulting from a combination of a short generation time with high numbers of offspring. This capacity is a prerequisite for an efficient evolutionary strategy based on a high genetic variability used for rapid changes of phenotypic characteristics. Parameters of pathogenicity and mechanisms for evading host defence mechanisms, both of which are directly related to survival, are of special interest in the context of selection for disease resistance. The parameters of pathogenicity are determined and limited by the necessity of preserving the host organism in a condition which allows successful reproduction and transmission of the pathogen. However, it is possible to increase the success (fitness) of the parasite either by increasing the pathogenicity, accompanied by higher fecundity and more efficient transmission, or by decreasing the pathogenicity in conjunction with longer survival and thus longer exploitation of the host (8). A mutual interaction with the host then determines optimal parasite virulence. There must be some cost of resistance to the host. If this did not exist, the genes underlying the host resistance would be fixed very rapidly within the population. The costs may be represented by indirect deleterious effects, such as reduction of resistance to other diseases ( 6 2 ) . A coevolutionary balance established between the parasite and the host leading to survival of both may be achieved and maintained by different mechanisms (73). This interaction is thus an evolving dynamic (18). The manifestation of disease reflects this balance. Due to the heterogeneity of pathogenic organisms, there are many features of the host-pathogen interaction specific for individual groups of pathogens. Prions Prions ( 5 0 ) seem to be very successful pathogens with regard to survival strategy. According to the prion hypothesis, these pathogens use not only the host cell machinery but also the host genetic information for their life processes: consequendy, they do not elicit host immune responses. It should be noted that, under these conditions, the defenceless host is not killed immediately. This concept of being both inherited and infectious is unique in disease genetics (49). Viroids and viruses All viruses are characterised by the use of the host cell machinery for reproduction. Viroids, which are nonenveloped RNA molecules, have been identified exclusively as plant pathogens to date. Their genetic information, which is characterised by an extraordinary capacity for variation, is replicated by the host enzymes. As the most host-dependent pathogens, viroids are logically also the most rapidly evolving organisms. (12). RNA and DNA viruses differ significantly with regard to the capacity for genetic variability. RNA viruses have a considerably larger capacity for genetic 308 Rev. sci tech. Off. int. Epiz., 17 (1) variability than DNA virases, due to a lack of repair mechanisms resulting in a higher mutation rate ( 1 0 - 1 0 and 10 -10 substitutions/nucleotide/year, respectively). In addition to the lack of proof-reading enzymes associated with DNA polymerases, a high number of synthesised virus particles and their ability to escape from host DNA regulatory functions contribute to their genomic variability. The population of closely related (but not identical) genome sequences derived from the original 'master sequence' has been termed 'quasi-species' ( 1 4 ) . The quasi-species concept implies that the virus particles may be genetically highly variable, even within a single host. The majority of the mutants do not necessarily differ in their pathogenic and other phenotypic characteristics. Selection for ability to replicate occurs among the genomes. New strains, new viruses and new diseases may thus emerge (41). - 1 -8 - 4 -11 The mutation rate of DNA viruses is lower than that of RNA viruses, but is still higher than the mean mutation rate of the host cell DNA. Their strategy often relies on co-evolution rather than on competition with the host. Co-evolution with the host implies an incorporation of the selective pressures exerted by the immune system into the evolutionary strategy of the virus (47). To avoid the host defence mechanisms, viruses use mechanisms of antigenic variability, mimicry and induction of immunosuppression. Viruses also encode proteins which interact with the immune system (especially with antibodies, complement, cytokines and cytotoxic T lymphocyte response). Establishment and maintenance of persistent or latent states may result from such an interaction. Examples of an extremely pathogenic virus attenuated by a natural selection process (rabbit myxomatosis in Australia) illustrate one possible type of host-virus interaction. Bacteria The DNA prokaryotes genome, represented by chromosomal and episomal DNA, is much larger than viral genomes. The size of the bacterial genome may vary from several hundreds of kilobases (kb) up to almost 10,000 kb (34). In contrast to the eukaryotic genome, bacterial DNA does not usually contain spacers, introns or repetitive sequences. The potential for genetic variability in bacteria in comparison with viruses is not increased solely by a different type of genome: in fact, the bacterial genome is more complex and more flexible than was initially believed (33). Additional sources of bacterial genetic variability are found in the existence of more than one different chromosome within a single bacterial cell, including so-called 'secondary chromosomes', and the existence of linear chromosomes and plasmids. Since a distinction between bacterial and phage genes may be difficult, the presence of bacteriophages contributes to the genetic variability of bacterial DNA as well ( 1 5 ) . Some pathogenic bacteria may have a rather clonal character, i.e., all the bacterial cells are genetically identical, whereas others have rather a sexual character that results in genetically different bacterial cells within a single population ( 1 1 ) . Horizontal exchanges due to sexual processes may have an impact on inter- and within-population variability in methods to escape the host defence mechanisms or in antibiotic resistance of pathogenic microbes. The potential for genetic variability in bacteria is reflected in the existence of a wider repertoire of different interactions with the host organism. Bacterial pathogenicity as a multifactorial phenomenon requires the action of multiple genes. Such genes have been identified and cloned (61). There have been suggestions that the structural microheterogeneity of bacterial DNA molecules may be involved in interactions with the host immune system (46). The genetic control of bacterial virulence consists of both antigenic variation (which allows evasion of the host immune system) and adaptive expression of gene products in a concrete host environment, such as temperature, pH, etc. (13). Mutant bacterial populations that result from in vivo exposure to factors challenging the survival of the microbe may be a cause of persistent bacterial infections, especially in immunocompromised hosts. The host-pathogen interaction may also be altered by normal bacterial flora ( 1 5 ) . Eukaryotic parasites A broad spectrum of different living organisms belongs to the group of eukaryotic parasites: from unicellular to multicellular organisms to intracellular endoparasites and ectoparasites. Various host defence mechanisms depend heavily on the type of organism and on the mode of parasitism. Parasites avoid the mechanisms either by passive immunoevasion or by an active immunomodulation. Some parasite species not only avoid but even exploit the host defence mechanisms for their development. Host cytokines or other molecules then serve as parasite growth factors ( 5 , 5 5 ) . General conclusions about pathogens Genetic variability, which is the underlying principle of pathogen survival strategy, is used to avoid host defence mechanisms. The variability of mechanisms used by different types of pathogens reflects an extremely strong selection pressure exerted by the immune system. The principal mechanisms common to all groups of pathogens are the capacity for antigenic variability, molecular mimicry, induction of host immunosuppression, induction of host unresponsiveness and evasion of host recognition mechanisms by antigen-masking and/or by active modulation of host immune responses. Some pathogen-evading mechanisms of the host are involved in the pathogenesis of diseases. Molecular mimicry may lead to autoimmune or other disease (10); expression of superantigens, which causes polyclonal triggering of the host immune system, seems to be beneficial for the replication and survival of at least some parasites (2). Rev. sci. tech. Off. int. Epiz., 17(1) 309 Genetics of i m m u n e r e s p o n s e s and the host survival strategy The principal task of host defence mechanisms must be to cope with the high evolutionary potential of pathogens. Bird and mammalian hosts cannot base their adaptation upon their own genetic plasticity. However, an. 'organism' with the potential for reproduction and genetic variability comparable to that of pathogens has evolved within the hosts: the lymphocyte. Lymphocytes are cells that transcribe the highest number of genes among all cells within an organism. The host strategy is thus based on genetic variability of specialised cells and their capacity to co-ordinate action within the immune system and within the organism. The existence of other defence mechanisms (e.g., natural immunity, barriers, receptors) complementary to this main evolutionary philosophy may also be used in selection for disease resistance. Therefore, two types of genes involved in immune mechanisms may be distinguished as far as their genetic variability (polymorphism) is concerned, as follows: a) Genes whose variability is a primary attribute and prerequisite for their function. The use of variability by these genes copes with the variability of pathogens. Immuno globulin (Ig) genes, genes encoding the T-cell receptor (TCR) and genes of the major histocompatibility complex (MHC) belong to this group. b) Genes whose variability is secondary. Every gene involved in immune responses or other defence mechanisms is potentially subject to mutation and thus may become a gene for disease resistance or susceptibility to disease, for example, CD18 (cluster of differentiation antigen 18) in the bovine leucocyte adhesion deficiency (BLAD) and mutations of the natural resistance-associated macrophage protein-1 (Nrampl) gene in mice. For instance, at least seven and nine different genes influencing basal Ig levels or antibody production have been identified in humans and mice, respectively (51). Evolutionary aspects of lymphocyte variability Two major principles govern the variability of lymphocytes: a foresight of the immune system during lymphocyte development and the polymorphism of MHC genes. With regard to lymphocyte development, since selection acting on Ig genes based on past experience with the pathogen would be useless, as argued by Ohno et al., an anticipation ('foresight') of the immune system evolved (43). The diversity of Ig and TCR genes is generated prior to contact with antigen, based on a restricted number of inherited genes encoding the variable (antigen-binding) part of the molecule. Somatic hypermutation may increase the number of potential variants. These mechanisms generate a basic repertoire of molecules with the capacity to bind approximately one billion antigenic determinants. Polymorphism of MHC genes is characterised not only by extremely high numbers of alleles but also by their relatively uniform distribution within a population, and thus differs from polymorphism in other vertebrate genes. In natural populations, MHC polymorphism is probably maintained by balancing selection at the antigen-binding site (27). According to this concept, no single allele is more advantageous than another, from a long-term perspective, and the repertoire represented by the whole pool of MHC alleles is desirable and maintained. Balancing selection is thought to be a direct consequence of the interactions of parasites with the immune system. The rarity of associations of MHC haplotypes with resistance to any particular infectious disease suggests that selection for resistance is probably mediated by a peptide repertoire covering multiple pathogens (45). The main forces maintaining MHC polymorphism are still a matter of debate, but the polymorphism may be driven by pathogen interaction and by mechanisms which serve to avoid inbreeding ( 1 ) . Pathogen-driven selection can be based on heterozygote advantage (overdominance) or frequency-dependent selection resulting from pathogen evasion of immune recognition. Both phenomena may be interpreted in terms of the binding specificities of different class I and class II alleles ( 4 5 ) . MHC heterozygosity may be maintained negatively by avoidance of homozygosity and positively by the advantage of a broad repertoire of peptide motifs recognised in pathogenic organisms. Frequency-dependent selection leads, due to a long-term interaction with an enzootic pathogen, to changes in the distribution of MHC polymorphism within a population. Whether all of these mechanisms operate (and by what means they do so) in natural and/or artificial populations is not clear. Changes in MHC allele frequencies in herds with enzootic bovine leukaemia virus infection were observed (9). High heterozygosity in MHC genes, as well as in microsatellite loci, has been observed in an inbred horse population (Horin et al., in preparation). Possible interpretations of these findings are equivocal. A comparison of heterozygosity in MHC genes in unexpressed microsatellite loci in sheep and horses showed that the provision of evidence for selection acting on MHC in domestic species is extremely difficult ( 3 ) . The putative 'inbreeding avoidance' mechanisms include MHC-dependent abortions and mate choice (1), MHC-linked effects on reproduction, growth, development and cancer were identified in humans and rodents. One of the costs of maintaining MHC heterozygosity is a propagation of MHC-linked reproductive defects leading to foetal losses (23). The effect of MHC on fertility has been described in cattle, pigs, horses and chickens (44). MHC haplotype sharing has been shown to influence fertility in humans as well as in some animal species. Mating preference, which could lead to an increased proportion of MHC heterozygotes in the offspring, was detected in mice and humans ( 4 8 , 6 9 ) . In rodents, MHC-associated (but also MHC-independent) olfactory signals mediating the mate 310 Rev. sci. tech. Off. int. Epiz., 17 (1) distinction were identified (4, 16). Since many species do not combination will occur which may never be repeated. The use smell for the selection of mating partners, the omnipresent individual variability in immune responsiveness may lead to parasites were probably the primary stimulus of MHC the use of a variety of defence mechanisms against the same selection during vertebrate evolution ( 3 2 ) . However, the pathogen. Diverse types of disease may be distinguished in the association of MHC genotypes with genes coding other traits mutual interaction of the pathogen and the defence reaction: involved in mate selection were described ( 6 7 ) . In mice, those in which the pathogen prevails, and those in which the female preference for non-parasitised males was reported symptomatology is determined mainly by immune or other (30). defence reactions. Disease symptomatology as described in Non-random MHC combinations found in mouse blastocysts indicated a possibility of choice for MHC the textbooks is therefore determined by multiple factors. In combinations during fertilisation ( 7 0 ) . In domestic animal general, it represents a statistical description which does not species, the effects of MHC homozygosity on the viability of necessarily fit a concrete individual case. As pointed out by newborn piglets and of MHC class I compatibility between Riffkin et al., the infection and the potential prophylactic and cow and calf on retained placenta in cattle have been reported therapeutic measures cannot be viewed as a simple clearance 5 4 ) . Here again, the significance of these findings in of an inert antigen by the host immune response, but must terms of the disease resistance of domestic animals remains rather be regarded as a dynamic interaction in the context of (29, unclear, although the results may be of potential importance. the countermeasures taken by the parasite. Only then may rational and effective anti-pathogen strategies be designed (55). As suggested by the existence of MHC associations with production traits, selection for these traits may be accompanied by unintentional selection for resistance to Data on host-pathogen interaction suggest that selection for common pathogens which may impair productivity (1) or disease resistance, as an intervention in a complex system, may lead to an increased susceptibility, perhaps due to a may have long-term systemic effects. The knowledge of reduced exposure of domestic animals to pathogens under biological backgrounds makes such interventions possible. modem management systems (68). The latter outcome seems Since the costs of selection for resistance must be comparable to be more frequent. to losses caused by the disease, only major pathogens or a group of pathogens with common resistance mechanisms are candidates for selection. Selection for resistance to a group of With regard to specific host versus pathogen interaction, diseases, which is one of multiple approaches to the control of genetic variants unable to react with the determinants of the animal health in populations, might thus be a practical counterpart do not survive and are considered as negative. compromise between specific and general resistance. Genes This attribute may be of relative value due to specific coding for proteins with multiple effects on the immune interactions between the pathogen and the host. For example, system (such as interferon gamma, tumour necrosis factor or a the same MHC haplotypes may be either resistant or nitric oxide transporter) have been identified as being susceptible, according to the parasite stock (1): polymorphic. Conclusion: practical outcomes of disease resistance Genetic resistance in domestic animals contributes to reduction of the use of drugs and other chemicals in animal production. Animal welfare based on disease-free status which results from genetic resistance lowers susceptibility to other diseases (59). The objective of selection for disease resistance is to reduce economic losses due to disease, and the results of such selection will indicate the actual biological limits of selection Breeding programmes based on recording and questionnaire for systems, have to integrate varying types of inheritance of productivity. This does not imply an automatic compromise of the objective, but rather a determination of different diseases and other undesirable traits, including optimal dynamics for the process of improvement. environmental effects, their mutual interrelationships, their economic impact, the costs of elimination and the relationships with other (especially production) traits. The Knowledge of biological mechanisms of disease resistance, programmes including the relationship between these mechanisms and significantly according to the actual situation in the country production traits, is necessary for the efficient incorporation of and economic considerations in different populations of disease resistance into breeding programmes. Any disease, domestic animals, but the underlying biological principles are including infectious disease, is not an entity per se, but is a universal. These principles allow an understanding of the result of the host defence reaction to the pathogenic stimulus. potential long-term effects of selection for health traits and the In efficient use of these effects. infectious disease, a unique host versus pathogen implemented in different countries vary 311 Rev. sci. tech. Off. int. Epiz., 17 (1) Acknowledgements Kentucky, Lexington, United States of America, for editorial The preparation of this manuscript was supported by grant 5 1 4 / 9 5 / 1 5 9 4 of the Grant Agency of the Czech Republic. The author thanks Dr D.G. Fraser from the University of comments on the manuscript. Principes biologiques de la transmission héréditaire des maladies et de la résistance à ces dernières P. Horiri Résumé La c o m p r é h e n s i o n d e s p r i n c i p e s b i o l o g i q u e s d e la t r a n s m i s s i o n h é r é d i t a i r e d e s m a l a d i e s e t d e la r é s i s t a n c e à c e s d e r n i è r e s e s t u n e c o n d i t i o n p r é a l a b l e à l'intégration de c e s facteurs dans les programmes de sélection portant s u r plusieurs caractères. Les mutations représentent u n a s p e c t é v o l u t i f d e la maladie. L'auteur examine les s c h é m a s de l'hérédité mendélienne e t les causes possibles de l'hérédité non-mendélienne, telles q u e l'hérédité l'expansion des répétitions de trinucléotides, l'hérédité multifactorielle, mitochondriale ou l'impression du génome, pour c e qui estdes maladies des animaux domestiques. Les i n t e r a c t i o n s h ô t e - a g e n t p a t h o g è n e s o u s - t e n d e n t la v a r i a b i l i t é g é n é t i q u e e n m a t i è r e d e r é s i s t a n c e aux m a l a d i e s . Les a g e n t s p a t h o g è n e s i n f e c t i e u x , d o t é s d'un important potentiel d'adaptation, utilisent c e dernier pour déjouer les divers m é c a n i s m e s d e défense d e l'hôte. Cette interaction peut revêtir u n c a r a c t è r e c o m p é t i t i f o u c o - é v o l u t i f . Le s y s t è m e i m m u n i t a i r e d e l ' h ô t e f a i t f a c e à la v a r i a b i l i t é des agents pathogènes e n u t i l i s a n t la d i v e r s i t é génétique potentielle d e s lymphocytes exprimée p a r les gènes codant pour les immunoglobulines, les r é c e p t e u r s d e la c e l l u l e T e t le c o m p l e x e majeur d'histocompatibilité. Les m é c a n i s m e s p o s s i b l e s d e m a i n t i e n d e c e t t e d i v e r s i t é f o n t l ' o b j e t d e la d i s c u s s i o n d a n s le c a d r e d e la s é l e c t i o n p o u r la r é s i s t a n c e a u x m a l a d i e s . Mots-clés A n i m a u x d o m e s t i q u e s - Complexe majeur d ' h i s t o c o m p a t i b i l i t é - Génétique - Interaction hôte-agent pathogène - Résistance a u x maladies - Transmission héréditaire d e s maladies. Principios biológicos de la resistencia a la enfermedad y de la transmisión hereditaria de enfermedades P. Horin Resumen La c o m p r e n s i ó n d e l o s p r i n c i p i o s b i o l ó g i c o s q u e r i g e n t a n t o la t r a n s m i s i ó n h e r e d i t a r i a d e e n f e r m e d a d e s c o m o la r e s i s t e n c i a a la e n f e r m e d a d e s u n requisito i n d i s p e n s a b l e p a r a i n c o r p o r a r e s o s f a c t o r e s a p r o g r a m a s d e c r í a q u e p e r s i g a n la reproducción simultánea de múltiples rasgos. Las mutaciones constituyen un a s p e c t o e v o l u t i v o d e la e n f e r m e d a d . El a u t o r p a s a r e v i s t a a l a s r e g l a s d e la h e r e n c i a m e n d e l i a n a y a l a s p o s i b l e s c a u s a s d e la h e r e n c i a n o m e n d e l i a n a Rev. sci. tech. Off. int. Epiz., 17 (1| 312 ( h e r e n c i a m u l t i f a c t o r i a l , e x p a n s i ó n d e r e p e t i c i o n e s d e t r e s p a r e s d e bases, h e r e n c i a m i t o c o n d r i a l o i m p r e s i ó n [imprinting] g e n ó m i c a ) e n r e l a c i ó n c o n las e n f e r m e d a d e s d e los a n i m a l e s d o m é s t i c o s . Las i n t e r a c c i o n e s e n t r e h u é s p e d y p a t ó g e n o s o n d e t e r m i n a n t e s p a r a la v a r i a b i l i d a d g e n é t i c a c a r a c t e r í s t i c a d e las r e s i s t e n c i a s a la e n f e r m e d a d . Los a g e n t e s i n f e c c i o s o s provistos d e u n a gran c a p a c i d a d p a r a el c a m b i o evolutivo s e v a l e n d e esta p r o p i e d a d p a r a e s c a p a r a los diversos m e c a n i s m o s d e f e n s i v o s d e l h u é s p e d . S e m e j a n t e i n t e r a c c i ó n puede revestir un c a r á c t e r bien c o m p e t i t i v o o bien c o e v o l u t i v o . El p o t e n c i a l para la d i v e r s i d a d g e n é t i c a linfocitaria q u e e n c i e r r a n los g e n e s d e l a s i n m u n o g l o b u l i n a s , los r e c e p t o r e s d e los linfocitos T y el c o m p l e j o m a y o r d e h i s t o c o m p a t i b i l i d a d sirve al s i s t e m a inmunitario d e l h u é s p e d p a r a h a c e r f r e n t e a la v a r i a b i l i d a d d e los p a t ó g e n o s . S e c o n s i d e r a n l u e g o posibles m e c a n i s m o s i m p l i c a d o s e n el m a n t e n i m i e n t o d e e s t a d i v e r s i d a d g e n é t i c a y s u e v e n t u a l utilidad p a r a la s e l e c c i ó n d e r a s g o s de r e s i s t e n c i a a las e n f e r m e d a d e s . Palabras clave Animales domésticos - Complejo mayor de h i s t o c o m p a t i b i l i d a d - Genética - Interacciones h u é s p e d / p a t ó g e n o - Resistencia a la e n f e r m e d a d - T r a n s m i s i ó n hereditaria de enfermedades. • References 1. Apanius V., Perm D., Slev P.R., Ruff R.L. & Potts W.K. (1997). - The nature of selection on the major histocompatibility complex. Crit. Rev. Immunol, 17,179-224. 2. Blackman M.A. & Woodland D.L. (1995). - In vivo effects of superantigens. Life Sci., 57 (19), 1717-1735. 3. Boyce W.M., Hedrick P.W., Muggli-Cockett N.E., Kalinowski S., Penedo M.C.T. & Ramey R.R. II (1996). Genetic variation of major histocompatibility complex and microsatellite loci: a comparison in bighorn sheep. Genetics, 145, 421-433. 4. Brown R.E. (1995). - What is the role of the immune system in determining individually distinct body odours? int. J. Immunopharmacol, 17 (8), 655-661. 5. Camus D., Zalis M.G., Vannier-Santos M.A. & Banic D.M. (1995). - The art of parasite survival. Braz. J. med. biol. Res., 28, 399-413. 6. Cockett N.E.Jackson S.P., Shay T.L., Farnir F., Berghams S., Snowder G.D., Nielsen D.M. & Georges M. (1996). - Polar overdominance at the ovine callipyge locus. Science, 273, 236-238. 7. Cockett N.E., Berghams S., Beckers M.C., Shay T.L., Jackson S.P., Snowder G.D. & Georges M. (1997). - The callipyge gene of sheep. Anim. Biotechnol, 8 (1), 23-30. 8. Combes C. (1997). - Fitness of parasites: pathology and selection. Int.J. Parasitol, 27 (1), 1-10. 9. Da Y., Shanks R.D., Stewart J.A. & Lewin H.A. (1993). - Milk and fat yields decline in bovine leukemia virus-infected Holstein cattle with persistent lymphocytosis. Proc. natl Acad. Sci. USA, 9 0 , 6538-6540. 10. Davies J.M. (1997). - Molecular mimicry: can epitope mimicry induce autoimmune disease? Immunol. Cell Biol., 75, 113-126. 11. Denamur E. & Picard B. (1995). - De la génétique des populations bactériennes à l'épidémiologie des maladies infectieuses. Méd. Sci, 11, 1399-1406. 12. Diener O. (1996). - Origin and evolution of viroids and viroid-like satellite RNAs. Virus Genes, 11 (2/3), 119-131. 13. DiRita V.J. & Mekalanos J.J. (1989). - Genetic regulation of bacterial virulence. Annu. Rev. Genet., 23, 455-482. 14. Domingo E. (1995). - The evolution of viruses. In Immunobiology of viral infections. Proc. 3rd Congress of the European Society for Veterinary Virology (M. Schwyzer, M. Ackermann, G. Bertoni, K. Kocherhans, K.C. McCullough, M. Engels, R. Wittek & R. Zanoni, eds), 4-7 September 1994, Interlaken, Switzerland. Foundation Marcel Mérieux, Lyons, France, 9-15. Rev. sci. tech. Off. int. Epiz., 17 (1) 15. Domingue G.J. Sr & Woody H.B. (1997). - Bacterial persistence and expression of disease. Clin. Microbiol Rev., 10 (2), 320-344. 16. Eggert F., Höller C , Luszyk D., Müller-Ruchholtz W. & Ferstl R. (1996). - MHC-associated and MHC-independent urinary chemosignals in mice. Physiol Behav., 59 (1), 57-62. 17. Elston R.C. (1990). - Models for discrimination between alternative modes of inheritance. In Advances in statistical methods for genetic improvement of livestock (D. Gianola & K. Hammond, eds). Springer-Verlag, New York, 41-55. 18. Falkow S., Isberg R.R. & Portnoy D.A. (1992). - The interaction of bacteria with mammalian cells. Annu. Rev. Cell Biol, 8, 333-363. 313 33. Kolsto A.B. (1997). - Dynamic bacterial organisation. Molec. Microbiol, 24, 241-248. genome 34. Krishnapillai V. (1995). - Comparative genome architecture and dynamics in bacteria. J. Genet, 74 (1-2), 61-76. 35. Lalande M. (1997). - Parental imprinting and human disease. Annu. Rev. Genet, 30, 173-195. 36. Leblanc C , Richard O., Kloareg B., Viehman S., Zetsche K. & Boyen C. (1997). - Origin and evolution of mitochondria: what have we learnt from red algae? Curr. Genet., 3 1 , 193-207. 37. Leipold H.W., Huston K. & Dennis S.M. (1983). - Bovine congenital defects. Adv. vet. Sci. comp. Med., 27, 197-271. 19. Gavora J . (1996). - Resistance of livestock to viruses: mechanisms and strategies for genetic engineering. Genet. Selec. Evol., 28, 385-414. 38. Long S.E. (1985). - Centric fusion translocations in cattle: a review. Vet. Rec., 116, 516-518. 20. Georges M. & Andersson L. (1996). - Livestock genomics comes of age. Genome Res., 6, 907-921. 39. Longshore J.W. & Tarleton J . (1996). - Dynamic mutations in human genes: a review of trinucleotide repeat diseases. J. Genet, 75, 193-217. 21. Ghosh S. & Collins F.S. (1996). - The geneticist's approach to complex disease. Annu. Rev. Med., 47, 333-353. 22. Gibson J.P., Freeman A.E. & Boettcher P.J. (1997). Cytoplasmic and mitochondrial inheritance of economic traits in cattle. Livestock Prod. Sci., 47, 115-124. 23. Gill T.J. III (1997). - Genetic factors in reproduction and their evolutionary significance. Am. J. reprod. Immunol., 37, 7-16. 24. Grossman L.I. & Shoubridge E.A. (1996). - Mitochondrial genetics and human disease. Bioessays, 18 (12), 983-991. 25. Hall J.G. (1997). - Genomic imprinting: nature and clinical relevance. Annu. Rev. Med., 48, 35-44. 26. Hannan A.J. (1996). - Trinucleotide-repeat expansions and neurodegenerative disease: a mechanism of pathogenesis. Clin, expl Pharmacol. Physiol, 23, 1015-1020. 27. Hughes A.L., Hughes M.K., Howell C.Y. & Nei M. (1994). Natural selection at the class II major histocompatibility complex loci of mammals. Phil. Trans. R. Soc. Lond., B, 3 4 5 , 359-367. 28. Hutt F.B. (1958). - Genetic resistance to disease in domestic animals. Cornell University Press, Ithaca, New York, 198 pp. 29. Joosten I., Sanders M.F. & Hensen E.J. (1991). - Involvement of major histocompatibility complex class I compatibility between dam and calf in the aetiology of bovine retained placenta. Anim. Genet., 22, 455-463. 30. Kavaliers M. & Colwell D. (1995). - Discrimination by female mice between the odours of parasitized and non-parasitized males. Proc. R. Soc. Lond., B, 2 6 1 , 31-35. 40. Müller M. & Brem G. (1991). - Disease resistance in farm animals. Experientia, 47, 923-934. 41. Nathanson N., McGann K.A., Wilesmith J., Desrosiers R. C. & Brookmeyer R. (1993). - The evolution of virus diseases: their emergence, epidemicity, and control. Virus Res., 29, 3-20. 42. Niikawa N. (1996). - Genomic imprinting and its relevance to genetic diseases. Jpn.J. hum. Genet, 4 1 , 351-361. 43. Ohno S., Epplen J.T., Matsunaga T. & Hozumi T. (1981). The curse of Prometheus is laid upon the immune system. Prog. Allergy, 28, 8-39. 44. Ostergard H., Kristensen B. & Andersen S. (1989). Investigations in farm animals of associations between the MHC system and disease resistance and fertility. Livestock Prod. Sci., 22, 46-67. 45. Parham P. & Ohta T. (1996). - Population biology of antigen presentation by MHC class I molecules. Science, 272, 67-73. 46. Pisetsky D.S. (1996). - Immune activation by bacterial DNA: a new genetic code. Immunity, 5, 303-310. 47. Ploegh H.L. (1995). - Trafficking and assembly of MHC molecules: how viruses elude the immune system. Cold Spring Harb. Symp. quant Biol, 60, 263-266. 48. Potts W.K., Manning C.J. & Wakeland E.K. (1994). - The role of infectious disease, inbreeding and mating preferences in maintaining MHC genetic diversity: an experimental test. Phil. Trans. R. Soc. Lond., B, 346, 369-378. 49. Prusiner S.B. (1996). - Molecular biology and pathogenesis of prion diseases. Trends biochem. Sci., 2 1 , 482-487. 31. Khoury M.J., Flanders W.D. & Beaty T.H. (1988). Penetrance in the presence of genetic susceptibility to environmental factors. Am. J. med. Genet, 29, 397-403. 50. Prusiner S.B. (1997). - Prion diseases and the BSE crisis. Science, 2 7 8 , 245-251. 32. Klein J . , Satta Y. & O'hUigin C. (1993). - The molecular descent of the major histocompatibility complex. Annu. Rev. Immunol, 11, 269-295. 51. Puel A. & Mouton D. (1996). - Genes responsible for quantitative regulation of antibody production. Crit. Rev. Immunol, 16, 223-250. 314 52. Pyeritz R.E. (1991). - Formal genetics in humans: mendelian and nonmendelian inheritance. In Genes, brain, and behavior (P.R. McHugh & V.A. McKusick, eds). Raven Press Ltd., New York, 47-73. 53. Rasmuson M. (1996). - Review: polygenes revisited or which are the genes behind quantitative variation or what can medical genetics learn from quantitative genetics and vice versa? Hereditas, 125, 1-9. 54. Renard C.H., Vaiman M., Capy P. & Sellier P. (1985). Relations d'un marqueur génétique, le complexe majeur d'histocompatibilité, avec la prolificité des traies et la mortalité des porcelets. J. Rech. porc. Fr., 17, 105-112. 55. Riffkin M., Seow H.F., Jackson D., Brown L. & Wood P. (1996). - Defence against the immune barrage: helminth survival strategies. Immunol Cell Biol, 74, 564-574. 56. Scriver C.R. (1984). - An evolutionary view of disease in man. Proc. R. Soc. Lond., B, 220, 273-298. 57. Scriver C.R. (1997). - Realities and virtual realities of inborn errors of metabolism: biochemical genetics in the molecular genetic era. Am. J. med. Genet., 69, 1-6. 58. Shook G.E. (1989). - Selection for disease resistance. J. Dairy Sci., 72, 1349-1362. 59. Simm G., Conington J . , Bishop S.C, Dwyer CM. & Pattinson S. (1996). - Genetic selection for extensive conditions. Appl. Anim. Behav. Sci., 49, 47-59. 60. Singer R.H. (1996). - Triplet repeats and human disease. Molec. Med. Today, 2, 65-69. 61. Smith H. (1995). - The revival of interest in mechanisms of bacterial pathogenicity. Biol Rev., 70, 227-316. 62. Sorci G., Moller A.P. & Boulinier T. (1996). - Genetics of host-parasite interaction. Trends Ecol. Evol, 12 (5), 196-199. 63. Summers K. (1996). - Relationship between genotype and phenotype in monogeneic diseases: relevance to polygenic diseases. Hum. Mutat., 7, 283-293. 64. Sutherland G.R. & Richards R.I. (1995). - Simple tandem DNA repeats and human genetic disease. Proc. natl Acad. Sci. USA, 92, 3636-3641. Rev. sci. tech. Off. int. Epiz., 17(1) 65. Thaller G., Dempfle L. & Hoeschele I. (1996). - Investigation on the inheritance of birth defects in swine by complex segregation analysis. J. Anim. Breed. Genet, 113, 77-92. 66. Tommerup N. (1993). Mendelian cytogenetics. Chromosome rearrangements associated with Mendelian disorders. J. med. Genet, 30, 713-727. 67. Von Schantz T., Wittzell H., Göransson G., Grahn M. & Persson K. (1996). - MHC genotype and male ornamentation: genetic evidence for the Hamilton-Zuk model. Proc. R. Soc. Lond., B, 2 6 3 , 265-271. 68. Warner C.M., Meeker D.L. & Rothschild M. (1987). Genetic control of immune responsiveness: a review of its use as a tool for selection for disease resistance. J . Anim. Sci., 64, 394-406. 69. Wedekind C , Seebeck T., Bettens F. & Paepke A. (1995). MHC-dependent mate preferences in humans. Proc. R. Soc. Lond., B, 2 6 0 , 245-249. 70. Wedekind C., Chapuisat M., Macas E. & Rülicke T. (1996). Non-random fertilization in mice correlates with the MHC and something else. Heredity, 77, 400-409. 71. Wellinger R.J. & Sen D. (1997). - The DNA structures at the ends of eukaryotic chromosomes. Eur. J. Cancer, 33 (5), 735-749. 72. Wolf U. (1995). - The genetic contribution to the phenotype. Hum. Genet, 95, 127-148. 73. Zinkemagel R.M. (1996). - Immunology taught by viruses. Science, 2 7 1 , 173-178.