Download Biological principles of heredity of and resistance to disease

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
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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
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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
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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.
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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
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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.
•
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