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Polymorphism and MHC gene function
DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY, Vol. 7 pp. 403-412, 0145-305X/83 $3.00 + .00 Printed in the USA. Copyright (c) 1983 Pergamon Press Ltd. All rights reserved.
1983.
POLYMORPHISM AND MHC GENE FUNCTION
Joerg Reimann and Richard G. Miller Ontario Cancer Institute 500 Sherbourne Street Toronto, Ontario, Canada M4X IK9
INTRODUCTION In man and some natural populations of rodents (e.g., mouse, rat) gene products encoded by loci within the major histocompatibility complex (MHC) are polymorphic. However, in at least one natural population of rodents (hamster) this does not seem to be the case. Although the function of MHC-encoded molecules is not established, most hypotheses 'explaining' MHC-directed function postulate a selective pressure in evolution that preserves variation in MHC products. The alternative interpretation seems almost never to be considered: polymorphism is compatible with, but not essential for, the functional efficiency of membrane glycoproteins encoded in MHC genes. The occurrence of highly polymorphic gene products at a certain locus in a given species may indicate a selective pressure preserving randomly generated allelic variability at this locus (i.e., polymorphism at this locus is adaptive). Alternatively, polymorphism may be the result of random genetic drift (i.e., many alleles reaching high frequencies and fixation through cumulative random sampling variation), which implies selective neutrality of polymorphism at this gene locus (I). It is intriguing that the presence (in the mouse) and the absence (in the hamster) of molecular MHC polymorphism coincides with alternative species-specific forms of gene pool size and turn-over rate, as well as random versus assortative recombinations of individual genes within this gene pool. These differences in the two related rodent species result in large chances for genetic drift of mutant alleles in the gene pool of the mouse, but in virtually no chance for drift of novel genetic variants in the gene pool of the hamster. Hence, it seems quite possible that MHC polymorphism is the result of genetic drift and has no adaptive value in itself. 403
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SOME ASPECTS OF MHC POLYMORPHISM
The species-specific differences, some features of the structural organisation and the possible evolutionary history of the polymorphism in MHC gene products are first described briefly, to facilitate the subsequent discussion of some questions which might find an answer in the comparison of the reproductive ecology of mouse and hamster. Species-specific
Differences
in MHC Polymorphism
Using serological methods, some 30 alleles at each of the two class I loci (K,D) have been identified in wild mice (Mus musculus) collected from many geographical regions of the world. In addition, some 20 alleles were found at each of the two polymorphic class II loci (A B , E B ) of the murine H-2 complex (2,3). If uncertainties of serotyping techniques in natural populations are taken into account (e.g., monospecificity of typing reagents, true allelic identity of gene products reacting with a given antibody, how representative the tested sample is of the total population, the interpretation of blanks in tested individuals), an estimate of i00 alleles at each K,D,A B and E B locus in mice populating the world seems most appropriate (3). This may still be an underestimate, as histogenetic techniques (i.e., the primed lymphocyte typing test) have revealed multiple distinct allo-determinants on serologically identical class I molecules (4), and furthermore, lymphomyeloid differentiation-dependent expression of allo-antigenic specificities on class II glycoprotelns has been described (5,6). Thus, the polymorphism of the products of some genes in the murine }{-2 complex is the most extensive yet discovered in a genetic locus with alternative alleles. In contrast, other class II antigens (A~ , E~ ) encoded within the H-2 complex show a very restricted polymorphism (3). In the human MHC (HLA), there are 20 alleles at the A locus, more than 40 alleles at the B locus, and at least 8 alleles at the C locus - all encoding class I antigens (7,8). Of class II antigens, 12 (DW) alleles have been defined with histogenetic techniques, and 10 (DR) alleles have been identified by serotyping (with a remarkably good correlation between antlbody-deflned DR antigens and MLR-defined D antigens) (9). As in the mouse, the $ -chains of human class II molecules are polymorphic, while the ~ -chains are invariant. The MHC of the hamster (Mesocricetus auratus), Hm-l, has a surprisingly low polymorphism: Only one class I gene product and 6 class II products (of an unknown number of linked loci) have been defined serologically and histogenetically in animals bred in captivity as well as in wild populations (10,11). Thus, polymorphism at the hamster MHC (as defined by five 'classical' and eight 'congenic' inbred strains) occurs at class II but not class I loci. These conclusions are based on a fairly limited sampling of the wild hamster gene pool. Thus the fine "classical" inbred strains appear to be derived from 3 littermates trapped in 1930 (12) and the recent addition of new "wild" material is from only 12 additional animals (13). Clearly, it would be useful to have further serotyping data on more wild hamsters with better selected reagents obtained from more extensive immunizations. Hence, at this stage, it can not be excluded that the system will finally prove to be as polymorphic as all the other MHCs. However, the limited data available certainly suggest that the hamster shows little MHC polymorphism, particularly of class I antigens.
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The probability of examining 15 wild mice or 15 humans, even if closely related, and finding no class I polymorphlsm is vanlshlngly small. The MHC polymorphism of the rat (Rattus norve~icus), RT-I, is intermediate between hamster and mouse: 12 class I antigens and 9 class II antigens have been identified serologlcally (14). Marked species differences in MHC polymorphism are apparent from this brief summary. The extremes seem to be the hamster and the mouse. Structural
Organisation
of MHC Gene Polymorphlsm
Class I allomorphs of two independent major H-2 haplotypes differ at an average of 10% of their amino acid sequence, or about 40 amino acid residues per K or D molecules (15,17,18). An interspecies comparison (man/mouse) of class I molecules shows a difference at an average of 25% amino acid residues (15). The existence and evolutionary history of such gene locl polymorphlc for alleles with extensively differing sequences appears unusual, as products of allellc genes usually differ by only one or a few amino acids. But there are examples of comparably high polymorphic non-MHC loci, e.g., the complex Rl-la and Rl-lb allotypes of rat < chains (19). A unique feature of H-2 polymorphlsm is that no 'common' allele occurs (in the species, or in the local population of the species) with a higher frequency than other alleles. This is in contrast to the HLA-system, in which significantly more frequent alleles (e.g., A2) occur (7). The average frequencies of alleles at the H-2D and H-2K loci in wild mice are probably around 0.01 (3). This is reflected in the fact that the average heterozygosity approaches I at H-2 locl. The extensive variability in protein sequences of H-2 molecules is confined to discrete regions or single positions interspersed with highly conserved regions. Variability is clustered in the first and second external domains of class I glycoproteins, as shown by amino acid sequence data (15,17), DNA sequence data (18,20), and serological studies (22). The third external domain of class I molecules is highly conserved, as the interaction with the invariant polypeptide 82m imposes constraints on allowable sequences. The transmembrane domain of the molecules seems to allow variability, as long as hydrophohlclty of the substituted amino acid residues is preserved. The cytoplasmic domains (that regulate the interactions of this integral membrane protein with cytoplasmic components) have restricted variability within a species, but dramatic divergence between species (reviewed in 15,16,17,20). Thus, hereditary variability has been allowed to accumulate in only a few restricted areas of class I molecules. This structural organization of allelic variation into two small clusters on the surface of the molecule provides no evidence whether the polymorphism of class I glycoproteins is compatible with, or essential for, the function of these gene products: the polymorphic areas may be either the 'active sites' of the molecules, or may have no functional role at all (and are therefore free of any constraints imposed on a structure to maintain its functional efficiency). The Evolutionary History of MHC Pol~morphism It is controversial whether dupllcatlon(s) of ancestral human and murlne class I genes preceded or followed speciatlon, i.e., that point in evolutionary history at which those phyletic lineages diverged that finally gave rise to the
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present day species Mus musculus and Homo sapiens. It is only for these two species that sufficient DNA or amino acid sequence data, and sufficient serotyping data, are available to ask the question. Biochemical and genetic data suggest a history of recent duplications (and deletions) from primordial MHC genes - still in a state of evolutionary flux that occurred after 'speciation' (15,16,17,18,20). The prominent arguments in favor of this view are: i) the occurrence of species-specific amino acid residues at many positions throughout the length of the human and mouse class I molecules; ii) the lack of evidence for a structural relationship between the gene products of particular human and mouse loci, despite a highly significant homology between human and mouse class I molecules; and iii) the finding that more homologous genes seem to cluster together in complex (coding or non-coding) class I gene families in the mouse. The alternative interpretation assumes a duplication event of MHC genes preceding speciation (2,3). The patterns of homologies described above would then be the result of sequences of duplicated genes converging to a 'mouse' and a 'human' sequence. The main argument for this view is the absence of any evidence for a rapid diversification of H-2 alleles (or for an exceptionally high mutation rate in H-2 genes). On the contrary, there is evidence that the K k, A k, E k and D w3 alleles have not significantly changed in at least two million years (3). Hence, MHC polymorphism may be very stable in evolution. It is usually assumed that the accumulation of point mutations in duplicated MHC genes has led to their present diversity. If this assumption is not correct, a reconstruction of evolutionary lineages by the inter-species comparison of sequence data may be invalid. Differential splicings of primariy RNA transcripts (containing more than one gene), recombination by unequal crossing over, or processes of gene conversion have all been proposed to be involved in the generation of diversity (21). But is is important for the present discussion to stress the fact, that class I genes are definitely alleles of a single gene locus (21) and not products of clusters of different genes (as are e.g., immunoglobulin genes). Independent of the mechanisms that create genetic variability, the spread and fixation of rare genes in a population has still to be explained. The complete spectrum of all H-2 alleles is unevenly distributed in 'local' populations of mice: the frequency distribution curve of H-2 alleles is something like a 'signature' of a given population, a feature identifying this local population, and distinguishing it from other populations (3). These data, reflecting the ongoing evolutionary change of the murine MHC, are of considerable interest for the question of whether selective or random events influence the differential transmission of genetic change from generation to generation. An indication for selective neutrality of genetic variation (i.e., for a predominant role of genetic drift in the preservation of diversity) is: i) a high level of polymorphism; ii) a highly variable polymorphism from 'locality' to 'locality'; and iii) the absence of polymorphism gradients (or 'character clines') if different local populations are compared (23). The data on absolute frequencies and frequency distributions of class I alleles in mouse populations fulfills the first two criteria; data on the third criterion are not yet available. Hence, we might have found a first hint suggesting that MHC polymorphism is generated randomly by drift. It remains to be shown that in the change of the genetic constitution of certain species, many alleles have the chance to drift to high frequencies, while in other species, this chance is absent. We would therefore expect that - in comparing species - the presence or absence of MHC polymorphism should correlate with the presence or absence of
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chances for genetic drift. Only if we do not find this correlation, would deterministic pressures of selection have to be invoked to explain the preservation of genetic variability at a certain gene locus. THE REPRODUCTIVE
ECOLOGY OF THE MOUSE
The following description of the reproductive taken from 23,24,26,27,28.
ecology of the house mouse is
Gene Pool The species Mus musculus is a genetic complex that is almost global in distribution. It is thought to have originated on the dry steppes of southeastern Russia and has gone (and is still going) through a successful history of global colonization, primarily as a commensal of man. The exceptionally high potential for colonization of the mouse is explained by a synergism of different factors: i) An unexcelled ecological opportunism: the mouse breeds in a very wide variety of climates and habitats; its range of climatic and habitat tolerance is the broadest known for any mammal (whether viewed from the perspective of precipitation, temperature, latitude or altitude); ii) A high reproduction rate and a basic reproductive flexibility: an ambient cueing system for the regulation of reproduction in mice is ideally suited for colonization; this system enables the mouse to adopt breeding strictly in response to dietary variation, completely independent of ambient temperature, photoperiodic regulation of seasonality, high-dark cycles, specific dietary components, etc. The sudden appearance of an abundant food supply can trigger an immediate and irruptive growth response of the mouse population; iii) A high dispersal rate: the aggressiveness of dominant males, the basis for all social structuring exhibited by the mouse, is the driving force for the large scale dispersal of the offspring; iv) An extensive genetic variation among dispersants reflected in the adaptability of colonizers to very adverse environmental challenges which led to the evolutionary success of the mouse; although some of the known genetic variation seems adaptive to an econiche, the genetic divergence in mice must be viewed beyond the scope of simple selection in response to regional differences in environmental demands (24,26). Hence, the gene pool of the house mouse is probably the largest of all mammals. The turn-over of individual genomes and the peculiar re-shuffllng genes within this gene pool in every generation are to be described.
of
Reproduction Rate The house mouse, as a nocturnal prey species, requires a high rate of reproduction. The female may be induced to sexual maturity at 2-3 weeks of age, the gestation period lasts for only 3 weeks, and each litter can comprise more than I0 offspring. As the female possesses the capacity of continuous rapid breeding (unless inhibited by a drastic reduction in caloric intake) with a new generation every 3 weeks, it could (theoretically) produce more than 106 offspring per year. This explosive reproduction rate is apparently designed to exploit an unstable, rapidly appearing food supply; it leads to a
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complete destruction of the habitat in a 'stable' econiche. "Natural selection for high reproductive success is known to contribute to enormous fluctuations in population size among many species of rodents that are subject to catastrophic population declines. The few individuals surviving such a crash find themselves in a virtually vacant habitat, in which premium is placed on the genotypes with the highest reproductive potential. Natural selection has evidently been unable to incorporate factors that would check the unhealthy fluctuations in the face of the high premium placed on sheer reproductive success" (23). The consequences of this exceptional reproduction rate of the house mouse depend on the social structure of the breeding population. It results either in the output of thousands of potentially colonizing dispersants, or in the irruptive growth of local populations.
Structuring
of Genetic Changes
House mice live in either stable, high-density, demic, commensal populations, or in unstable, low-density, non-demic, feral populations. flow is unidirectional, from commensal to feral populations.
Gene
An insular division of the living area of the mouse defines small home ranges for a commensal breeding population. The food supply of this area is (temporally and spatially) stable; the fairly high carrying capacity of this econiche therefore supports a high population density. The simple non-linear hierarchy of the breeding group is composed of a single dominant, fertile male, up to a dozen breeding females and their offspring, and a few subordinate, infertile males. This form of territorial and social compartmentalization of the mouse population can be conceptualized as demic. The fairly stable structuring of the commensal mouse breeding population results in: i) a high output of potential colonizers (as the dominant male's aggressiveness promotes large-scale dispersal of offspring as soon as the saturated carrying capacity of the territory is reached), and ii) a lack of potential for irruptive population growth in situ. Interdemic gene flow is extremely restricted because of the dominant male's aggressive defense of the territory (this has been dramatically described by K. Lorenz in rats (24), it is equally valid for mice (24,28)). In contrast, feral mouse populations live in unstable environments, in which favourable habitats appear and disappear rapidly. A low and unstable carrying capacity of the feral substrate supports only a low-density population with large, often shifting home ranges. This is incompatible with strict territoriality and the rigid, stable demic structure (which depends critically on the stability of the habitat). Only relative and changing dominance relationships of adult resident males with their nearest neighbours regulate the structure of semi-nomadic breeding groups. The unstable social structuring of feral mouse populations is characterized by: i) a high potential for irruptive population growth in suddenly appearing favourable habitat conditions; ii) a high chance for dramatic population declines, leading to very high turn-over rates of individual genomes within the 'local' gene pool (with up to 30% mortality per month), and many 'bottlenecks' (23) in 'local' populations: iii) a high potential for dispersal, due to constantly shifting home ranges and high intraspecific aggression; and iv) a high potential to absorb and amplify gene flow derived from dispersants of commensal populations.
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Hence, the exceedingly large, rapidly replicating and frequently fluctuating gene pool of the house mouse is structured in such a way that strictly demic 'local' populations multiply at fairly constant rate under steady state conditions, thus resulting in a preponderance of genetic drift (26). Part of this randomly amplified genetic variation 'flows' through colonizing dispersants into feral habitats where it constitutes a regional 'founder effect' (23). This gene flow is important as, e.g., some feral populations in colder climates survive only the warmer parts of the year and require a seasonal input from commensal populations to persist. The feral populations with their potential for irruptive population growth and ensuing dramatic population decline - have to pass repeatedly through 'bottle-necks' (23) which further amplify large random genetic drift. Thus, it has to be acknowledged that, under these conditions, many alleles have a chance to drift to high frequencies and fixation (if selective neutrality of these variants is assumed). THE REPRODUCTIVE
ECOLOGY OF THE HAMSTER
Although the behavioural ecology of the hamster is less thoroughly investigated than that of the house mouse, a substantial set of data is available (28) and suffices to sketch an outline of the structure of change in the hamster gene pool. The hamster's range of habitat tolerance is narrow. Individuals (male and female) occupy fairly large, mutually exclusive territories which are defended with a high degree of intraspecific aggression, thus allowing only a low-density population even in a favourable habitat with a high carrying capacity. The global gene pool of this species is therefore small. This gene pool has a low turn-over rate: hamsters have normally one (sometimes up to three) seasonal breeding cycles per year, producing litters of up to 6 offspring. There is no cooperative social organization of reproduction in hamsters. Male and female individuals live in separate territories; they cooperate only briefly for copulation and separate again immediately thereafter. Only the female raises the offspring. Young hamsters are dispersed at an early age of life (through maternal intolerance and the early development of aggressive interactions between siblings of a litter). These data were mainly obtained in European hamsters (Cricetus cricetus); they appear to be equally valid for Syrian hamsters (Mesocricetus auratus). The organization of the gene pool of the hamster is the exact opposite of that of the house mouse: the slow turn-over of randomly recombined genomes in a small gene pool does not allow genetic drift to play any significant role. A SELECTIVE VALUE OF MHC POLYMORPHISM We conclude from the above arguments that it is at least plausible that MHC polymorphism in the mouse results from the ample chances for genetic drift in the evolutionary history of this species. We argue that, since monomorphic MHC gene products are seen in the hamster, it is unlikely that there is a selective pressure in evolution operating in favor of the preservation of randomly generated variability at MHC loci (through phenomena such as, e.g., 'over dominance' or 'frequency dependence'). It then follows that different allelic products of the H-2 loci are phenotypically equivalent or selectively neutral. This is obviously in conflict with the current dogma which assigns the capacity of specific antigen recognization to MHC gene products. The various regions of class I and class II MHC gene products are most often viewed as specific recognition structures for foreign antigenic determinants (29). Hence, it is concluded that natural selection favours many mutant MHC
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gene variants in the gene pool of a species: the more MHC gene variants are phenotypically expressed, the more foreign epitopes are potentially recognizable by 'processing' (or 'presenting') cells and therefore indirectly by T-lymphocytes, the larger the repertoire of offending agents that may be eliminated by 'immune defense' or 'immuno-surveillance' effector mechanisms. In strict analogy to selective forces that drive recognition structures encoded in the immunoglobulin locl to diversity, this interpretation endows the MHC system with 'Promethean foresight' (30); the outcome of the evolutionary race with many environmental pathogens has depended mainly upon the MHC's ability to generate or preserve randomly a large variety of antigen-receptor specificities. Furthermore, the non-clonal distribution of MHC-encoded antigen receptor sites on accessory or target cells had to be compensated in evolution by multiple duplications of gene loci for class I or class II molecules, and by codominantly expressing a heterozygous set of all functional MHC genes. Despite these diversifying mechanisms, the repertoire of antigen-specific 'MHC recognition sites' would be small, even in the most polymorphic species (the mouse). At the most 500-1000 'receptor specificities' would be expressed by class I molecules in the global mouse population. This receptor repertoire could cover the epitopic universe only at the price of extensive cross-reactions - which raises the further problem of envisaging a set of degenerate recognition sites discriminating self from non-self, a crucial issue that is expected to find a solution at the level of this MHC-guided T cell reactivity. These problems, encountered by the 'antigen recognition site hypothesis' of MHC gene function, are aggravated by the finding of low or absent MHC polymorphism in some species. The finding of just one monomorphic product of class I genes in the hamster MHC cannot be explained by a low incidence of enzootic pathogens or neoplastic diseases in this species (31). A single class I molecule does not appear to constitute a receptor system with a repertoire, or an even rudimentary ability to discriminate 'specificities'. The interpretation that implies selective forces to preserve diversity at some MHC gene loci thus encounters major difficulties. As proposed in this review, an alternative is to describe MHC polymorphism as the result of random genetic drifts. This explains the marked interspecies differences in the extent of MHC polymorphism as well as the specific MHC allele distribution patterns of 'local' populations of mice. It would even be predicted that mice derived from different corners of the same barn express distinguishable MHC allele frequency patterns (in analogy to 26). This view is by no means an attempt to explain MHC gene function in alternative terms. It simply emphasizes the point that it is the class I and class II MHC-encoded molecules in themselves which are of functional importance - and not the polymorphic parts of these molecules which have been so tremendously helpful in defining them. It is tempting to speculate that the genetic polymorphism at loci of the murine H-2 complex is not affected by natural selection because it mimics the epigenetically induced polymorphism involved in the normal functioning of the complex, i.e. the association of MHC-encoded glycoproteins with "foreign" antigenic determinants which constitutes the immunogenic complex effective in T cell stimulation. An invariant molecule associated with many different "antigen molecules" would display a high degree of polymorphism to which the recognition capability of T cells can adapt. This way of thinking would deprive allodeterminants of MHC class I and class II molecules of any "special" status. Another way of looking at the difference in polymorphism between mouse and hamster is as follows: As the range of habitat distribution of the hamster is very limited, while that of the mouse is extremely varied, MHC polymorphism could be argued to represent the 'stored' experience of many different
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selective pressures to which the mouse successfully adapted in the course of its large scale dispersion. According to this view, the MHC mono- (or oligo-) morphism of the hamster results from a stable selection pressure of a small and limited habitat. This implies that MHC polymorphism is i) stored as past evolutionary experiences in the genome, with no immediate actual selective value for the given local population; and ii) compatible with effective function of MHC molecules because it is obviously not selected against. This view leads ultimately to the same conclusions on the significance of polymorphism as were outlined above. Polymorphism of MHC gene products may resemble that of blood group substances. The polymorphism of blood group 'antigens' is fairly extensive and has obvious clinical importance. Yet, there is no evidence that polymorphism is essential for the adequate function of this biological system. On the contrary: individuals with a 'BOMBAY' or O h phenotype (who express no H, A or B 'antigens') are perfectly healthy (32). (J. Reimann is supported by a Deutsche Forschungsgemeinschaft fellowship).
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1963,
1983.
POLYMORPHISM AND MHC GENE FUNCTION
Joerg Reimann and Richard G. Miller Ontario Cancer Institute 500 Sherbourne Street Toronto, Ontario, Canada M4X IK9
INTRODUCTION In man and some natural populations of rodents (e.g., mouse, rat) gene products encoded by loci within the major histocompatibility complex (MHC) are polymorphic. However, in at least one natural population of rodents (hamster) this does not seem to be the case. Although the function of MHC-encoded molecules is not established, most hypotheses 'explaining' MHC-directed function postulate a selective pressure in evolution that preserves variation in MHC products. The alternative interpretation seems almost never to be considered: polymorphism is compatible with, but not essential for, the functional efficiency of membrane glycoproteins encoded in MHC genes. The occurrence of highly polymorphic gene products at a certain locus in a given species may indicate a selective pressure preserving randomly generated allelic variability at this locus (i.e., polymorphism at this locus is adaptive). Alternatively, polymorphism may be the result of random genetic drift (i.e., many alleles reaching high frequencies and fixation through cumulative random sampling variation), which implies selective neutrality of polymorphism at this gene locus (I). It is intriguing that the presence (in the mouse) and the absence (in the hamster) of molecular MHC polymorphism coincides with alternative species-specific forms of gene pool size and turn-over rate, as well as random versus assortative recombinations of individual genes within this gene pool. These differences in the two related rodent species result in large chances for genetic drift of mutant alleles in the gene pool of the mouse, but in virtually no chance for drift of novel genetic variants in the gene pool of the hamster. Hence, it seems quite possible that MHC polymorphism is the result of genetic drift and has no adaptive value in itself. 403
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SOME ASPECTS OF MHC POLYMORPHISM
The species-specific differences, some features of the structural organisation and the possible evolutionary history of the polymorphism in MHC gene products are first described briefly, to facilitate the subsequent discussion of some questions which might find an answer in the comparison of the reproductive ecology of mouse and hamster. Species-specific
Differences
in MHC Polymorphism
Using serological methods, some 30 alleles at each of the two class I loci (K,D) have been identified in wild mice (Mus musculus) collected from many geographical regions of the world. In addition, some 20 alleles were found at each of the two polymorphic class II loci (A B , E B ) of the murine H-2 complex (2,3). If uncertainties of serotyping techniques in natural populations are taken into account (e.g., monospecificity of typing reagents, true allelic identity of gene products reacting with a given antibody, how representative the tested sample is of the total population, the interpretation of blanks in tested individuals), an estimate of i00 alleles at each K,D,A B and E B locus in mice populating the world seems most appropriate (3). This may still be an underestimate, as histogenetic techniques (i.e., the primed lymphocyte typing test) have revealed multiple distinct allo-determinants on serologically identical class I molecules (4), and furthermore, lymphomyeloid differentiation-dependent expression of allo-antigenic specificities on class II glycoprotelns has been described (5,6). Thus, the polymorphism of the products of some genes in the murine }{-2 complex is the most extensive yet discovered in a genetic locus with alternative alleles. In contrast, other class II antigens (A~ , E~ ) encoded within the H-2 complex show a very restricted polymorphism (3). In the human MHC (HLA), there are 20 alleles at the A locus, more than 40 alleles at the B locus, and at least 8 alleles at the C locus - all encoding class I antigens (7,8). Of class II antigens, 12 (DW) alleles have been defined with histogenetic techniques, and 10 (DR) alleles have been identified by serotyping (with a remarkably good correlation between antlbody-deflned DR antigens and MLR-defined D antigens) (9). As in the mouse, the $ -chains of human class II molecules are polymorphic, while the ~ -chains are invariant. The MHC of the hamster (Mesocricetus auratus), Hm-l, has a surprisingly low polymorphism: Only one class I gene product and 6 class II products (of an unknown number of linked loci) have been defined serologically and histogenetically in animals bred in captivity as well as in wild populations (10,11). Thus, polymorphism at the hamster MHC (as defined by five 'classical' and eight 'congenic' inbred strains) occurs at class II but not class I loci. These conclusions are based on a fairly limited sampling of the wild hamster gene pool. Thus the fine "classical" inbred strains appear to be derived from 3 littermates trapped in 1930 (12) and the recent addition of new "wild" material is from only 12 additional animals (13). Clearly, it would be useful to have further serotyping data on more wild hamsters with better selected reagents obtained from more extensive immunizations. Hence, at this stage, it can not be excluded that the system will finally prove to be as polymorphic as all the other MHCs. However, the limited data available certainly suggest that the hamster shows little MHC polymorphism, particularly of class I antigens.
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The probability of examining 15 wild mice or 15 humans, even if closely related, and finding no class I polymorphlsm is vanlshlngly small. The MHC polymorphism of the rat (Rattus norve~icus), RT-I, is intermediate between hamster and mouse: 12 class I antigens and 9 class II antigens have been identified serologlcally (14). Marked species differences in MHC polymorphism are apparent from this brief summary. The extremes seem to be the hamster and the mouse. Structural
Organisation
of MHC Gene Polymorphlsm
Class I allomorphs of two independent major H-2 haplotypes differ at an average of 10% of their amino acid sequence, or about 40 amino acid residues per K or D molecules (15,17,18). An interspecies comparison (man/mouse) of class I molecules shows a difference at an average of 25% amino acid residues (15). The existence and evolutionary history of such gene locl polymorphlc for alleles with extensively differing sequences appears unusual, as products of allellc genes usually differ by only one or a few amino acids. But there are examples of comparably high polymorphic non-MHC loci, e.g., the complex Rl-la and Rl-lb allotypes of rat < chains (19). A unique feature of H-2 polymorphlsm is that no 'common' allele occurs (in the species, or in the local population of the species) with a higher frequency than other alleles. This is in contrast to the HLA-system, in which significantly more frequent alleles (e.g., A2) occur (7). The average frequencies of alleles at the H-2D and H-2K loci in wild mice are probably around 0.01 (3). This is reflected in the fact that the average heterozygosity approaches I at H-2 locl. The extensive variability in protein sequences of H-2 molecules is confined to discrete regions or single positions interspersed with highly conserved regions. Variability is clustered in the first and second external domains of class I glycoproteins, as shown by amino acid sequence data (15,17), DNA sequence data (18,20), and serological studies (22). The third external domain of class I molecules is highly conserved, as the interaction with the invariant polypeptide 82m imposes constraints on allowable sequences. The transmembrane domain of the molecules seems to allow variability, as long as hydrophohlclty of the substituted amino acid residues is preserved. The cytoplasmic domains (that regulate the interactions of this integral membrane protein with cytoplasmic components) have restricted variability within a species, but dramatic divergence between species (reviewed in 15,16,17,20). Thus, hereditary variability has been allowed to accumulate in only a few restricted areas of class I molecules. This structural organization of allelic variation into two small clusters on the surface of the molecule provides no evidence whether the polymorphism of class I glycoproteins is compatible with, or essential for, the function of these gene products: the polymorphic areas may be either the 'active sites' of the molecules, or may have no functional role at all (and are therefore free of any constraints imposed on a structure to maintain its functional efficiency). The Evolutionary History of MHC Pol~morphism It is controversial whether dupllcatlon(s) of ancestral human and murlne class I genes preceded or followed speciatlon, i.e., that point in evolutionary history at which those phyletic lineages diverged that finally gave rise to the
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present day species Mus musculus and Homo sapiens. It is only for these two species that sufficient DNA or amino acid sequence data, and sufficient serotyping data, are available to ask the question. Biochemical and genetic data suggest a history of recent duplications (and deletions) from primordial MHC genes - still in a state of evolutionary flux that occurred after 'speciation' (15,16,17,18,20). The prominent arguments in favor of this view are: i) the occurrence of species-specific amino acid residues at many positions throughout the length of the human and mouse class I molecules; ii) the lack of evidence for a structural relationship between the gene products of particular human and mouse loci, despite a highly significant homology between human and mouse class I molecules; and iii) the finding that more homologous genes seem to cluster together in complex (coding or non-coding) class I gene families in the mouse. The alternative interpretation assumes a duplication event of MHC genes preceding speciation (2,3). The patterns of homologies described above would then be the result of sequences of duplicated genes converging to a 'mouse' and a 'human' sequence. The main argument for this view is the absence of any evidence for a rapid diversification of H-2 alleles (or for an exceptionally high mutation rate in H-2 genes). On the contrary, there is evidence that the K k, A k, E k and D w3 alleles have not significantly changed in at least two million years (3). Hence, MHC polymorphism may be very stable in evolution. It is usually assumed that the accumulation of point mutations in duplicated MHC genes has led to their present diversity. If this assumption is not correct, a reconstruction of evolutionary lineages by the inter-species comparison of sequence data may be invalid. Differential splicings of primariy RNA transcripts (containing more than one gene), recombination by unequal crossing over, or processes of gene conversion have all been proposed to be involved in the generation of diversity (21). But is is important for the present discussion to stress the fact, that class I genes are definitely alleles of a single gene locus (21) and not products of clusters of different genes (as are e.g., immunoglobulin genes). Independent of the mechanisms that create genetic variability, the spread and fixation of rare genes in a population has still to be explained. The complete spectrum of all H-2 alleles is unevenly distributed in 'local' populations of mice: the frequency distribution curve of H-2 alleles is something like a 'signature' of a given population, a feature identifying this local population, and distinguishing it from other populations (3). These data, reflecting the ongoing evolutionary change of the murine MHC, are of considerable interest for the question of whether selective or random events influence the differential transmission of genetic change from generation to generation. An indication for selective neutrality of genetic variation (i.e., for a predominant role of genetic drift in the preservation of diversity) is: i) a high level of polymorphism; ii) a highly variable polymorphism from 'locality' to 'locality'; and iii) the absence of polymorphism gradients (or 'character clines') if different local populations are compared (23). The data on absolute frequencies and frequency distributions of class I alleles in mouse populations fulfills the first two criteria; data on the third criterion are not yet available. Hence, we might have found a first hint suggesting that MHC polymorphism is generated randomly by drift. It remains to be shown that in the change of the genetic constitution of certain species, many alleles have the chance to drift to high frequencies, while in other species, this chance is absent. We would therefore expect that - in comparing species - the presence or absence of MHC polymorphism should correlate with the presence or absence of
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chances for genetic drift. Only if we do not find this correlation, would deterministic pressures of selection have to be invoked to explain the preservation of genetic variability at a certain gene locus. THE REPRODUCTIVE
ECOLOGY OF THE MOUSE
The following description of the reproductive taken from 23,24,26,27,28.
ecology of the house mouse is
Gene Pool The species Mus musculus is a genetic complex that is almost global in distribution. It is thought to have originated on the dry steppes of southeastern Russia and has gone (and is still going) through a successful history of global colonization, primarily as a commensal of man. The exceptionally high potential for colonization of the mouse is explained by a synergism of different factors: i) An unexcelled ecological opportunism: the mouse breeds in a very wide variety of climates and habitats; its range of climatic and habitat tolerance is the broadest known for any mammal (whether viewed from the perspective of precipitation, temperature, latitude or altitude); ii) A high reproduction rate and a basic reproductive flexibility: an ambient cueing system for the regulation of reproduction in mice is ideally suited for colonization; this system enables the mouse to adopt breeding strictly in response to dietary variation, completely independent of ambient temperature, photoperiodic regulation of seasonality, high-dark cycles, specific dietary components, etc. The sudden appearance of an abundant food supply can trigger an immediate and irruptive growth response of the mouse population; iii) A high dispersal rate: the aggressiveness of dominant males, the basis for all social structuring exhibited by the mouse, is the driving force for the large scale dispersal of the offspring; iv) An extensive genetic variation among dispersants reflected in the adaptability of colonizers to very adverse environmental challenges which led to the evolutionary success of the mouse; although some of the known genetic variation seems adaptive to an econiche, the genetic divergence in mice must be viewed beyond the scope of simple selection in response to regional differences in environmental demands (24,26). Hence, the gene pool of the house mouse is probably the largest of all mammals. The turn-over of individual genomes and the peculiar re-shuffllng genes within this gene pool in every generation are to be described.
of
Reproduction Rate The house mouse, as a nocturnal prey species, requires a high rate of reproduction. The female may be induced to sexual maturity at 2-3 weeks of age, the gestation period lasts for only 3 weeks, and each litter can comprise more than I0 offspring. As the female possesses the capacity of continuous rapid breeding (unless inhibited by a drastic reduction in caloric intake) with a new generation every 3 weeks, it could (theoretically) produce more than 106 offspring per year. This explosive reproduction rate is apparently designed to exploit an unstable, rapidly appearing food supply; it leads to a
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complete destruction of the habitat in a 'stable' econiche. "Natural selection for high reproductive success is known to contribute to enormous fluctuations in population size among many species of rodents that are subject to catastrophic population declines. The few individuals surviving such a crash find themselves in a virtually vacant habitat, in which premium is placed on the genotypes with the highest reproductive potential. Natural selection has evidently been unable to incorporate factors that would check the unhealthy fluctuations in the face of the high premium placed on sheer reproductive success" (23). The consequences of this exceptional reproduction rate of the house mouse depend on the social structure of the breeding population. It results either in the output of thousands of potentially colonizing dispersants, or in the irruptive growth of local populations.
Structuring
of Genetic Changes
House mice live in either stable, high-density, demic, commensal populations, or in unstable, low-density, non-demic, feral populations. flow is unidirectional, from commensal to feral populations.
Gene
An insular division of the living area of the mouse defines small home ranges for a commensal breeding population. The food supply of this area is (temporally and spatially) stable; the fairly high carrying capacity of this econiche therefore supports a high population density. The simple non-linear hierarchy of the breeding group is composed of a single dominant, fertile male, up to a dozen breeding females and their offspring, and a few subordinate, infertile males. This form of territorial and social compartmentalization of the mouse population can be conceptualized as demic. The fairly stable structuring of the commensal mouse breeding population results in: i) a high output of potential colonizers (as the dominant male's aggressiveness promotes large-scale dispersal of offspring as soon as the saturated carrying capacity of the territory is reached), and ii) a lack of potential for irruptive population growth in situ. Interdemic gene flow is extremely restricted because of the dominant male's aggressive defense of the territory (this has been dramatically described by K. Lorenz in rats (24), it is equally valid for mice (24,28)). In contrast, feral mouse populations live in unstable environments, in which favourable habitats appear and disappear rapidly. A low and unstable carrying capacity of the feral substrate supports only a low-density population with large, often shifting home ranges. This is incompatible with strict territoriality and the rigid, stable demic structure (which depends critically on the stability of the habitat). Only relative and changing dominance relationships of adult resident males with their nearest neighbours regulate the structure of semi-nomadic breeding groups. The unstable social structuring of feral mouse populations is characterized by: i) a high potential for irruptive population growth in suddenly appearing favourable habitat conditions; ii) a high chance for dramatic population declines, leading to very high turn-over rates of individual genomes within the 'local' gene pool (with up to 30% mortality per month), and many 'bottlenecks' (23) in 'local' populations: iii) a high potential for dispersal, due to constantly shifting home ranges and high intraspecific aggression; and iv) a high potential to absorb and amplify gene flow derived from dispersants of commensal populations.
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Hence, the exceedingly large, rapidly replicating and frequently fluctuating gene pool of the house mouse is structured in such a way that strictly demic 'local' populations multiply at fairly constant rate under steady state conditions, thus resulting in a preponderance of genetic drift (26). Part of this randomly amplified genetic variation 'flows' through colonizing dispersants into feral habitats where it constitutes a regional 'founder effect' (23). This gene flow is important as, e.g., some feral populations in colder climates survive only the warmer parts of the year and require a seasonal input from commensal populations to persist. The feral populations with their potential for irruptive population growth and ensuing dramatic population decline - have to pass repeatedly through 'bottle-necks' (23) which further amplify large random genetic drift. Thus, it has to be acknowledged that, under these conditions, many alleles have a chance to drift to high frequencies and fixation (if selective neutrality of these variants is assumed). THE REPRODUCTIVE
ECOLOGY OF THE HAMSTER
Although the behavioural ecology of the hamster is less thoroughly investigated than that of the house mouse, a substantial set of data is available (28) and suffices to sketch an outline of the structure of change in the hamster gene pool. The hamster's range of habitat tolerance is narrow. Individuals (male and female) occupy fairly large, mutually exclusive territories which are defended with a high degree of intraspecific aggression, thus allowing only a low-density population even in a favourable habitat with a high carrying capacity. The global gene pool of this species is therefore small. This gene pool has a low turn-over rate: hamsters have normally one (sometimes up to three) seasonal breeding cycles per year, producing litters of up to 6 offspring. There is no cooperative social organization of reproduction in hamsters. Male and female individuals live in separate territories; they cooperate only briefly for copulation and separate again immediately thereafter. Only the female raises the offspring. Young hamsters are dispersed at an early age of life (through maternal intolerance and the early development of aggressive interactions between siblings of a litter). These data were mainly obtained in European hamsters (Cricetus cricetus); they appear to be equally valid for Syrian hamsters (Mesocricetus auratus). The organization of the gene pool of the hamster is the exact opposite of that of the house mouse: the slow turn-over of randomly recombined genomes in a small gene pool does not allow genetic drift to play any significant role. A SELECTIVE VALUE OF MHC POLYMORPHISM We conclude from the above arguments that it is at least plausible that MHC polymorphism in the mouse results from the ample chances for genetic drift in the evolutionary history of this species. We argue that, since monomorphic MHC gene products are seen in the hamster, it is unlikely that there is a selective pressure in evolution operating in favor of the preservation of randomly generated variability at MHC loci (through phenomena such as, e.g., 'over dominance' or 'frequency dependence'). It then follows that different allelic products of the H-2 loci are phenotypically equivalent or selectively neutral. This is obviously in conflict with the current dogma which assigns the capacity of specific antigen recognization to MHC gene products. The various regions of class I and class II MHC gene products are most often viewed as specific recognition structures for foreign antigenic determinants (29). Hence, it is concluded that natural selection favours many mutant MHC
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gene variants in the gene pool of a species: the more MHC gene variants are phenotypically expressed, the more foreign epitopes are potentially recognizable by 'processing' (or 'presenting') cells and therefore indirectly by T-lymphocytes, the larger the repertoire of offending agents that may be eliminated by 'immune defense' or 'immuno-surveillance' effector mechanisms. In strict analogy to selective forces that drive recognition structures encoded in the immunoglobulin locl to diversity, this interpretation endows the MHC system with 'Promethean foresight' (30); the outcome of the evolutionary race with many environmental pathogens has depended mainly upon the MHC's ability to generate or preserve randomly a large variety of antigen-receptor specificities. Furthermore, the non-clonal distribution of MHC-encoded antigen receptor sites on accessory or target cells had to be compensated in evolution by multiple duplications of gene loci for class I or class II molecules, and by codominantly expressing a heterozygous set of all functional MHC genes. Despite these diversifying mechanisms, the repertoire of antigen-specific 'MHC recognition sites' would be small, even in the most polymorphic species (the mouse). At the most 500-1000 'receptor specificities' would be expressed by class I molecules in the global mouse population. This receptor repertoire could cover the epitopic universe only at the price of extensive cross-reactions - which raises the further problem of envisaging a set of degenerate recognition sites discriminating self from non-self, a crucial issue that is expected to find a solution at the level of this MHC-guided T cell reactivity. These problems, encountered by the 'antigen recognition site hypothesis' of MHC gene function, are aggravated by the finding of low or absent MHC polymorphism in some species. The finding of just one monomorphic product of class I genes in the hamster MHC cannot be explained by a low incidence of enzootic pathogens or neoplastic diseases in this species (31). A single class I molecule does not appear to constitute a receptor system with a repertoire, or an even rudimentary ability to discriminate 'specificities'. The interpretation that implies selective forces to preserve diversity at some MHC gene loci thus encounters major difficulties. As proposed in this review, an alternative is to describe MHC polymorphism as the result of random genetic drifts. This explains the marked interspecies differences in the extent of MHC polymorphism as well as the specific MHC allele distribution patterns of 'local' populations of mice. It would even be predicted that mice derived from different corners of the same barn express distinguishable MHC allele frequency patterns (in analogy to 26). This view is by no means an attempt to explain MHC gene function in alternative terms. It simply emphasizes the point that it is the class I and class II MHC-encoded molecules in themselves which are of functional importance - and not the polymorphic parts of these molecules which have been so tremendously helpful in defining them. It is tempting to speculate that the genetic polymorphism at loci of the murine H-2 complex is not affected by natural selection because it mimics the epigenetically induced polymorphism involved in the normal functioning of the complex, i.e. the association of MHC-encoded glycoproteins with "foreign" antigenic determinants which constitutes the immunogenic complex effective in T cell stimulation. An invariant molecule associated with many different "antigen molecules" would display a high degree of polymorphism to which the recognition capability of T cells can adapt. This way of thinking would deprive allodeterminants of MHC class I and class II molecules of any "special" status. Another way of looking at the difference in polymorphism between mouse and hamster is as follows: As the range of habitat distribution of the hamster is very limited, while that of the mouse is extremely varied, MHC polymorphism could be argued to represent the 'stored' experience of many different
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selective pressures to which the mouse successfully adapted in the course of its large scale dispersion. According to this view, the MHC mono- (or oligo-) morphism of the hamster results from a stable selection pressure of a small and limited habitat. This implies that MHC polymorphism is i) stored as past evolutionary experiences in the genome, with no immediate actual selective value for the given local population; and ii) compatible with effective function of MHC molecules because it is obviously not selected against. This view leads ultimately to the same conclusions on the significance of polymorphism as were outlined above. Polymorphism of MHC gene products may resemble that of blood group substances. The polymorphism of blood group 'antigens' is fairly extensive and has obvious clinical importance. Yet, there is no evidence that polymorphism is essential for the adequate function of this biological system. On the contrary: individuals with a 'BOMBAY' or O h phenotype (who express no H, A or B 'antigens') are perfectly healthy (32). (J. Reimann is supported by a Deutsche Forschungsgemeinschaft fellowship).
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