Evolution of diversity at the major histocompatibility complex

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2 McClure, M.A., Johnson, MS., Feng, D-F. and Doolittle, R.F. ( 1988) froc. Nat/ Acad. Sci. USA 85, 2469-2474 3 Varmus, H. and Brown, P. (19891 in Mobile DNA (Berg. D.E. and Howe, M.M., eds), pp. 53-108, American Society for Microbiology 4 Benveniste, R.E., Sherr, C.I. and Todaro, G.J. (19751 Science 190,886-888 5 Gojobori. T. and Yokoyama, S. (19851 Proc. Nat/ Acad. Sci. USA 82,4 I9%420 I 6 Gallo, R.C. eta/. ( 19831 Cancer Res. 43, 3892-3899 7 Barre-Sinoussi, F. et a/. ( I9831 Science 220,868-870 8 Chiu, I-M. et a/. ( 19851 Nature 3 17, 366-368 9 Haase, A. ( 19861 Nature 322, 130-l 36 IO Thormar, H. and Palsson, P.A. (I9671 Perspect Viral. 5. 291-308 I I Sigurdsson, B. and Palsson, P.A. ( I9581 Br. 1. Exp. Pathol. 39, 5 19-528 12 Nathanson, N. et a/. (I985I Rev. Infect.

Dis. 7. 75-82 I3 Sonigo, P. eta/.

(I9851 Cell 42, 369-382 14 Pedersen, N.C., Ho, E.W., Brown, M.L. and Yamamoto, j.K. (19871 Science 235, 790-793 15 Talbott, R.L. eta/. 119891 Proc. Nat/Acad. Sci. USA 86, 5743-5747 16 Gonda, M.A. et a/. ( I9871 Nature 330, 388-39 I I7 Gallo, R.C. et al. ( 19841 Science 224, 500-503 18 Ratner, L. et a/. ( 19851 Nature 3 13, 277-283 I9 Sanchez-Pescador, R. et al. ( I9851

Science 227, 484-492 20 Wain-Hobson. S., Sonigo,

P.. Danos,

O.,

Cole, S. and Alizon, M. II9851 Cell 40, 9-l 7 21 Serwadda, D. eta/. (1985) Lancet ii,

849-852 22 Clavel, F. et a/. ( 19861 Science 233, 343-346 23 Guyader, M. et a/. ( 19871 Nature 326, 662-669 24 Alizon, M., Wain-Hobson, S., Montagnier, L. and Sonigo, P. ( 1986) Cell 46,63-74 25 Daniel, M.D. et a/. ( 19851 Science 228. 1201-1204 26 Desrosiers, R.C. ( 1988) Annu. Rev. Microbial. 42, 607-625 27 Ohta, Y. et a/. ( 19881 Int. 1. Cancer 41, 115-122 28 F&z, P.N. et a/. ( 1986) Proc. Nat/ Acad. Sci. USA 83,5286-5290 29 Hirsch, V.M., Olmsted, R.A., MurpheyCorb, M., Purcell, R.H. and Johnson. P.R. (1989) Nature 339, 389-391 30 Dietrich, U. et a/. I I9891 Nature 342, 948-950 31 Fenner, F. and Ratcliffe, F.N. (I9651 Myxomatosis, Cambridge University Press 32 Marlink, R.G. et a/. ( 19881 AIDS Res. Hum Retroviruses 4, 137-l 48 33 Kanki, P., Alroy, I. and Essex, M. ( 19851 Science 230.95 l-954 34 Tsujimoto, H. et a/. ( 19881 /. Viral. 62, 4044-4050 35 Fukasawa, M. et a/. (I9881 Nature 333, 457-46 I 36 Tsujimoto, H. et a/. (I9891 Nature 341, 539-54 I 37 Sharp, P.M. and Li, W-H. (19881 Nature 336, 315 38 Desrosiers, R.C., Daniel, M.D. and Li, Y.

The class I and II genes of the major histocompatibility complex (MHCI are the most polymorphic Wayne Pottsand

Edward Wakeland are at the Dept

of Pathology, University of Florida, Gainesville,

FL

32610, USA.

0

1990

E~sev~er Sc~rnce

Pub!,shers

Ltd

IUKI 0169.5347!90:$02

440-444 48 Li, W-H., Tanimura,

M. and Sharp, P.M. MO/. Biol. Evol. 5, 3 I 3-330 49 Yokoyama, S.. Chung, L. and Goiobori, T. (1988) Mol. Biol. Evol. 5, 237-251 50 Smith, T.F., Srinavasan, A., Schochetman, G., Marcus, M. and Myers, G. C19881 Nature 333,573-575 51 Koyonagi, Y. et al. ( 1987) Science 236, 819-822 52 Cartner, S. eta/. (I9861 Science 233, 215 53 Li, Y., Naidu, Y.M.. Daniel, M.D. and Desrosiers, R.C. ( 1989) /. Viral. 63, 1800-1802 54 Johnson, P.R. eta/. (19901 /. Viral. 64, 1086-1092

( 1988)

Evolutionof Diversityat the Major HistocompatibilityComplex

-. Recent evidence from 60th population data and DNA sequence analyses indicates that the unprecedented genetic diversity found at MHC loci is selectively maintained in contemporary natural populations, although the strength and nature of this selection are currently unclear. Due to the critical role played 6y MHC moleculesin immune recognition, it is generally assumed that some form of parasite-driven selection is operating. However, the general failure to implicate MHC in the susceptibility to specific infectious diseases has been troubling, and may indicate that selection is too weakto detect directly. Alternatively, strong selection can be reconciled by a variety of factors including the amplification of minor (disease-based) vigor differences into large fitness differences by intraspecific competition, or non-disease-based selection such as mating preferences and selective a6ortion.

I 1989) AIDS Res. Hum. Retroviruses 5, 465-473 39 Saitou, N. and Nei, M. (I9861 Mol. Bio/. Evol. 3, 57-74 40 Leigh Brown, A. and Monaghan, P. (I9881 AIDS Res. Hum. Retroviruses 4, 399-407 41 Scott, J.V., Stowring, L., Haase, A.T., Narayan, 0. and Vigne. R. (1979) Cell 18. 321-327 42 Carpenter, S., Evans, L.H.. Sevoian, M. and Chesebro, B. (198711. Viral. 61, 3783-3789 43 Payne, S.L. et a/. 119871 Virology 161, 321-331 44 Starcich, B.R. et al. ( I9861 Cell 45, 637-648 45 Yokoyama, S. and Goiobori, T. (19871 1. Mol. Evol. 24, 330-336 46 Hahn, B.H. et a/. ( 19861 Science 232, 1548-1553 47 Saag, M.S. et al. ( I9881 Nature 334,

Wayne K. Potts and Edward KmWakeland coding loci known for vertebrates, with over IO0 alleles per locus estimated for some species’. Understanding the causes of this unprecedented genetic polymorphism requires elucidation of the mechanisms responsible for both the origin and the maintenance of the polymorphisms. The mechanisms responsible for the origin of MHC diversity have been the subject of much recent progress2. In contrast, the mechanisms responsible for the maintenance of MHC polymorphisms have remained a matter for speculation. Since the discovery of the role of MHC in the recognition of foreign antigens by the vertebrate immune system3 (Box I), most investigators have assumed that MHC polymorphisms are maintained by some form of parasite-driven selection 00

(throughout this paper, ‘parasite’ is used broadly to include microand macro-parasites). Disease-based mechanisms are consistent with the established influence of MHC polymorphisms on immune responsiveness1,4. However, the general failure to find associations between MHC alleles and susceptibility to specific infectious diseases has led to the suggestion that MHC alleles are generally selectively neutral5 or maintained by non-disease-based mechanisms6,‘. Here, we review evidence relevant to the selection and neutrality hypotheses. In addition, we evaluate the four mechanisms most likely to be involved in the selective maintenance of MHC polymorphisms and discuss several disease-based explanations for the general absence of strong 181

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Foreign Presentation

Antigen-presenting cell 1 The fvlHCis a tightly linked cluster of genes that encode cell-surface proteins responsible for the presentation of foreign antigens to T-lymphocytes during the immune recognition process”. Foreign proteins enter c&Is either by an infectious route (in the case of ihtraceltular parasites) or through phagocytosis by antigen-presenting cells (macrophages). These endocytosed proteins are subsequently degraded into small peptides (4-20 amino acids long). MHC molecules are receptors capable of binding a range of structuralty distinct peptide@. Only the small subset of foreign peptides that are bound by an individual’s MHC molecules are transported to the cell surface and ‘presented’to T cells. An immune responseis initiated when Tcells bind the foreign peptides displayed by MHC molecules. Each T cell expresses a single type of antigen receptor (TCR) whose binding propertiesare, unlike thoseofMHCmolecules, highly specific. The binding sitesofTCRsare generated by programmed gene rearrangements during T-cell ontogeny in the thymu.+‘. Each progenitor f cell rearranges its TCR gems individually, and consequently each expresses a TCR with a unique binding site. This process produces a population of progenitor T cells expressing a diverse repertoire of TCR antigen-binding sites (>101’ TCR antigen-binding sites can be produced in a single individua16’). Progenitor T cells with receptors that recognize MHC plussetf-peptide are eliminated during T-cell ontogeny in the [email protected] surviving T ~~~v~~be~~usa~d migrate intotheperiphery,wherethey normally recogkize only l#lC p&s foreign-peptide. Such recognition tfiggers the cascade of events leading to an immune response. Immune response de&&s occur &her because MXC molecules fail to bind and present any peptides derived from a specific foreign protein, or because no TCRs recognize the MHC plus peptide that is presented. Recent evidence suggeststhat, on average, only one or two peptides from a given protein are successfully bound and presented by a given MI-K gene produe. Consequently, many proteins eswpe, or are only a few mutations away from escaping, immune recognition at the level of MHC. At the level of the TCR repertoire, appropriate receptors for recognizing a specific MHC plus peptide may be absent due to germ-line deficiencies@or because T cells with appropriate TCRs were deleted during tolerization to self-peptides@. Parasite evolution would be expected to exploit immune response defects by evading either T-cell recognition or MNC presentation. The former is achieved by mimicking host wptides and the latter by changing (through mutation) peptides bound by host NIHC. Either tactic could give rise to overdominant or frequencydependent selection, as discussed in the text.

acsociations between MHC polymorphisms and susceptibility to infectious diseases. Selection or neutrality? in two Selection may be detected ways: directly, by measuring fitnesses of individuals in natural populations; or indirectly, by detecting the vestiges of selection, such as non-neutral allelic frequency distributions or non-random nucleotide substitution patterns. No direct studies are available for MHC genes, but a number of in182

direct methods have been used, and three of the major results are reviewed below. Additional indirect evidence concerning linkage disequilibriuma10 and latitudinal clines” is available. All of these indirect studies conclude that some form of selection is acting on MHC genes. Diversifyitig selectiour at the arrtigenbinding site The recent elucidation of the three-dimensional structure of a human class I MHC moleculeL2 revealed a cleft that appears to be the

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site of antigen binding. The codons for this binding site contain the majority of the polymorphic nucleotides, and Hughes and Nei have shown that substitution patterns for these codons differ markedly from the remaining codons within the gene’ <,14.Their results, illustrated in Fig. I, show that in all intralocus comparisons (for both humans and mice, Musl, antigen-binding site lABSI codons accumulate more nonsynonymous than synonymous substitutions, whereas the opposite is true for non-ABS codons within the same gene. These results indicate that ABS codons experience diversifying selection (non-synonymous mutations have a selective advantage), whereas surrounding codons not directly involved in the antigenbinding site are experiencing purifying selection I non-synonymous mutations are at a selective disadvantage). Consequently, the key to understanding the maintenance (and probably function) of MHC polymorphism lies in understanding the nature of the selection operating on the antigen-binding site. Allelic frequencydistributions The frequency distribution of alleles under selective neutrality differs markedly from allelic distributions under balancing selection”j. Consequently, deviations from neutrality expectations can be detected by comparing the observed homozygosity (F, calculated as ZP,~, where pi is the frequency of allele ij with that expected under neutral modelsi 17. Figure 2 shows observed F values for MHC and nonObMHC loci of humans and Mus. served Fvalues that are significantly greater than neutrality expectations (dotted line) indicate purifying selection. Relatively low F values result from more uniform allelic frequencies and indicate that some type of balancing selection is operating. The data in Fig. 2 demonstrate that all class I and II MHC loci fall significantly below neutrality expectations, while f values for non-MHC loci are near or above neutrality expectations. Similarly, Nadeau and co-workers demonstrated that allelic frequency distributions of Mm class I loci were significantly more uniform than (presumably neutral) allozyme loci’H.

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Estimtiug the strengtk of selection from the extent of genetic diversity The number of alleles that can be maintained in a finite population by symmetric overdominant selection (heterozygote advantage) has been modeled by numerous authors’5,‘9,20. Assuming random mating, the equilibrium number of alleles depends on three parameters: the effective population size (N,), mutation rate (~1, and the level of selection (s) operating against homozygotes, relative to heterozygotes. Consequently, if mutation rates and population sizes can be estimated, then the intensity of overdominant selection required to maintain an observed number of alleles can be obtained. The mean mutation rate measured for Mus MHC genes is between 10e5 and IO-6 (Ref. 2 I 1.Estimating N, is difficult due to the uncertainties concerning the rate of gene flow between demes. Current estimates for Mus N, range between 500 (Refs 22,231 and 50000 (Ref. 24). Figure 3 shows the relationship between the mean number of (symmetric) overdominant alleles that can be maintained for various values of s, k and N,. This approach shows that within biologically reasonable ranges for s, I_Land N,, a wide range of alleles is possible from overdominant selection. In Fig. 4, the expected number of alleles is adjusted for sample size20 and can be compared to the number of observed alleles from local populations of Mus for two MHC class I loci (K and D)25 and the class II A, locus. Figure 4c shows that even with a high N,, selective neutrality cannot account for the observed number of alleles. If N,=5000, then the empirical data suggest that ~~0.1 (Fig. 4b). If however, N,=50000, then the data conform to s=O.Ol (Fig. 4~). This difference has important practical consequences because when s is significantly lower than 0.1, the sample size required to measure selection directly becomes unfeasibly large26. Other forms of balancing selection may require larger or smaller coefficients of selection to achieve the same result. It should be noted that this type of analysis will almost certainly yield different results when applied to Rams, whose (global) MHC polymorphism appears to be an order of magnitude lower than

that of Mus5. These results indicate four important properties of MHC diversity. First, selective neutrality is inconsistent with all of the above results, suggesting that some form of balancing selection is operating on MHC loci. Second, the population data indicate that selection is operating in contemporary populations and is not episodic with long intervening periods of neutrality, as has been postulated5. Third, diversifying selection is operating directly on the antigen-binding region; all future hypotheses to explain the maintenance of MHC polymorphism must take this into account. Fourth, selection may be strong enough (szO. I I, at least for species like Mus, to measure directly in population studies.

The nature of selection operating on MHC genes Here, we evaluate two diseasebased and two reproductive mechanisms that are the strongest candidates for involvement in the maintenance of MHC polymorphisms. These mechanisms are not mutually exclusive: each alone, or in concert, could generate the patterns of selection reviewed above. Immune response overdominance Overdominant selection was first proposed by Doherty and Zinkernage12’ and is based on the now well-established experimental observation that MHC-linked immune responsiveness is a codominant genetic trait’,“. MHC heterozygotes are capable of responding to any of the antigens recognized by either parental MHC haplotype, which presumably leads to enhanced immune responsiveness relative to homozygotes. These results are derived from simple antigenic systems where the host is normally challenged with only a single peptide or protein. It is generally assumed that these results can be extrapolated to the increased complexity of hostparasite interactions, although direct data to support this assumption are lacking. A general criticism of this hypothesis is: why has overdominance not led to gene duplication and the diversification of a family of genes rather than a family of alleles? This

z

I

Class

I

Class

II fi

Class

II c1

Fig. I. The mean difference between the percentage of non-synonymous and the percentage of synonymous nucleotide substitutions for both antigen-binding site (ABS) codons (diagonal shading1 and non-ABS codons (vertical shading]. Pooled intralocus comparisons for both humans and mice are made between ABS codons and non-ABS codons for the following genes. Class I: exons 2 and 3 of A, 6 and C IHLAI and K and D (H-2). Class II p chains: exon 2 IABS codons only1 and exon 3 (non-ABSI of DP, DO and DR lHLAl and A and E IH-21 Class II (Y chains: exon 2 IABS codons only) and exon 3 Inon-ABSI of DO IHLA) and A (H-21 Data are from Hughes and Neil’ ‘* lsee original articles for statistical analysesl.

would eliminate the genetic load associated with the production of low-fitness homozygotes. The conventional answer is that MHC gene duplication has reached an upper limit set either by the inverse relationship between MHC diversity and size of the T-cell receptor (TCR) repertoire 28 (Box 1I, or by density requirements for cell-surface expression of MHC gene products4. Evidence that there are narrow limits on the number of different MHC genes expressed comes from the demonstration that MHC class I and II genes have reverted to diploidy in a series of tetraploid Xenopus species2a. However, the presence of these limits does not resolve the original problem, because in an MHC monomorphic population all individuals could, in principle, express the optimal number of different MHC gene products, whereas in populations with polymorphic loci the number of different MHC products expressed will vary and some individuals will be suboptimal. We suggest that the monomorphic condition is unstable because parasites will ultimately ‘win’ against a single host MHC genotype (Box I I. Consequently, mutant or immigrant individuals that carry polymorphisms at these previously monomorphic loci would be favored. This explanation assumes that MHC is important in antagonistic host-pathogen coevolution. 183

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0

0.7 0 c3

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maintenance of genetic diversity for both host and parasitel*. To summarize the disease-based models, both overdominance and rare-allele advantage generated by host-pathogen coevolution are conceptually compelling and potentially capable of accounting for the maintenance of MHC genetic diversity. Given the current understanding of the MHC and hostpathogen interactions, it is likely that both mechanisms are operating. If selection operating on MHC genes is strong enough to be measured directly, this approach will offer the best opportunity to distinguish between different disease-based (and non-diseasebased) hypotheses.

to estimate quantitatively the influence that mating preferences may have on MHC polymorphism. Of the six pairs of MHC combinations tested in the principal study, four made disassortative choices, one mated at random, and one made assortative choices’. These results are in the right direction (disassottative preferences would be diversityenhancing because rare genotypes would enjoy a mating advantage), but with this sample it would be premature to draw general conclusions concerning the influence of MHC on mating preferences. Furthermore, the strength of the preference is far from absolute (20-30%above random preference), and it is impossible to extrapolate the strength of these laboratorymeasured preferences to natural social systems. Finally, since the process of producing inbred strains exerts strong selection against reproductive traits that reduce fecundity (e.g. selective mating or abortion 1. results obtained from inbred strains should be confirmed for mice with natural genomes in natural populations37,3R. (Although some humans can olfactorily distinguish mice on the basis of MHC differences39, no evidence exists for a major influence of MHC on current human mating patterns”O.1 If mating preference is to remain a viable hypothesis, then polymorphic residues of the antigenbinding site must be the primary determinants of the chemosensory information used to choose mates. An intriguing clue to how this may operate comes from the recent demonstration in Rattus that MHCbased chemosensory discrimination is eliminated when the animals are reared under microbe-free conditions4’. This suggests that MHC-related odors result from some interaction between MHC and pathogens, and provides a feasible explanation for how selection through mating preferences could act specifically on the antigenbinding site.

Mating preferences Inbred mice and rats can distinguish individual odors and in some cases express mating preferences based only on genetic differences at the MHC7.34-36. Unfortunately, these results cannot be used

Selective abortion Mechanisms favoring the abortion of histocompatible fetuses (or the selective fertilization equivalent) would be a potent force in maintaining MHC polymorphism42, as first proposed by Clarke and

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Fig. 2. The Hardy-Weinberg homozygosity IF, the sum of allelic frequencies squared) for a variety of MHC loci (solid symbols) and non-MHC loci lopen symbols) in humans (squares1 and Mus Icirclesl. Since the expected values for neutral alleles vary according to the number of genes sampled (nl, the neutrality expectation (dotted] lineb5 is based on a sample size In=3001 intermediate to the empirical samples. The dashed line represents the minimum possible Fvalues, when all alleles are at equal frequency in the population. The non-MHC loci for Mus (open circles) were chosen from the literature on the basis of having at least four alleles and are as follows: ES-~‘, esterase-2 lTexaslob; ES-~‘. esterase-2 (Great Gpi- I, glucose phosphate isomerase- I Britain)“; Gpi-2,glucose phosphate isomerase-2 (Great Britain?‘; Representative values for the human IAustralia)? and C3, complement component 3 (West Germany)“’ complement component genes (open squares) BF, C4A and C46, and the human MHC (HLAI loci (solid squares) A, B, C, DO and DR, are from Klitz eta/.‘O The A, points (solid circles) are Fvalues of class II A,, gene RFLP alleles (from three restriction endonuclease digests: BarnHI, EcoRl and Taql) from three in Florida (with sample sizes of 52, 54 and 56; unpublished data). Allelic separate Mus populations frequencies of all MHC loci are significantly more uniform than neutrality expectations lp
Rare-allele advantage via antagonistic host-pathogen caevolution Antagonistic host-pathogen coevolution is generally thought to lead to frequency-dependent selection29,30 , although the problem is complicated and different models and parameters can lead to a variety of results ranging from diversityreducing selection3’ to chaotic behavior (see Ref. 32 for a recent overview). In the specific case of MHC genes, it has been proposed that parasite antigenicity will be selected to exploit MHC-linked immune response defects (Box I ) of the most common host genotypes33. This would decrease the relative fitness of common host genotypes and would provide a selective advantage to new or rare MHC alleles whose immune response profiles differ from those produced by common alleles. The time-lag nature of these antagonistic coevolutionary responses could lead to the cycling of fitness values for both host and parasite genotypes, resulting in the

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Kirby6. Support for this hypothesis comes from the demonstration that human couples experiencing recurrent abortions share MHC alleles more often than controi coupies (Ref. 43 and refs therein). Immunization of these females with paternal or third-party antigens reduces the abortion rate, which suggests that an immunological mechanism is involved44. However, the predicted transmission distortion of MHC genes has not been confirmed in a preliminary study showing no deviations from mendelian expectations among offspring from human couples sharing MHC class I alleIes45. More data are needed from animal systems, as it has proved difficult to F6nlir;ltP PArlV nncitive p..V-.--.a, r--*-m--

parents, because a disproportionate number of offspring would be high-fitness MHC heterozygotes7. The second hypothesis suggests _~..^. that MHL-based seiective mating or abortion is similar to other genetic incompatibility systems, which presumably function to reduce inbreeding35J8148. A variety of properties may have preadapted MHC gene products for use in incompatibility systems, including: cell-surface expression, a strong influence on individual odor, or pre-existing MHC polymorphism (presumably resulting from disease-based balancing selection j. Alternatively, MHC molecules may have originally had a recognition function in an in-

results in both Ratttu#’ (Ref. 47 and refs therein).

these loci for recognition of non-self in a host-parasite context (Ref. I and refs therein). Even if diseasebased balancing selection operates on MHC genes, selective mating or abortion could become the major contributor to the maintenance (or exaggeration 1of MHC polymorphism.

rnmnrrtihilihl UVL”~...UUfi’fiCJ

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Evolution of reproductive mechanisms favoring MHC polymorphisms There are two leading explanations to account for the development of reproductive mechanisms favoring MHC polymorphisms. First, an underlying diseasebased fitness difference between MHC genotypes would favor reproductive mechanisms that preferentially produced the high-fitness genotype. For example, in the case of overdominance, MHC disassortative mating preferences (or the abortional equivalent) would increase the fitness of ‘choosy’

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MHC and disease Given the antigen-presentation function of MHC, it would be surprising if some form of disease-based balancing selection was not involved in the maintenance of MHC polymorphisms. How, then, can the following two observations, which recently formed the basis of an argument for the selective neutrality of

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contemporary MHC alleles5, be explained? First, MHC monomorphic populations have been discovered (albeit rarely) and they appear to be quite viable. Second, although examples of MHC haplotypes that impart resistance or susceptibility to specific infectious diseases have been reported49-56, such associations

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Fig. 4. The number of observed alleles from local Mus populations (symbols) plotted with the expected number of alleles corrected for sample sizelO (lines), under various levels of symmetric overdominant selection and a mutation rate of 10m6.Expected numbers of alleles are provided for effective population sizes IN,) of (al 500, fb) 5000. and Ic) 50000. Data for the K loci (squares) and D loci (triangles) are from serological analysis of I? European populations25. and the total number of alleles was estimated by assuming that the allelic frequency distributions of blanks and identified alleles were the samej7. Data for A,, loci (circles) are from RFLP analysis of three Florida populations (see Fig. 2)

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are not widespreadl,40; this is true for human correlational studies as well as for studies on inbred and congenic strains of mice’. Superficially, these two observations may seem to be inconsistent with disease-based selection. But beyond the obvious explanation of nondisease-based selection (such as reproductive mechanisms), each of the following disease-based mechanisms could be operating and they would be difficult to detect either through disease associations or in MHC monomorphic populations. First, selection may be too weak to detect directly or in correlational studies. Strong MHC-linked immune response defects occur when inbred hosts are challenged with antigens of limited immunogenicity4. The general failure to find similarly strong MHC-disease associations may occur because the antigenic complexity of even the most simple pathogens yields a sufficient number of recognizable antigens to elicit a relatively effective immune response. Still, graded immune responsiveness may occur at the whole-pathogen level, based on the total number of antigens recognized, but the symptomatic differences may be slight and remain unnoticed at the clinical level. The resulting slight vigor differences could provide the basis for weak selection, as proposed by Hughes and Neil?, or could be amplified into strong selection (see below). Second, MHC genotype may have only a minor influence on the susceptibility of individuals to specific infectious diseases, but the cumulative impact of many slight differences, systematically favoring one genotypic class over others, could affect the general health of individuals over their lifetimes. Evidence supporting this type of hypothesis comes from studies in MUS~~ and humans (Ref. 40, pp. 445-446) that show increased longevity of MHC heterozygotes over homozygotes. Third, relatively small (diseasebased) vigor differences may be amplified into relatively large fitness differences by intraspecific competition. For example, if MHC heterozygotes enjoyed a small but significant enhancement of vigor due to disease resistance, they would tend to win fights with homozygotes over resources. This would have a dramatic effect on fitness. If 186

this amplification process is an important component of the selection operating on MHC, it would have been overlooked because the model systems for investigating MHC-disease associations are lacking in strong, physical, intraspecific competition (e.g. laboratory animals in cages and humans in modern civilization 1. Future directions Understanding the nature of the selection operating on the MHC is one of the outstanding questions in immunogenetics, and may shed light on a variety of issues including host-parasite interactions, sexual selection, the evolution of incompatibility systems and the importance of inbreeding depression. This area of research affords an excellent opportunity for population-level investigators to study a system whose molecular details are both well known and indicative of exciting population-level discoveries. Acknowledgements We thank M. Nei, M. Slatkin, R. Lande, Cl. Manning, I. Nadeau and D. MacDonald for helpful criticisms, and I. Nadeau for supplying unpublished results on the frequency of C3alleles in natural mouse populations. The computer program used to generate data for Figs 3 and 4 was written by S. Emerson and R. Mclndoe. This work was supported by NIH grants Al-l 7966, GM-39578 and DK-39079.

References

I Klein, j. ( 1986) Natural History of the Major Histocompatibiliry Complex, Wiley 2 Moller, C.. ed. Immunol. Rev. II3 lin press) (entire issue1 3 Zinkernagel, R.M. and Doherty, P.C. ( 1974) Nature 248, 70 I-702 4 Schwartz, R.H. (19861 Adv. Immunol. 38. 31-201 5 Klein, 1. II9871 Hum. Immunol. 19, 155-162 6 Clarke, B. and Kirby, D.R.S. II9661 Nature 21 I, 999-1000 7 Yamazaki, K. et a/. ( 1976) /. Exp. Med. 144, 1324-1335 8 Bodmer, W.F., Trowsdale, I., Young, I. and Bodmer, 1. 119861 Phi/OS. Trans. R. Sot. London Ser. B 3 12.303-3 I5 9 Klitz, W. and Thomson, C. 119871 Genetics I 16,633-643 IO Hedrick, P.W., Thomson, G. and Klitz, W. ( 1987) Bio/. /. Linn. Sot. 3 I, 3 I l-33 I II Piazza, A., Menozzi, P. and Cavalli-Sforza, L.L. II9801 Hum. Immunol. I, 297-304 12 Bjorkman. P.I. et a/. ( 19871 Nature 329, 506-5 I2 I3 Hughes, A.L. and Nei, M. II9881 Nature 335, 167-170 I4 Hughes, A.L. and Nei, M. t 19891 Proc. Nat/ Acad. Sci. USA 86,958-962 I5 Li, W-H. (1978) Genetics 90, 349-382 I6 Ewens, W.1. (19721 Theor. Popul. Bio/. 3, 87-l 12 I7 Watterson. G.A. 11978) Genetics 88, 405-4 I7

I8 Nadeau, I.H., Britton-Davidian, I., Bonhomme, F. and Thaler. L. ( 19881 Genetics I IS, 131-140 I9 Wright, S. ( 19661 Proc. Nat/ Acad. Sci. USA 55, 1074-1081 20 Yokoyama, S. and Nei, M. t 19791 Genetics 9 I, 609-626 21 Melvold, R.W. and Kohn. H.I. in Transgenic Mice and Mutants in MHC Research (Egorov, I.K. and David, C.S., eds), Springer-Verlag (in press) 22 Petras, M.L. 11965) Evolution 21, 259-274 33, 234-251 23 !_ande, R. (19791 Evolution 24 Nei, M. and Graur, D. (1984) Evol. Biol. 17, 73-118 25 Nadeau, I.H., Wakeland, E.K., Cotze, D. and Klein, I. (1981 I Cenet Res. 37, 17-3 I 26 Mulcahy, D.L. and Kaplan, S.M. 11979) Am. Nat. ll3,419-425 27 Doherty, PC. and Zinkernagel. R.M. ( 19751 Nature 256, 50-52 28 Du Pasquier. L., Schwager, 1. and Flajnik, M.F. (1989) Annu. Rev. Immunol. 7, 251-275 29 Clarke, B. ( 1976) in Genetic Aspects of (Taylor, A.E.R. Host-Parasite Relationships and Muller, R., edsl, pp. 87-103, Blackwell Scientific Publications 30 Hamilton, W.D. (1980) Oikos 35, 282-290 31 Nei, M. ( 19881 Phi/OS. Trans. R. Sot. London Ser. B 3 I9,6 15-629 32 Seger, J. ( 1988) Philos. Trans. R. Sot. London Ser. B 319,54l-555 33 Bodmer, W.F (1972) Nature 237, 139-145 34 Yamazaki, K. et al. II9881 Science 240. 1331-1332 35 Egid, K. and Brown, I.L. 119891 Anim. Behav. 38, 548-549 36 Singh, P.B., Brown, R.E. and Roser, B. (19871 Nature 327, 161-164 37 Potts, W.K., Manning, C.J., Peck, A.B., Price-LaFace, M. and Wakeland. E.K. II9881 in Major Histocompatibility Genes and their Role in Immune Function (David, C.S., ed.1, pp. 89-102, Plenum Press 38 Partridge, L. ( 1988) Philos. Trans. R. Sot. London Ser. El 3 19, 525-539 39 Gilbert, A.N., Yamazaki, K. and Beauchamp, G.K. (198611. Camp. Pathol. 100, 262-265 40 Tiwari, j.L. and Terasaki, P.I. II9851 HLA and Disease Associations, Springer-Verlag 41 Singh, P.B. etal. (19901 1. Chem. Ecol. 16, 1667-1682 42 Hedrick, P.W. and Thomson, G. (19881 Genetics I 19. 205-2 I2 43 Thomas, M-L., Harger, I.H., Wagner, D.K., Rabin, B.S. and Gill. T.1. (19851 Am. /. Obstet. I5 I, 1053-1058 Cynecol. 44 Mowbray, I.F., Underwood, I.L., Michel. M., Forbes, P.B. and Beard, R.W. (19871 Lancet ii, 679-680 45 Wenk, R.E. and Boughman, B.A. i 19891 Am. 1. Hum. Genet. 45, a251 (abstr.1 46 Hings. I. and Billingham, R.E. 119851 I. Reprod. Immunol. 7, 337-350 47 Hamilton, B.L., Hamilton, A. and 8. Hamilton, M.S. II9851 / Reprod. Immunol. 257-26 I 48 Uyenoyama, M.K. i 1988) in The Evolution of Sex IMichod, R.E. and Levin, B.R., eds). pp. 2 12-232, Sinauer Associates 49 Pazderka, F., Longenecker, B.M., Law, C.R.I.. Stone, H.A. and Ruth, R.F. (19751 Immunogenetics 2.93-l 00 50 Lynch, D.H.. Cole, B.C.. Bluestone, LA. and Hodes, R.I. (I9861 Eur. /. Immunol. 16. 74 7-75 I 51 Wassom, D.L.. Krco. C.I. and David. C.S. I I9871 Immunol. Today 8. 39-43

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52 Hirayama. K. eta/. II9881 Nature 327, 426-429 53 Nauciel, C., Ronco, E., Cuenet, j.L. and Marika, P. I I9881 infect. Immun. 56, 2407-24 I I 54 Hormaeche, C.E., Harrington. K.A. and Joysey, H.S. ( I9851 /. Infect. Dis. 152, 1050-1056 55 Kennedy, M.W., Gordon, A.M.% Tomlinson, L.A. and Qureshi, F. (19861 Parasite Immunol. 9, 269-273 56 Hamelin-Bourassa, D., Skamene. E. and Cervais, F. (19891 immunogenetics 30. 266-272 57 Williams, R.M.. Kraus, L.J., Lavin, P.T., Steele, L.L. and Yunis. E.I. (1981) in

Immunological Aspects of Ageing (Segre, E. and Smith, L., edsl, pp. 247-266, Marcel Dekker 58 Allen, P.M., Babbitt, B.P. and Unanue, E.R. (1987) Immunol. Rev. 98, 171-187 59 Buus, S., Sette, A. and Crey, H.M. (1987) Immonol. Rev. 98, Il5-141 60 Davis, M.M. (1985) Annu. Rev. lmmunol. 3, 537-560 61 Davis, M.M. and Bjorkman, Pd. (19881 Nature 334, 395-402 62 Vidovic, D. and Matzinger, P. (1988) Nature 336, 222-225 63 Roy, S., Scherer, M.T.. Briner, T.J., Smith, I.A. and Gefter, M.L. (I9891 Science 244, 572-575

Whether vertebrate carnivores can work to man’s advantage in controlling vertebrate pests has, until recently, rarely been tested experimentally. Elton found that subsidizing cats (Fe/is catus) with milk kept buildings free of rats (/?attus norvegicus) during World War II’. Even without being fed, cats can influence seasonal changes in rat populations*. Islands provide relatively simple experimental environments also. The lighthouse keeper on Berlinger Island off Portugal imported cats to control the infesting rabbits. Following their complete success in this task, the cats themselves died off3. Had there been substitute prey, however, some rabDits might have survived to irrupt subsequently. In complex communities, prey substitution may -es& in continuously low popuations of prey, as is the case for :.odents in parts of Sweden; but in simpler communities of northern latitudes, prey populations can become cyclicL7. s\.Newsome is at the CSIRODivision of Wildlife and I?ology. PO Box 84. Lyneham, ACT 2600,Australia. 3 1990,

Elswer

Science

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IUKI 0169~5347,9Os$OZ

437-450 69 Nadeau, J.H., Collins, R.L. and Klein, 1. II9821 Genetics 102, 583-598 70 Klitz, W., Thomson, G. and Baur, M.P. I I9861 Am. 1. Hum. Genet. 39, 340-349

The Controlof VertebratePestsby VertebratePredators

-. Carnivores can control mammalian pests for long periods, but on/y aper pest numbers have been reduced by other means. In Australia, the cause is prolonged dry weather. The consequent low populations of rabbits can then be regulated 6g European foxes, feral cats and dingoes. Kangaroos, and probably feral goatsand pigs, succumb to dingoes at the same time, as su6stitute prey for ra66its. In the general case, such regulatory predation may 6e triggered climatically, 6g disease or 6g human intervention. When predators are themselves pests to be controlled, integrated pest management may 6e required to avoid unwunted resurgences of other pests.

64 Pullen, A.M., Kappier, I.W. and Marrack. P. (1989) Immunol. Rev. 107, 125-139 65 Ewens, W.J. ( 19791 Mathematical Population Genetics, Springer-Verlag 66 Selander. R.K., Yang, S.Y. and Hunt, W.G. ( 19691 in Studies in Genetics V (Wheeler, M.R., ed.1, pp. 271-337, University of Texas Press 67 Berry, R.j. and Peters, I. ( 19771 Proc. R. Sot. London Ser. B 197, 485-503 68 Singleton, C.R. (1985) Aust. /. Zoo/. 33,

A. Newsome The causes of regular and synchronized fluctuations in arctic mammals have been a source of interest for more than 400 year+. Elton and Nicholson’s analysis9 of the Hudson Bay Company’s records of Lynx canadensis pelts, kept since 1763, maintains a germinal place in scientific thought on predator-prey relations. Recent further analysis of those records indicates that three factors may be involved: the dynamics of snowshoe hare (Lepus americanus) populations, of lynx populations, and perhaps of the vegetation as well’“~L’. Cyclicalmammals:‘nopredators, no cycles’ Predators were once thought merely to mop up the doomed prey surplus’*; but evidence is accumulating that they have a greater role than that. The seminal studies of Pearson were the first to address this question13-‘6. On a 14 ha plot of grassland in California, free-ranging house-cats plus some racoons (Procyan lotor), gray foxes (Urocyon cinereoargenteusl, skunks (Mephitis mephitis) and some raptors were found to remove 88% of California voles (Microtus californicus) during one decline in the population cycle that had a total mortality of 97.7%14. Predation was the major cause of the decline. A second crash had a similar total mortality - 97.4% - but the predators took only an estimated 25% of the population. Although something other than predation was involved in this second 00

crash, the lack of cycles in the absence of carnivores on a nearby island nevertheless implicates the basic role of predation in the processL7. Also, cyclical declines in the montane vole (Microtus montanus), which lives snowbound for the in the Sierra Nevada, North winter America, were caused solely by weasels (Mustela erminea and Mustela frenata)18. Current experimental studies of cyclicity in snowshoe hares in the North American Arctic are comparing the effects of environmental and biotic factors19-*I. They indicate that low winter food supplies and lynx predation interact synergistically to cause cyclical declines in hare populations. Extensive freefeeding did not prevent cyclicity, but may produce higher population peaks than elsewhere and thus delay population declines. Another North American experiment, with the vole Microtus ochrogaster, showed that addition of supplemental food and removal of predation had additive and equal effects on densities**. Previous extensive field studies had concluded that food supplies and predation were interactive*‘. Increases in some larger herbivore populations have been associated with predator removal. The most-quoted example concerns the irruption of mule deer (Odocoileus hemionus) on the Kaibab Plateau, Arizona, USA, in the 1920s. Caughley24 has examined the records in detail. Pumas (Fe/is concolorl and coyotes 187