Copyright 0 1992 by the Genetics Society of America
Letters to the Editor Overdominant vs. Frequency-Dependent Selectionat MHC Loci There has been much discussion recently about the relative roles of overdominant and frequency-dependent selection in the maintenance of polymorphism at major histocompatibility complex (MHC) loci. This has arisen since theconfirmation, using nucleotide sequencedatafrom the antigenbinding sites, that balancing selection is mainly responsible for the observed polymorphism (HUGHES and NEI 1988, 1989). So far, only one study has addressed the question directly. TAKAHATA and NEI (1990) conducted simulations comparing allelic genealogy under various selection regimes. They concluded that frequency-dependent selection (specifically, rare allele advantage) and overdominance could not be distinguished mathematically, and that both could explain the extreme polymorphism, and long term persistence of alleles, at the MHC. Nevertheless, they argued against the former on biological grounds: they asserted that whilst a new rare allele may have a selective advantage as no pathogen strain is adapted to it, a rare old allele should have no such advantage and should disappear from the population by selection or genetic drift. Recent developments in theoretical studies of hostpathogen coevolution do not support this assertion (see MAY and ANDERSON 1990). Host-parasite interactions are intrinsically frequency dependent, anddynamic, because transmission efficiency increases with the frequency of susceptible hosts. A rare MHC allele A1 of recent origin may, as TAKAHATA and NEI state, initially have a selective advantage, as no pathogen strain may be adapted to it. In response, the rare allele A1 will increase in frequency, and there will be selection pressure in favor of a pathogen strain (say P I ) that is able to attack it. Should such a strain arise by mutation, it will also increase in frequency, to a point where it begins to decrease the frequency of A I . This seems to be the endpoint of TAKAHATA and NEI’S argument. It may well, however, bejust the first stage in a dynamic cycle. Once Al is sufficiently rare, its density may be insufficient to maintain P I , which will then decline in frequency until the selective advantage of A, is restored. Thisverbal argument has been made explicit mathematically (BECK 1984).Infrequency dependent selection, rare alleles do not necessarily disappear fromthe population by selection, and would not drift outof the population because allele frequencies may cycle over relatively short time periods. While overdominance has not been incorporatedin Genetics 132: 861-862 (November, 1992)
many of the current genetic models of host-parasite interactions, it is clear that there is no justification, given current understanding, for excluding rare allele frequency-dependent selection as a possible mechanism to maintain MHC polymorphism. As HILLet al. (1992)correctlyobserve,overdominance andfrequency dependent selection can only be distinguished by careful field studies. NEI and HUGHES(199 1) suggested an experiment for this which comparesthe fitness of a homozygote for a rareallele with that of a heterozygote fortwo common alleles. Given the above argument on host-parasite interactions,theexperiment proposed would only be valid in a population context. A crucial difference between the two types of balancing selection is that overdominance predicts a stable polymorphism, whereas a polymorphism maintained by frequencydependence will be dynamic. Many MHC alleles are foundin closely related species and genera (e.g., MCCONNELL et al. 1988; LAWLOR et al. 1988), and comparing allelic frequency distributions among species, or among populations within species, may provide information on allele dynamics. Haplotypefrequencies should also becompared. HAMILTON (1980), in a two locus model of frequency dependent host-parasite interactions, showed that gene frequencies may remain relatively constant but that fluctuating selection is reflected by fluctuating linkage disequilibria. With this in mind, it is interesting tonotethatHLAhaplotypefrequencies show greater variation among racial groups than individual alleles (BODMER and BODMER, 1978). ROBERTW. SLADE Department of Zoology, and Centre for Molecular Biology and Biotechnology, University of Queensland, 4072, Australia HAMISHI. MCCALLUM Department of Zoology, and Centre for Conservation Biology, University of Queensland, 4072, Australia
LITERATURE CITED BECK,K . , 1984 Coevolution: mathematical analysis of host-parasite interactions. J. Math. Biol. 19: 63-77.
862
R. W. Slade and H. I. McCallum
BODMER, W. F., and J. G. BODMER, 1978 Evolution and function of the HLA system. Br. Med. Bull. 3 4 309-316. HAMILTON, W. D., 1980 Sex versus non-sex versus parasite. Oikos 35: 282-290. A. J. MCMICHAEL, B. M. GREENHILL,A. V. S., D. KWIATKOWSKI, WOOD and S. BENNETT, 1992 Maintenance of MHC polymorphism. Nature 355 403. HUGHES, A. L., and M. NEI, 1988 Pattern of nucleotide substitution at major histocompatibility complex class I loci reveals overdominant selection. Nature 335: 167-170. HUGHES, A. L., and M. NEI, 1989 Nucleotidesubstitution at major histocompatibilitycomplex class I1 loci: Evidence for overdominant selection. Proc. Natl. Acad. Sci. USA 86: 958-962. LAWLOR, D. A., F. E. WARD,P. D. ENNIS,A. P. JACKSON and P. PARHAM, 1988 HLA-A and E polymorphisms predatethe
divergence of humans and chimpanzees. Nature 335: 268-27 1. MAY, R. M., and R. M. ANDERSON, 1990 Parasite-host coevolution. Parasitology 100: S89-SlOl. MCCONNELL, T . J., W. S. TALBOT,R. A. MCINDOE and E. K. WAKELAND, 1988The origin of MHC class I1 gene polymorphism within the genus Mus. Nature 332: 651-654. NEI, M., and A. L. HUGHES,1991 Polymorphism and evolution of the major histocompatibility complex loci in mammals, pp. 222-247 in Evolution at the Molecular Level, edited by R. K. SELANDER, A. G. CLARKand T. S. WHITTAM.Sinauer Press, Sunderland, Mass. TAKAHATA, N., and M. NEI, 1990 Allelic genealogy under overdominant and frequency-dependent selection and polymorphism of major histocompatibility complex loci. Genetics 124: 967-978.
Letters to the Editor Overdominant vs. Frequency-Dependent Selectionat MHC Loci There has been much discussion recently about the relative roles of overdominant and frequency-dependent selection in the maintenance of polymorphism at major histocompatibility complex (MHC) loci. This has arisen since theconfirmation, using nucleotide sequencedatafrom the antigenbinding sites, that balancing selection is mainly responsible for the observed polymorphism (HUGHES and NEI 1988, 1989). So far, only one study has addressed the question directly. TAKAHATA and NEI (1990) conducted simulations comparing allelic genealogy under various selection regimes. They concluded that frequency-dependent selection (specifically, rare allele advantage) and overdominance could not be distinguished mathematically, and that both could explain the extreme polymorphism, and long term persistence of alleles, at the MHC. Nevertheless, they argued against the former on biological grounds: they asserted that whilst a new rare allele may have a selective advantage as no pathogen strain is adapted to it, a rare old allele should have no such advantage and should disappear from the population by selection or genetic drift. Recent developments in theoretical studies of hostpathogen coevolution do not support this assertion (see MAY and ANDERSON 1990). Host-parasite interactions are intrinsically frequency dependent, anddynamic, because transmission efficiency increases with the frequency of susceptible hosts. A rare MHC allele A1 of recent origin may, as TAKAHATA and NEI state, initially have a selective advantage, as no pathogen strain may be adapted to it. In response, the rare allele A1 will increase in frequency, and there will be selection pressure in favor of a pathogen strain (say P I ) that is able to attack it. Should such a strain arise by mutation, it will also increase in frequency, to a point where it begins to decrease the frequency of A I . This seems to be the endpoint of TAKAHATA and NEI’S argument. It may well, however, bejust the first stage in a dynamic cycle. Once Al is sufficiently rare, its density may be insufficient to maintain P I , which will then decline in frequency until the selective advantage of A, is restored. Thisverbal argument has been made explicit mathematically (BECK 1984).Infrequency dependent selection, rare alleles do not necessarily disappear fromthe population by selection, and would not drift outof the population because allele frequencies may cycle over relatively short time periods. While overdominance has not been incorporatedin Genetics 132: 861-862 (November, 1992)
many of the current genetic models of host-parasite interactions, it is clear that there is no justification, given current understanding, for excluding rare allele frequency-dependent selection as a possible mechanism to maintain MHC polymorphism. As HILLet al. (1992)correctlyobserve,overdominance andfrequency dependent selection can only be distinguished by careful field studies. NEI and HUGHES(199 1) suggested an experiment for this which comparesthe fitness of a homozygote for a rareallele with that of a heterozygote fortwo common alleles. Given the above argument on host-parasite interactions,theexperiment proposed would only be valid in a population context. A crucial difference between the two types of balancing selection is that overdominance predicts a stable polymorphism, whereas a polymorphism maintained by frequencydependence will be dynamic. Many MHC alleles are foundin closely related species and genera (e.g., MCCONNELL et al. 1988; LAWLOR et al. 1988), and comparing allelic frequency distributions among species, or among populations within species, may provide information on allele dynamics. Haplotypefrequencies should also becompared. HAMILTON (1980), in a two locus model of frequency dependent host-parasite interactions, showed that gene frequencies may remain relatively constant but that fluctuating selection is reflected by fluctuating linkage disequilibria. With this in mind, it is interesting tonotethatHLAhaplotypefrequencies show greater variation among racial groups than individual alleles (BODMER and BODMER, 1978). ROBERTW. SLADE Department of Zoology, and Centre for Molecular Biology and Biotechnology, University of Queensland, 4072, Australia HAMISHI. MCCALLUM Department of Zoology, and Centre for Conservation Biology, University of Queensland, 4072, Australia
LITERATURE CITED BECK,K . , 1984 Coevolution: mathematical analysis of host-parasite interactions. J. Math. Biol. 19: 63-77.
862
R. W. Slade and H. I. McCallum
BODMER, W. F., and J. G. BODMER, 1978 Evolution and function of the HLA system. Br. Med. Bull. 3 4 309-316. HAMILTON, W. D., 1980 Sex versus non-sex versus parasite. Oikos 35: 282-290. A. J. MCMICHAEL, B. M. GREENHILL,A. V. S., D. KWIATKOWSKI, WOOD and S. BENNETT, 1992 Maintenance of MHC polymorphism. Nature 355 403. HUGHES, A. L., and M. NEI, 1988 Pattern of nucleotide substitution at major histocompatibility complex class I loci reveals overdominant selection. Nature 335: 167-170. HUGHES, A. L., and M. NEI, 1989 Nucleotidesubstitution at major histocompatibilitycomplex class I1 loci: Evidence for overdominant selection. Proc. Natl. Acad. Sci. USA 86: 958-962. LAWLOR, D. A., F. E. WARD,P. D. ENNIS,A. P. JACKSON and P. PARHAM, 1988 HLA-A and E polymorphisms predatethe
divergence of humans and chimpanzees. Nature 335: 268-27 1. MAY, R. M., and R. M. ANDERSON, 1990 Parasite-host coevolution. Parasitology 100: S89-SlOl. MCCONNELL, T . J., W. S. TALBOT,R. A. MCINDOE and E. K. WAKELAND, 1988The origin of MHC class I1 gene polymorphism within the genus Mus. Nature 332: 651-654. NEI, M., and A. L. HUGHES,1991 Polymorphism and evolution of the major histocompatibility complex loci in mammals, pp. 222-247 in Evolution at the Molecular Level, edited by R. K. SELANDER, A. G. CLARKand T. S. WHITTAM.Sinauer Press, Sunderland, Mass. TAKAHATA, N., and M. NEI, 1990 Allelic genealogy under overdominant and frequency-dependent selection and polymorphism of major histocompatibility complex loci. Genetics 124: 967-978.
