HLA      MHC     Genetics      Evolution      Epidemiology     Biostatistics      Glossary       Homepage


Origin of the MHC


M.Tevfik DORAK, MD, PhD


There is not a definite candidate for the primordial MHC gene. According to one hypothesis the class II MHC evolved first 1, whereas another hypothesis holds that the class I MHC originated first as a result of a recombination between an immunoglobulin-like C-domain and the peptide-binding domain of an HSP70 heat-shock protein 2. A phylogenetic analysis supports a relationship between the class II MHC alpha chain and beta 2-microglobulin and between the class II MHC beta-chain and the class I alpha chain 1. Most evidence supports the hypothesis that the ancestral MHC molecule had a class II-like structure and it gave rise to the class I molecule 1; 3; 4. This still does not explain the nature of the very first MHC gene. Ohno suggested that plasma membrane cell adhesion proteins (N-CAM) that were involved in ontogenic organogenesis since time immemorial were the ultimate ancestor of the adaptive immune system. N-CAM of the chicken for neuronal organogenesis possesses four beta 2-microglobulin-like domains and it is this domain from which the adaptive immune system originated 5. Hughes and Nei calculated the divergence time for class II A and B genes and found 446 to 521 million years depending on the method 6. This fits with the observation that amphibians, which diverged 370 million years ago, have both class II A and B genes 7. The presence of all class I, III, and II genes in the amphibian Xenopus suggests that the physical linkage of these MHC region may be as old as 370 million years or more 8. MHC loci do not always exist in a single tightly linked cluster as they do in mammals, but can be found in two (e.g., chicken 9) or multiple (e.g., zebrafish 10) clusters.

The innate immune system is the only defensive system in invertebrates. It also exists in vertebrates but the main immune defense in vertebrates is the adaptive immune system with its components MHC, TCR and Ig genes (and enzymes with recombinase activity such as RAG1). These main components of the adaptive immune system are missing not only in invertebrates but also in primitive ‘jawless’ vertebrates 11; 12. The adaptive immune system seems to have evolved from the most primitive ‘jawed’ vertebrates, i.e., cartilaginous fish (sharks, rays) upwards. There is no molecular evidence to suggest whether vertebrate immune systems (and particularly the MHC molecules) are evolutionarily related to invertebrate allorecognition systems, and the functional evidence can be interpreted either way. The MHC itself does not exist in the jawless fish 4; 12. MHC class I and class II molecules do exist in the cartilaginous fish (sharks) 13; 14. The overall data suggest that the MHC evolved following duplication of housekeeping genes sometime soon after the evolutionary divergence of the agnathans (jawless vertebrates) 15; 16. It is thought that duplication allowed one copy of the genes to preserve their housekeeping functions and the other copy to diversify.

There is clearly an MHC in amphibians and birds with many characteristics like the MHC of mammals (a single genetic region encoding polymorphic class I and class II molecules) and evidence for polymorphic class I and class II molecules in reptiles. However, many details differ from the mammals, and it is not clear whether these reflect historical accident or selection for different lifestyles or environment. For example, the adult frog Xenopus has a vigorous immune system with many similarities to mammals, a ubiquitous class I molecule, but a much wider class II tissue distribution than human, mouse and chicken. The Xenopus tadpole has a much more restricted immune response, no cell surface class I molecules and a mammalian class II distribution. The axolotl (an amphibian - salamander) has a very poor immune response (as though there are no helper T cells), a wide class II distribution and, for most animals, no cell surface class I molecule. It would be enlightening to understand both the mechanisms for the regulation of the MHC molecules during ontogeny and the consequences for the immune system and survival of the animals. These animals also differ markedly in the level of MHC polymorphism. Another difference from mammals is the presence of previously uncharacterized molecules. In Xenopus and reptiles, there are two populations of class I alpha chain on the surface of erythrocytes, those in association with b 2m and those in association with a disulphide-linked homodimer 7.

MHC class I genes do not show orthologous (i.e., homologous by descent from a common ancestral locus) relationship between mammals of different orders; whereas orthologous relationships have been found among mammalian class II loci 6. The HLA-C locus has been found only in humans, gorilla and chimpanzees but not in monkeys 17. The class II gene regions seem to have arisen prior to the divergence of the orders of placental mammals. The most ancient polymorphic class II locus appears to be HLA-DQA1 18. The polymorphism of this locus also correlates to the MHC class II supertypical groupings 19; 20. There is evidence that MHC genes are subject to a birth-and-death process 21. New genes are created by repeated gene duplication and some duplicate genes are maintained in the genome for a long time but others are deleted or become non-functional by deleterious mutations. This concept disagrees with the earlier idea that the MHC diversity and evolution are governed by concerted evolution of the multigene families of major histocompatibility complex (MHC) genes and immunoglobulin (Ig) genes. The alleles seem to have a fast turnover rate. The lack of correspondence between the human and chimpanzee alleles suggests that 5 million years of separation have been sufficient to reconfigure MHC alleles. This means that the alleles are constantly undergoing modifications during their transspecies evolution 22. In Amerindian population studies, the emergence of new recombinant HLA-B alleles is accompanied by the loss of founding alleles 23.

The origin of diversity of MHC alleles

The major histocompatibility complex (MHC) loci are known to be highly polymorphic in humans, mice and certain other mammals, with heterozygosity as high as 80-90%. Four different hypotheses have been considered to explain this high degree of polymorphism: (1) a high mutation rate, (2) gene conversion or interlocus genetic exchange, (3) overdominant (balancing) selection and (4) frequency-dependent selection.

The distribution of the pattern of sequence polymorphism in human and mouse class I genes provides evidence for four co-ordinate factors that contribute to the origin and sustenance of abundant allele diversity that characterizes the MHC in the species. These include: (a) a gradual accumulation of spontaneous mutational substitution over evolutionary time but not an unusually high mutation rate; (b) selection against mutational divergence in regions of the class I molecule involved in T cell receptor interaction and also in certain regions that interact with common features of antigens; (c) positive selection pressure in favor of persistence of polymorphism and heterozygosity at the antigen recognition site; and (d) periodic intragenic (interallelic) and more rarely, intergenic, recombination within the class I genes.

It has to be emphasized that the evolutionary interplay between mutation and recombination varies with MHC locus, and even for subregions of the same gene 22; 24; 25. For example, phylogenetic inferences based on the exon 2 region of HLA-DRB loci are complicated by selection and recombination (gene conversion). Noncoding region analysis may help clarify patterns of allele evolution usually with contrasting results to those obtained from coding region analyzes 26. The main source for the variability in the HLA gene sequences is point mutation but the mutation rate is by no means higher in the MHC than elsewhere in the genome 27; 28. Because of transspecies polymorphism, accumulation of point mutations over millions of years results in extensive polymorphism. In contrast, gene conversions have produced at least 80 new class I alleles since the separation of the Homo lineage and the rate of conversion is much higher than that of point mutation 29.

Mechanisms maintaining the extreme polymorphism of the MHC

1. Pathogen-driven selection favors genetic diversity of the MHC through both heterozygote advantage (overdominance) and frequency-dependent selection 30. Selection is thought to favor rare MHC genotypes, since pathogens are more likely to have developed mechanisms to evade the MHC-dependent immunity encoded by common MHC genotypes. Six molecular models of pathogen-driven selection have been presented 31:

A. Pathogen Evasion Models

    Escape of a single T-cell clone recognition

    Escape into holes in the T-cell repertoire produced by T-cells anergized by pathogen variants

    Escape into holes in the T-cell repertoire induced by self-tolerance (molecular mimicry)

    Escape of MHC presentation


B. Host-Pathogen Interactions:

    Heterozygote advantage

    Pathogens bearing allo-MHC antigens


MHC associations with specific infectious diseases have been difficult to demonstrate. The best known ones are Marek's disease in chickens 32, parasitic infestations in Soay sheep 33, and malaria in humans 34. Since most infectious agents have multiple epitopes the MHC has to deal with 35, this is not surprising. Rather than resistance of specific heterozygous genotypes to specific agents, it is more likely that a promiscuous heterozygous advantage is operating. This is to say that all heterozygotes are favored over all homozygotes as proposed by Flaherty 36. Only two examples of heterozygote advantage in human infectious diseases have been reported to date: one for a specific genotype in HIV infection 37 and another promiscuous heterozygote advantage in HBV infection 38; 39.

2. Non-pathogen driven mechanisms

a. Selection through inbreeding depression acts indirectly by favoring MHC-based disassortative mating (mating preferences) 40; 41. Here, the MHC is exploited to discriminate against genetic similarity at highly polymorphic loci to avoid inbreeding. MHC-based disassortative matings would produce heterozygous progeny at least at the MHC which would result in increased fitness. Progeny derived from MHC-dissimilar parents would enjoy increased fitness because of reduced levels of inbreeding depression and increased resistance to infectious diseases thanks to increased MHC heterozygosity. The basis of this mechanism is that vertebrate species can detect MHC genotype by smell 42-44. Since sharing highly polymorphic genetic markers is predictive of kinship, avoiding mating with animals that have a similar MHC genotype will reduce the likelihood of matings with relatives (inbreeding). Kinship recognition through MHC-linked chemosensory identity has been documented 45-47. Thus, as the most polymorphic system, the MHC contributes to the genetic identity of an individual at the highest resolution and this is expressed as chemosensory identity. The self-incompatibility system in plants evolved to assure disassortative matings to avoid inbreeding 48; 49, and the vertebrate MHC may be doing the same. Behavioral observations and genetic typing indicated that female mice often left their territories and mated with extraterritorial males with MHC-dissimilar haplotypes 40. A surprising 50% of offspring born in enclosures were from extra-pair copulations. Disassortative mating with respect to self-incompatibility system in plants and the MHC in vertebrates results in the rare-male-effect, and consequently, frequency-dependent selection 50. This selection contributes to the high levels of genetic polymorphism observed at the MHC loci.

b. Reproductive mechanisms: Fetuses which are unlike their mothers have increased chance to survive 51. This is achieved through mate selection 40; 41; 52, selective fertilization 53-56 and selective abortion 51; 57; 58. The mechanisms involved are unknown but the plant self-incompatibility system 59; 60 and the invertebrate allorecognition system 61; 62 provide good examples of selective fertilization.

There is no human study examined the deficit for MHC homozygosity in newborns, but there are studies in mice 58 and rats 54; 57; 63. In one of the earliest studies and its continuation, Palm found that depending on the MHC type, newborn rats might have deficits for homozygosity which appeared as increased heterozygosity. He repeatedly showed that this only occurs in newborn males 57; 63; 64. Also in mice, it has been noted that when deficit for homozygosity for an MHC type occurs, this concerns males 58. Another mouse study found excess heterozygosity at a different histocompatibility locus, H-3, only in males for certain combinations 65. The mouse t-complex, in which the MHC is embedded, contains recessive embryonic lethal genes 66. While most fetus homozygous for a particular recessive t-lethal die, some who bear two different t-lethals may survive till birth. In the group of t6/tw5 heterozygotes, sex affects lethality and a deficit of males among live births was observed in two independent experiments 67; 68. It was also shown that this deficit was not due to sex-reversal 68. These findings also suggest the higher sensitivity of males to prenatal lethality. Thus, maternal-fetal interactions result in heterozygote advantage for MHC haplotypes as a non-pathogen-mediated selection but with a gender effect.

Evidence for Selection on MHC alleles

1. One important feature of the MHC genes is that (as in the plant self-incompatibility and fungal compatibility system alleles 69-71) the ratio of non-synonymous (replacement) to synonymous (silent) substitutions (dn/ds ratio) is very high in the codons encoding the antigen recognition site of polymorphic class II molecules compared to other codons 24; 25; 72; 73. This pattern is evidence that the polymorphism at the antigen recognition sites is maintained by overdominant selection of which the most common form is heterozygote advantage. This kind of selection has been noted for all expressed DRB genes including DRB3 and DRB4 25; 73; 74. By contrast, in the case of monomorphic class II loci, no such enhancement of the rate of non-synonymous substitution was observed. This feature and the others such as (1) an extremely large number of alleles; (2) ancient allelic lineages that pre-date contemporary species (trans-species evolution) and; (3) extremely high sequence divergence of alleles make the MHC a unique system in the whole genome. These features are only shared by the self-incompatibility system of the plants 69; 70; 75-78, fungal mating types 71; 79-81 and invertebrate allorecognition systems 62; 82-84.

2. The expected number of alleles under neutrality is far lower than the number of MHC alleles observed in natural population indicating some form of balancing (diversifying) selection has been acting on them 85-87. In the case of neutral polymorphism, one common allele and a few rare alleles are expected. Only under large effective population sizes (105) and high mutation rates (10-4) does the number of selectively neutral alleles maintained approach observed numbers. For a subdivided population over a large range of migration rates, it appears that the number of self-incompatibility alleles (or MHC-alleles) observed can provide a rough estimate of the total number of individuals in the population but it underestimates the neutral effective size of the subdivided population 77.

3. The large number of alleles showing a relatively even distribution is against neutrality expectations and indicates that diversifying, and not simply directional, selection operates in contemporary populations.

4. The observed deficiency of homozygotes in some human 88-90; 90-93 and animal populations 40; 57; 63; 94-96 indicates that selection favors heterozygotes, presumably because of heightened immune responsiveness. When the amino acid heterozygosities per site for HLA-A and -B loci were determined, for the 54 amino acid sites thought to have functional importance, the average heterozygosity per site was 0.301. Sixteen positions have heterozygosities greater than 0.5 at one or both loci and the frequencies of amino acids at a given position are very even, resulting in nearly the maximum heterozygosity possible. Furthermore, the high heterozygosity is concentrated in the peptide-interacting sites, whereas the sites that interact with the T-cell receptor have lower heterozygosity. Overall, these results indicate the importance of some form of balancing selection operating at HLA loci, maybe even at the individual amino acid level 97. A recent review points out that deficiencies of homozygotes may be overlooked if functional homozygotes are misclassified as heterozygotes 52. Most human MHC alleles belong to only a few supertypes based on similarities in their peptide-binding properties 98. Thus, classifying individuals as "heterozygotes" based on high-resolution typing of alleles may fail to detect true (functional) homozygotes.

5. The observed linkage disequilibrium among tightly linked MHC genes suggests that the strength of selection is uneven within the MHC 99.

6. Studies in West Africa showed that resistance against malaria is HLA-B53 associated and this is the reason for an increased frequency of B53 in that area. The selection differential for HLA-B*5301 is estimated to be 0.028 34. In a Soay sheep population, the variation within the MHC is associated with juvenile survival and parasite resistance 33.

Maintenance of deleterious MHC genes has also puzzled researchers. In an attempt to explain why MHC haplotypes that predispose individuals to autoimmune diseases are common in contemporary populations, Apanius et al 99 suggested that they confer some benefit such as resistance to infectious diseases that outweighs the deleterious effects from autoimmunity. This would be especially pertinent if the benefits were expressed early in life, while the cost due to autoimmunity is paid late in life (i.e., post-reproductive period) when selection against the haplotype would be weaker. This model is based on antagonistic pleiotropy, which is one of the theories proposed to explain the senescence 100; 101. A related explanation for the maintenance of autoimmune-predisposing MHC haplotypes is that these alleles protect against initial infection, but the pathogen triggers autoimmunity through molecular mimicry 102 or other factors 99.

(Original publication: 2000. Expected update: Late 2004)

More recent articles not covered in this review include the following:

1. Kulski JK et al. Comparative genomic analysis of the MHC. Immunol Rev 2002;190:95-122

2. Flajnik MF & Kasahara M. Comparative genomics of the MHC. Immunity 2001;15:351-62

3. Meyer D & Thomson G. How selection shapes variation of the human MHC. Ann Hum Genet. 2001;65:1-26

4. Etienne - Vitiello D et al. The MHC origin. Immunol Rev 2004;198:216-32


  1. Hughes AL, Nei M: Evolutionary relationships of the classes of major histocompatibility complex genes. Immunogenetics 37:337, 1993
  2. Flajnik MF, Canel C, Kramer J, Kasahara M: Which came first, MHC class I or class II? Immunogenetics 33:295, 1991
  3. Lawlor DA, Zemmour J, Ennis PD, Parham P: Evolution of class-I MHC genes and proteins: from natural selection to thymic selection. Annual Review of Immunology 8:23, 1990
  4. Klein J, O'hUigin C: Composite origin of major histocompatibility complex genes [Review]. Current Opinion in Genetics & Development 3:923, 1993
  5. Ohno S: The ancestor of the adaptive immune system was the CAM system for organogenesis. Experimental & Clinical Immunogenetics 4:181, 1987
  6. Hughes AL, Nei M: Evolutionary relationships of class II major-histocompatibility- complex genes in mammals. Molecular Biology & Evolution 7:491, 1990
  7. Kaufman J, Skjoedt K, Salomonsen J: The MHC molecules of nonmammalian vertebrates. Immunological Reviews 113:83, 1990
  8. Nonaka M, Namikawa C, Kato Y, Sasaki M, Salter-Cid L, Flajnik MF: Major histocompatibility complex gene mapping in the amphibian Xenopus implies a primordial organization. Proceedings of the National Academy of Sciences USA 94:5789, 1997
  9. Miller MM, Goto R, Bernot A, Zoorob R, Auffray C, Bumstead N, Briles WE: Two Mhc class I and two Mhc class II genes map to the chicken Rfp-Y system outside the B complex. Proceedings of the National Academy of Sciences USA 91:4397, 1994
  10. Bingulac-Popovic J, Figueroa F, Sato A, Talbot WS, Johnson SL, Gates M, Postlethwait JH, Klein J: Mapping of mhc class I and class II regions to different linkage groups in the zebrafish, Danio rerio. Immunogenetics 46:129, 1997
  11. Klein J, Sato A: Birth of the major histocompatibility complex. Scandinavian Journal of Immunology 47:199, 1998
  12. Matsunaga T, Rahman A: What brought the adaptive immune system to vertebrates? Immunological Reviews 166:177, 1998
  13. Kasahara M, Vazquez M, Sato K, McKinney EC, Flajnik MF: Evolution of the major histocompatibility complex: isolation of class II A cDNA clones from the cartilaginous fish. Proceedings of the National Academy of Sciences USA 89:6688, 1992
  14. Okamura K, Ototake M, Nakanishi T, Kurosawa Y, Hashimoto K: The most primitive vertebrates with jaws possess highly polymorphic MHC class I genes comparable to those of humans. Immunity 7:777, 1997
  15. Kasahara M, Hayashi M, Tanaka K, Inoko H, Sugaya K, Ikemura T, Ishibashi T: Chromosomal localization of the proteasome Z subunit gene reveals an ancient chromosomal duplication involving the major histocompatibility complex. Proceedings of the National Academy of Sciences USA 93:9096, 1996
  16. Kasahara M, Nakaya J, Satta Y, Takahata N: Chromosomal duplication and the emergence of the adaptive immune system. Trends in Genetics 13:90, 1997
  17. Boyson JE, Shufflebotham C, Cadavid LF, Urvater JA, Knapp LA, Hughes AL, Watkins DI: The MHC class I genes of the rhesus monkey. Different evolutionary histories of MHC class I and II genes in primates. Journal of Immunology 156:4656, 1996
  18. Gyllensten UB, Erlich HA: Ancient roots for polymorphism at the HLA-DQ alpha locus in primates. Proceedings of the National Academy of Sciences USA 86:9986, 1989
  19. Moriuchi J, Moriuchi T, Silver J: Nucleotide sequence of an HLA-DQ alpha chain derived from a DRw9 cell line: genetic and evolutionary implications. Proceedings of the National Academy of Sciences USA 82:3420, 1985
  20. Karr RW, Gregersen PK, Obata F, Goldberg D, Maccari J, Alber C, Silver J: Analysis of DR beta and DQ beta chain cDNA clones from a DR7 haplotype. Journal of Immunology 137:2886, 1986
  21. Nei M, Gu X, Sitnikova T: Evolution by the birth-and-death process in multigene families of the vertebrate immune system. Proceedings of the National Academy of Sciences USA 94:7799, 1997
  22. Parham P, Ohta T: Population biology of antigen presentation by MHC class I molecules. Science 272:67, 1996
  23. Parham P, Arnett KL, Adams EJ, Little AM, Tees K, Barber LD, Marsh SG, Ohta T, Markow T, Petzl-Erler ML: Episodic evolution and turnover of HLA-B in the indigenous human populations of the Americas. Tissue Antigens 50:219, 1997
  24. Hughes AL, Nei M: Pattern of nucleotide substitution at major histocompatibility complex class I loci reveals overdominant selection. Nature 335:167, 1988
  25. Hughes AL, Nei M: Nucleotide substitution at major histocompatibility complex class II loci: evidence for overdominant selection. Proceedings of the National Academy of Sciences USA 86:958, 1989
  26. Hickson RE, Cann RL: Mhc allelic diversity and modern human origins. Journal of Molecular Evolution 45:589, 1997
  27. Lawlor DA, Ward FE, Ennis PD, Jackson AP, Parham P: HLA-A and B polymorphisms predate the divergence of humans and chimpanzees. Nature 335:268, 1988
  28. Parham P, Adams EJ, Arnett KL: The origins of HLA-A,B,C polymorphism. [Review]. Immunological Reviews 143:141, 1995
  29. Zangenberg G, Huang MM, Arnheim N, Erlich H: New HLA-DPB1 alleles generated by interallelic gene conversion detected by analysis of sperm. Nature Genetics 10:407, 1995
  30. Potts WK, Wakeland EK: Evolution of MHC genetic diversity: a tale of incest, pestilence and sexual preference. Trends in Genetics 9:408, 1993
  31. Potts WK, Slev PR: Pathogen-based models favoring MHC genetic diversity [Review]. Immunological Reviews 143:181, 1995
  32. Briles WE, Briles RW, Taffs RE: Resistance to a malignant disease in chickens is mapped to a subregion of major histocompatibility (B) complex. Science 219:977, 1983
  33. Paterson S, Wilson K, Pemberton JM: Major histocompatibility complex variation associated with juvenile survival and parasite resistance in a large unmanaged ungulate population. Proceedings of the National Academy of Sciences USA 95:3714, 1998
  34. Hill AV, Allsopp CE, Kwiatkowski D, Anstey NM, Twumasi P, Rowe PA, Bennett S, Brewster D, McMichael AJ, Greenwood BM: Common west African HLA antigens are associated with protection from severe malaria. Nature 352:595, 1991
  35. Fienberg SE: The analysis of multidimensional contingency tables. Ecology 51:419, 1970
  36. Flaherty L: Major histocompatibility complex polymorphism: a nonimmune theory for selection. Human Immunology 21:3, 1988
  37. Carrington M, Nelson GW, Martin MP, Kissner T, Vlahov D, Goedert JJ, Kaslow R, Buchbinder S, Hoots K, O'Brien SJ: HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage. Science 283:1748, 1999
  38. Thursz MR, Thomas HC, Greenwood BM, Hill AV: Heterozygote advantage for HLA class-II type in hepatitis B virus infection [letter]. Nature Genetics 17:11, 1997
  39. Thio CL, Carrington M, Marti D, et al.: Class II HLA alleles and hepatitis B virus persistence in African Americans. Journal of Infectious Diseases 179:1004, 1999
  40. Potts WK, Manning CJ, Wakeland EK: Mating patterns in seminatural populations of mice influenced by MHC genotype. Nature 352:619, 1991
  41. Ober C, Weitkamp LR, Cox N, Dytch H, Kostyu DD, Elias S: HLA and mate choice in humans. American Journal of Human Genetics 61:497, 1997
  42. Boyse EA, Beauchamp GK, Yamazaki K: Critical review: the sensory perception of genotypic polymorphism of the major histocompatibility complex and other genes: some physiological and phylogenetic implications. Human Immunology 6:177, 1983
  43. Brown RE, Singh PB, Roser B: The major histocompatibility complex and the chemosensory recognition of individuality in rats. Physiology & Behavior 40:65, 1987
  44. Singh PB, Brown RE, Roser B: MHC antigens in urine as olfactory recognition cues. Nature 327:161, 1987
  45. Manning CJ, Wakeland EK, Potts WK: Communal nesting patterns in mice implicate MHC genes in kin recognition. Nature 360:581, 1992
  46. Yamazaki K, Yamaguchi M, Baranoski L, Bard J, Boyse EA, Thomas L: Recognition among mice. Evidence from the use of a Y-maze differentially scented by congenic mice of different major histocompatibility types. Journal of Experimental Medicine 150:755, 1979
  47. Brown JL, Eklund A: Kin recognition and the major histocompatibility complex: an integrative review. American Naturalist 143:435, 1994
  48. Matton DP, Nass N, Clarke AE, Newbigin E: Self-incompatibility: How plants avoid illegitimate offspring. Proceedings of the National Academy of Sciences USA 91:1992, 1994
  49. Kao TH, McCubbin AG: How flowering plants discriminate between self and non-self pollen to prevent inbreeding. Proceedings of the National Academy of Sciences USA 93:12059, 1996
  50. Partridge L: The rare-male effect: what is its evolutionary significance? Philosophical Transactions of the Royal Society of London - Series B: Biological Sciences 319:525, 1988
  51. Clarke B, Kirby DR: Maintenance of histocompatibility polymorphisms. Nature 211:999, 1966
  52. Penn DJ, Potts WK: The evolution of mating preferences and major histocompatibility complex genes. American Naturalist 153:145, 1999
  53. Ho HN, Yang YS, Hsieh RP, Lin HR, Chen SU, Chen HF, Huang SC, Lee TY, Gill TJI: Sharing of human leukocyte antigens in couples with unexplained infertility affects the success of in vitro fertilization and tubal embryo transfer. American Journal of Obstetrics & Gynecology 170:63, 1994
  54. Michie D, Anderson NF: A strong selective effect associated with a histocompatibility gene in the rat. Annals of the New York Academy of Sciences 129:88, 1966
  55. Kirby DR: The egg and immunology. Proceedings of the Royal Society of Medicine 63:59, 1970
  56. Wedekind C, Chapuisat M, Macas E, Rulicke T: Non-random fertilization in mice correlates with the MHC and something else. Heredity 77:400, 1996
  57. Palm J: Maternal-fetal histoincompatibility in rats: an escape from adversity. Cancer Research 34:2061, 1974
  58. Hamilton MS, Hellstrom I: Selection for histoincompatible progeny in mice. Biology of Reproduction 19:267, 1978
  59. Haring V, Gray JE, McClure BA, Anderson MA, Clarke AE: Self-incompatibility: a self-recognition system in plants [Review]. Science 250:937, 1990
  60. Thompson RD, Kirch HH: The S locus of flowering plants: when self-rejection is self- interest. Trends in Genetics 8:381, 1992
  61. Oka H: Colony specificity in compound Ascidians, in Yukova M (ed): Profiles of Japanese Science & Scientists, Tokyo, Kodansha, 1970, p 195
  62. Scofield VL, Schlumpberger JM, West LA, Weissman IL: Protochordate allorecognition is controlled by a MHC-like gene system. Nature 295:499, 1982
  63. Palm J: Association of maternal genotype and excess heterozygosity for Ag-B histocompatibility antigens among male rats. Transplantation Proceedings 1:82, 1969
  64. Palm J: Maternal-fetal interactions and histocompatibility antigen polymorphisms. Transplantation Proceedings 2:162, 1970
  65. Hull P: Maternal-foetal incompatibility associated with the H-3 locus in the mouse. Heredity (Edinburgh) 24:203, 1969
  66. Dorak MT, Burnett AK: Major histocompatibility complex, t-complex, and leukemia [Review]. Cancer Causes & Control 3:273, 1992
  67. Bechtol KB: Lethality of heterozygotes between t-haplotype complementation groups of mouse: sex-related effect on lethality of t6/tw5 heterozygotes. Genetical Research 39:79, 1982
  68. King TR: Partial complementation by murine t haplotypes: deficit of males among t6/tw5 double heterozygotes and correlation with transmission-ratio distortion. Genetical Research 57:55, 1991
  69. Ioerger TR, Clark AG, Kao TH: Polymorphism at the self-incompatibility locus in Solanaceae predates speciation. Proceedings of the National Academy of Sciences USA 87:9732, 1990
  70. Clark AG, Kao TH: Excess nonsynonymous substitution of shared polymorphic sites among self-incompatibility alleles of Solanaceae. Proceedings of the National Academy of Sciences USA 88:9823, 1991
  71. Wu J, Saupe SJ, Glass NL: Evidence for balancing selection operating at the het-c heterokaryon incompatibility locus in a group of filamentous fungi. Proceedings of the National Academy of Sciences USA 95:12398, 1998
  72. Hughes AL, Hughes MK, Howell CY, Nei M: Natural selection at the class II major histocompatibility complex loci of mammals. Philosophical Transactions of the Royal Society of London - Series B: Biological Sciences 346:359, 1994
  73. Hughes AL: Evolution of the HLA complex, in Jackson M, Strachan T, Dover G (eds): Human Genome Evolution, Oxford, Bios Scientific Publishers, 1996, p 73
  74. Klein J, O'hUigin C: Class II B Mhc motifs in an evolutionary perspective [Review]. Immunological Reviews 143:89, 1995
  75. Dwyer KG, Balent MA, Nasrallah JB, Nasrallah ME: DNA sequences of self-incompatibility genes from Brassica campestris and B. oleracea: polymorphism predating speciation. Plant Molecular Biology 16:481, 1991
  76. Charlesworth D, Awadalla P: Flowering plant self-incompatibility: the molecular population genetics of Brassica S-loci. Heredity 81 ( Pt 1):1, 1998
  77. Schierup MH: The number of self-incompatibility alleles in a finite, subdivided population. Genetics 149:1153, 1998
  78. Boyes DC, Nasrallah ME, Vrebalov J, Nasrallah JB: The self-incompatibility (S) haplotypes of Brassica contain highly divergent and rearranged sequences of ancient origin. Plant Cell 9:237, 1997
  79. Rivers BA, Bernatzky R, Robinson SJ, Jahnen-Dechent W: Molecular diversity at the self-incompatibility locus is a salient feature in natural populations of wild tomato (Lycopersicon peruvianum). Molecular & General Genetics 238:419, 1993
  80. Hartl DL, Dempster ER, Brown SW: Adaptive significance of vegetative incompatibility in Neurospora crassa. Genetics 81:553, 1975
  81. Saupe SJ, Glass NL: Allelic specificity at the het-c heterokaryon incompatibility locus of Neurospora crassa is determined by a highly variable domain. Genetics 146:1299, 1997
  82. Grosberg RK: The evolution of allorecognition specificity in clonal invertebrates. Quarterly Review of Biology 63:377, 1988
  83. Weissman IL, Saito Y, Rinkevich B: Allorecognition histocompatibility in a protochordate species: is the relationship to MHC somatic or structural? Immunological Reviews 113:227, 1990
  84. Magor BG, De Tomaso A, Rinkevich B, Weissman IL: Allorecognition in colonial tunicates: protection against predatory cell lineages? Immunological Reviews 167:69, 1992
  85. Hedrick PW, Thomson G: Evidence for balancing selection at HLA. Genetics 104:449, 1983
  86. Klitz W, Thomson G, Baur MP: Contrasting evolutionary histories among tightly linked HLA loci. American Journal of Human Genetics 39:340, 1986
  87. Potts WK, Wakeland EK: Evolution of diversity at the major histocompatibility complex. Trends in Ecology and Evolution 5:181, 1990
  88. Degos L, Colombani J, Chaventre A, Bengtson B, Jacquard A: Selective pressure on HL-A polymorphism. Nature 249:62, 1974
  89. Kostyu DD, Dawson DV, Elias S, Ober C: Deficit of HLA homozygotes in a Caucasian isolate. Human Immunology 37:135, 1993
  90. Black FL, Hedrick PW: Strong balancing selection at HLA loci: evidence from segregation in South Amerindian families. Proceedings of the National Academy of Sciences USA 94:12452, 1997
  91. Hedrick PW: Evolution at HLA: possible explanations for the deficiency of homozygotes in two populations. Human Heredity 40:213, 1990
  92. Markow T, Hedrick PW, Zuerlein K, Danilovs J, Martin J, Vyvial T, Armstrong C: HLA polymorphism in the Havasupai: evidence for balancing selection. American Journal of Human Genetics 53:943, 1993
  93. Black FL, Salzano FM: Evidence for heterosis in the HLA system. American Journal of Human Genetics 33:894, 1981
  94. von Schantz T, Wittzell H, Goransson G, Grahn M, Persson K: MHC genotype and male ornamentation: genetic evidence for the Hamilton-Zuk model. Proceedings of the Royal Society of London - Series B: Biological Sciences 263:265, 1996
  95. Duncan WR, Wakeland EK, Klein J: Heterozygosity of H-2 loci in wild mice. Nature 281:603, 1979
  96. Ritte U, Neufeld E, O'hUigin C, Figueroa F, Klein J: Origins of H-2 polymorphism in the house mouse. II. Characterization of a model population and evidence for heterozygous advantage. Immunogenetics 34:164, 1991
  97. Hedrick PW, Whittam TS, Parham P: Heterozygosity at individual amino acid sites: extremely high levels for HLA-A and -B genes. Proceedings of the National Academy of Sciences USA 88:5897, 1991
  98. Sidney J, Grey HM, Kubo RT, Sette A: Practical, biochemical and evolutionary implications of the discovery of HLA class I supermotifs. Immunology Today 17:261, 1996
  99. Apanius V, Penn D, Slev PR, Ruff LR, Potts WK: The nature of selection on the major histocompatibility complex. Critical Reviews in Immunology 17:179, 1997

100. Curtsinger JW, Fukui HH, Khazaeli AA, Kirscher A, Pletcher SD, Promislow DE, Tatar M: Genetic variation and aging. Annual Review of Genetics 29:553, 1995

101. Albin RL: Antagonistic pleiotropy, mutation accumulation, and human genetic disease. Genetica 91:279, 1993

102. Hall R: Molecular mimicry. Advances in Parasitology 34:81, 1994.

M.Tevfik Dorak, M.D., Ph.D.

Last edited on 23 January  2007

HLA      MHC     Genetics      Evolution      Epidemiology     Biostatistics      Glossary       Homepage