Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Full Paper
  • Published:

Increased heterozygosity for MHC class II lineages in newborn males

Abstract

In plants, fungi and marine invertebrates, there are genetic compatibility systems to ensure diversity in the offspring. The importance of genetic compatibility in gametic union and selective abortion in vertebrate animals has also been appreciated recently. There have been suggestions that the major histocompatibility complex (HLA in humans) may be a compatibility system in vertebrates. HLA class II haplotypes often contain a second expressed DRB locus which can be either DRB3, DRB4 or DRB5. These encode the supertypical specificities and mark the ancestral lineages. The members of each lineage have related DNA sequences at the main class II locus HLA-DRB1. We analysed 415 newborns at all expressed DRB loci by PCR analysis to seek evidence for sex-specific prenatal selection events. While there was no significant change in heterozygosity rates between males and females at DRB1, the proportion of males carrying two DRB1 specificities from different ancestral lineages was significantly increased (53.7% in males vs 39.3% in females, Pā€‰=ā€‰0.003). The genotypes consisting of phylogenetically most distinct ones, namely the DRB3 and DRB4 haplotypes, showed the most striking difference between sexes (Pā€‰=ā€‰0.007). These results suggested a more favourable outcome for male concepti heterozygous for supertypical haplotypes. Heterozygosity for most divergent haplotypical families ensures the highest degree of functional heterozygosity at the main HLA class II locus DRB1 while increasing the likelihood of heterozygosity also at other MHC loci. Our observations agree with the previously reported heterozygote excess in male newborn rats and mice. Correlations between MHC class II heterozygosity and advertised male quality in deer and pheasant as well as increased reproductive success in MHC class II heterozygous male macaques are examples of postnatal benefits of heterozygosity in males that may be behind the development of prenatal selection mechanisms. The MHC-mediated prenatal selection of males may also be one of the selective events suggested by the very high primary (male-to-female) sex ratio at fertilization reaching close to unity at birth in humans. These results provide an appealing working hypothesis for further studies in humans and other vertebrates.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Marshall DL, Folsom MW . Mate choice in plants: an anatomical to population perspective Annu Rev Ecol Syst 1991 22: 37ā€“63

    ArticleĀ  Google ScholarĀ 

  2. Kao TH, McCubbin AG . How flowering plants discriminate between self and non-self pollen to prevent inbreeding Proc Natl Acad Sci USA 1996 93: 12059ā€“12065

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  3. Willson MF . Sexual selection in plants and animals Trends Ecol Evol 1990 5: 210ā€“214

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  4. Kronstad JW, Staben C . Mating type in filamentous fungi Annu Rev Genet 1997 31: 245ā€“276

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  5. Grosberg RK . The evolution of allorecognition specificity in clonal invertebrates Q Rev Biol 1988 63: 377ā€“412

    ArticleĀ  Google ScholarĀ 

  6. Burnet FM . ā€œSelf-recognitionā€ in colonial marine forms and flowering plants in relation to the evolution of immunity Nature 1971 232: 230ā€“235

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  7. Jones JS, Partridge L . Tissue rejection: the price for sexual acceptance Nature 1983 304: 484ā€“485

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  8. Alberts SC, Ober C . Genetic variability of the MHC: a review of non-pathogen-mediated selective mechanisms Yearbook Phys Anthropol 1993 36: 71ā€“89

    ArticleĀ  Google ScholarĀ 

  9. Apanius V, Penn D, Slev PR, Ruff LR, Potts WK . The nature of selection on the major histocompatibility complex Crit Rev Immunol 1997 17: 179ā€“224

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  10. Penn DJ, Potts WK . The evolution of mating preferences and major histocompatibility complex genes Am Nat 1999 153: 145ā€“164

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  11. Tregenza T, Wedell N . Genetic compatibility, mate choice and patterns of parentage: invited review Mol Ecol 2000 9: 1013ā€“1027

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  12. The MHC sequencing consortium. Complete sequence and gene map of a human major histocompatibility complex Nature 1999 401: 921ā€“923

  13. Potts WK, Wakeland EK . Evolution of diversity at the major histocompatibility complex Trends Ecol Evol 1990 5: 181ā€“187

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  14. Little AM, Parham P . Polymorphism and evolution of HLA class I and II genes and molecules Rev Immunogenet 1999 1: 105ā€“123

    CASĀ  PubMedĀ  Google ScholarĀ 

  15. Kasahara M, Klein D, Vincek V, Sarapata DE, Klein J . Comparative anatomy of the primate major histocompatibility complex DR subregion: evidence for combinations of DRB genes conserved across species Genomics 1992 14: 340ā€“349

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  16. Trowsdale J . ā€œBoth man & bird & beastā€: comparative organization of MHC genes Immunogenetics 1995 41: 1ā€“17

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  17. Andersson G, Andersson L, Larhammar D, Rask L, Sigurdardottir S . Simplifying genetic locus assignment of HLA-DRB genes Immunol Today 1994 15: 58ā€“61

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  18. Satta Y, Mayer WE, Klein J . HLA-DRB intron 1 sequences: implications for the evolution of HLA-DRB genes and haplotypes Hum Immunol 1996 51: 1ā€“12

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  19. Satta Y, Oā€™Huigin C, Takahata N, Klein J . Intensity of natural selection at the major histocompatibility complex loci Proc Natl Acad Sci USA 1994 91: 7184ā€“7188

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  20. Black FL, Hedrick PW . Strong balancing selection at HLA loci: evidence from segregation in South Amerindian families Proc Natl Acad Sci USA 1997 94: 12452ā€“12456

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  21. Hedrick PW . Balancing selection and MHC Genetica 1999 104: 207ā€“214

    ArticleĀ  CASĀ  Google ScholarĀ 

  22. Edwards SV, Hedrick PW . Evolution and ecology of MHC molecules: from genomics to sexual selection Trends Ecol Evol 1998 13: 305ā€“311

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  23. Richman AD . Evolution of balanced genetic polymorphism Mol Ecol 2000 9: 1953ā€“1963

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  24. Thursz MR, Thomas HC, Greenwood BM, Hill AV . Heterozygote advantage for HLA class-II type in hepatitis B virus infection Nat Genet 1997 17: 11ā€“12 (letter)

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  25. Carrington M, Nelson GW, Martin MP et al. HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage Science 1999 283: 1748ā€“1752

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  26. Jeffery KJ, Siddiqui AA, Bunce M et al. The influence of HLA class I alleles and heterozygosity on the outcome of human T cell lymphotropic virus type I infection J Immunol 2000 165: 7278ā€“7284

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  27. Dorak MT, Lawson T, Machulla HKG, Darke C, Mills Kl, Burnett AK . Unravelling an HLA-DR association in childhood acute lymphoblastic leukemia Blood 1999 94: 694ā€“700

    CASĀ  PubMedĀ  Google ScholarĀ 

  28. Dorak MT . A search for a leukaemia susceptibility gene in the HLA complex. PhD Dissertation The University of Wales College of Medicine, UK 2000

    Google ScholarĀ 

  29. Kaye SA, Robison LL, Smithson WA, Gunderson P, King FL, Neglia JP . Maternal reproductive history and birth characteristics in childhood acute lymphoblastic leukemia Cancer 1991 68: 1351ā€“1355

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  30. Yeazel MW, Buckley JD, Woods WG, Ruccione K, Robison LL . History of maternal fetal loss and increased risk of childhood acute leukemia at an early age. A report from the Childrens Cancer Group Cancer 1995 75: 1718ā€“1727

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  31. Klein J, Gutknecht J, Fischer N . The major histocompatibility complex and human evolution Trends Genet 1990 6: 7ā€“11

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  32. Ayala FJ, Escalante A, Oā€™hUigin C, Klein J . Molecular genetics of speciation and human origins Proc Natl Acad Sci USA 1994 91: 6787ā€“6794

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  33. Zeh JA, Zeh DW . The evolution of polyandry II: post-copulatory defences against genetic incompatibility Proc R Soc Lond B Biol Sci 1997 264: 69ā€“75

    ArticleĀ  Google ScholarĀ 

  34. Jennions MD, Petrie M . Why do females mate multiply? A review of the genetic benefits Biol Rev Camb Philos Soc 2000 75: 21ā€“64

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  35. Ditchkoff SS, Lochmiller RL, Masters RE, Hoofer SR, van den Bussche RA . Major-histocompatibility-complex-associated variation in secondary sexual traits of white-tailed deer (Odocoileus Virginianus): evidence for good-genes advertisement Evolution 2001 55: 616ā€“625

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  36. Wakeland EK, Boehme S, She JX et al. Ancestral polymorphisms of MHC class II genes: divergent allele advantage Immunol Res 1990 9: 115ā€“122

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  37. Flaherty L . Major histocompatibility complex polymorphism: a nonimmune theory for selection Hum Immunol 1988 21: 3ā€“13

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  38. Sette A, Sidney J . HLA supertypes and supermotifs: a functional perspective on HLA polymorphism Curr Opin Immunol 1998 10: 478ā€“482

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  39. Bell Jl, Denney D Jr, Foster L, Belt T, Todd JA, McDevitt HO . Allelic variation in the DR subregion of the human major histocompatibility complex Proc Natl Acad Sci USA 1987 84: 6234ā€“6238

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  40. Gorski J, Rollini P, Mach B . Structural comparison of the genes of two HLA-DR supertypic groups: the loci encoding DRw52 and DRw53 are not truly allelic Immunogenetics 1987 25: 897ā€“402

    Google ScholarĀ 

  41. Palm J . Association of maternal genotype and excess heterozygosity for Ag-B histocompatibility antigens among male rats Transplant Proc 1969 1: 82ā€“84

    CASĀ  PubMedĀ  Google ScholarĀ 

  42. Palm J . Maternal-fetal interactions and histocompatibility antigen polymorphisms Transplant Proc 1970 2: 162ā€“173

    CASĀ  PubMedĀ  Google ScholarĀ 

  43. Palm J . Maternal-fetal histoincompatibility in rats: an escape from adversity Cancer Res 1974 34: 2061ā€“2065

    CASĀ  PubMedĀ  Google ScholarĀ 

  44. Hamilton MS, Hellstrom I . Selection for histoincompatible progeny in mice Biol Reprod 1978 19: 267ā€“270

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  45. Hull P . Maternal-foetal incompatibility associated with the H-3 locus in the mouse Heredity 1969 24: 203ā€“209

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  46. Bechtol KB . Lethality of heterozygotes between t-haplotype complementation groups of mouse: sex-related effect on lethality of t6/tw5 heterozygotes Genet Res 1982 39: 79ā€“84

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  47. King TR . Partial complementation by murine t haplotypes: deficit of males among t6/tw5 double heterozygotes and correlation with transmission-ratio distortion Genet Res 1991 57: 55ā€“59

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  48. Wedekind C, Chapuisat M, Macas E, Rulicke T . Non-random fertilization in mice correlates with the MHC and something else Heredity 1996 77: 400ā€“409

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  49. Crew FA . The sex ratio Am Nat 1937 71: 529ā€“559

    ArticleĀ  Google ScholarĀ 

  50. McMillen MM . Differential mortality by sex in fetal and neonatal deaths Science 1979 204: 89ā€“91

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  51. Kellokumpu-Lehtinen P, Pelliniemi LJ . Sex ratio in human conceptuses Obstet Gynecol 1984 64: 220ā€“222

    CASĀ  PubMedĀ  Google ScholarĀ 

  52. Byrne J, Warburton D . Male excess among anatomically normal fetuses in spontaneous abortions Am J Med Genet 1987 26: 605ā€“611

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  53. Roberts CJ, Lowe CR . Where have all the conceptions gone? Lancet 1975 1: 498ā€“499

    ArticleĀ  Google ScholarĀ 

  54. Drife JO . What proportion of pregnancies are spontaneously aborted? Br Med J 1983 286: 294

    Google ScholarĀ 

  55. Diamond JM . Causes of death before birth Nature 1987 329: 487ā€“488

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  56. Kirby DR . The egg and immunology Proc Roy Soc Med 1970 63: 59ā€“61

    CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  57. Amos DB . HL-A, fertility and natural selection Acta Endocrinol Suppl (Copenhagen) 1975 194: 318ā€“335

    ArticleĀ  CASĀ  Google ScholarĀ 

  58. Brown JL . Some paradoxical goals of cells and organisms: the role of the MHC In: Pfaff DW (ed) Ethical Questions in Brain and Behavior: Problems and Opportunities Springer-Verlag: New York 1983 pp 111ā€“124

    ChapterĀ  Google ScholarĀ 

  59. Mori T, Guo MW, Sato E, Baba T, Takasaki S, Mori E . Molecular and immunological approaches to mammalian fertilization Am J Reprod Immunol 2000 47: 139ā€“158

    ArticleĀ  CASĀ  Google ScholarĀ 

  60. Grob B, Knapp LA, Martin RD, Anzenberger G . The major histocompatibility complex and mate choice: inbreeding avoidance and selection of good genes Exp Clin Immunogenet 1998 15: 119ā€“129

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  61. Landry C, Garant D, Duchesne P, Bernatchez L . The good genes as heterozygosity: MHC and mate choice in Atlantic salmon (Salmo salar) Proc R Soc Lond B Biol Sci 2001 268: 1279ā€“1285

    ArticleĀ  CASĀ  Google ScholarĀ 

  62. Wedekind C, Seebeck T, Bettens F, Paepke AJ . MHC-dependent mate preferences in humans Proc R Soc Lond B Biol Sci 1995 260: 245ā€“249

    ArticleĀ  CASĀ  Google ScholarĀ 

  63. Ober C, Weitkamp LR, Cox N, Dytch H, Kostyu DD, Elias S . HLA and mate choice in humans Am J Hum Genet 1997 61: 497ā€“504

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  64. Hedrick PW, Black FL . HLA and mate selection: no evidence in South Amerindians Am J Hum Genet 1997 61: 505ā€“511

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  65. Michie D, Anderson NF . A strong selective effect associated with a histocompatibility gene in the rat Ann New York Acad Sci 1966 129: 88ā€“93

    ArticleĀ  Google ScholarĀ 

  66. Brown JL . A theory of mate choice based on heterozygosity Behav Ecol 1997 8: 60ā€“65

    ArticleĀ  Google ScholarĀ 

  67. Brown JL . The new heterozygosity theory of mate choice and the MHC Genetica 1998 104: 215ā€“221

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  68. Wedekind C, Furi S . Body odour preferences in men and women: do they aim for specific MHC combinations or simply heterozygosity? Proc R Soc Lond B Biol Sci 1997 264: 1471ā€“1479

    ArticleĀ  CASĀ  Google ScholarĀ 

  69. von Schantz T, Wittzell H, Goransson G, Grahn M, Persson K . MHC genotype and male ornamentation: genetic evidence for the Hamilton-Zuk model Proc R Soc Lond B Biol Sci 1996 263: 265ā€“271

    ArticleĀ  CASĀ  Google ScholarĀ 

  70. Sauermann U, Nurnberg P, Bercovitch FB et al. Increased reproductive success of MHC class II heterozygous males among free-ranging rhesus macaques Hum Genet 2001 108: 249ā€“254

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  71. Yuhki N, Oā€™Brien SJ . DNA variation of the mammalian major histocompatibility complex reflects genomic diversity and population history Proc Natl Acad Sci USA 1990 87: 836ā€“840

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  72. Wright S . Variability Within and Among Natural Populations University of Chicago Press: Chicago 1978

    Google ScholarĀ 

  73. Nei M . Estimation of average heterozygosity and genetic distance from a small number of individuals Genetics 1978 89: 583ā€“590

    CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  74. Yeh FC, Yang R-C, Boyle TBJ, Ye Z-H, Mao JX . POPGENE, the user-friendly shareware for population genetic analysis Molecular Biology and Biotechnology Centre, University of Alberta, Canada 1997

    Google ScholarĀ 

  75. Daly LE, Bourke GJ . Interpretation and Uses of Medical Statistics. 5th edition Blackwell Scientific Publications: Oxford 2000

    BookĀ  Google ScholarĀ 

Download references

Acknowledgements

We are grateful to Drs Mary Carrington and Bill Klitz for a critical review of an earlier version of this report. We thank the staff at Interbranch HLA Laboratory in Halle, Germany for technical assistance.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M T Dorak.

Additional information

This study was supported by the Leukaemia Research Appeal for Wales (UK).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dorak, M., Lawson, T., Machulla, H. et al. Increased heterozygosity for MHC class II lineages in newborn males. Genes Immun 3, 263ā€“269 (2002). https://doi.org/10.1038/sj.gene.6363862

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6363862

Keywords

This article is cited by

Search

Quick links