Original Article

Heredity (1996) 77, 400–409; doi:10.1038/hdy.1996.160

Non-random fertilization in mice correlates with the MHC and something else

Claus Wedekind1, Michel Chapuisat2, Ervin Macas3 and Thomas Rülicke4

  1. 1Abteilung Verhaltensökologie, Zoologisches Institut, Universität Bern, 3032 Hinterkappelen, Switzerland
  2. 2Musée de Zoologie, CP 448, 1017 Lausanne and Institut de Zoologie et d'Ecologie Animate, Bâtiment de Biologie, Université de Lausanne, 1015 Lausanne, Switzerland
  3. 3Departement für Frauenheilkunde, Klinik für Endokrinologie, Universitätsspital Zürich, 8091 Zürich, Switzerland
  4. 4Biologisches Zentrallabor, Universitätsspital Zürich, 8091 Zürich, Switzerland

Correspondence: Claus Wedekind, Abteilung Verhaltensökologie, Zoologisches Institut, Universität Bern, 3032 Hinterkappelen, Switzerland

Received 22 November 1995.



One evolutionary explanation for the success of sexual reproduction assumes that sex is an advantage in the coevolutionary arms race between pathogens and hosts. Accordingly, an important criterion in mate choice and maternal selection thereafter could be the allelic specificity at polymorphic loci involved in parasite-host interactions, e.g. the MHC (major histocompatibility complex). The MHC has been found to influence mate choice and selective abortions in mice and humans. However, it could also influence the fertilization process itself, i.e. (i) the oocyte's choice for the fertilizing sperm, and (ii) the outcome of the second meiotic division after the sperm has entered the egg. We tested both hypotheses in an in vitro fertilization experiment with two inbred mouse strains congenic for their MHC. The genotypes of the resulting blastocysts were determined by polymerase chain reaction. We found nonrandom MHC combinations in the blastocysts which may result from both possible choice mechanisms. The outcome changed significantly over time, indicating that a choice for MHC combinations during fertilization may be influenced by one or several external factors.


fertilization, gamete choice, MHC, second meiotic division, sexual selection



  1. Agulnik, S I, Sabantsev, I D, and Ruvinski, A O. 1993. Effect of sperm genotype on chromatid segregation in female mice heterozygous for aberrant chromosome 1. Genet Res, 61, 97–100. | PubMed | ISI | ChemPort |
  2. Arnaiz-Villena, A, and Festenstein, H. 1976. HLA genotyping by using spermatozoa: evidence for haploid gene expression. Lancet, 707–709.
  3. Beer, A E, Semprini, A E, Zhu, X Y, and Quebbeman, J F. 1985. Pregnancy outcome in human couples with recurrent spontaneous abortions: HLA antigen profiles, HLA antigen sharing, female serum MLR blocking factors, and paternal leukocyte immunization. Exp Clin Immunogenet, 2, 137–153.
  4. Blalock, J E. 1984. The immune system as a sensory organ. J Immunol, 132, 1067–1070. | PubMed | ISI | ChemPort |
  5. Blalock, J E. 1994. The immune system - our sixth sense. Immunologist, 2, 8–15. | ChemPort |
  6. Bolis, P F, Soro, V, Martinetti Bianchi, M, and Belvedere, M. 1985. HLA compatibility and human reproduction. Clin Exp Obstet Gynecol, 12, 9–12.
  7. Clegg, K B, and Pikó, L. 1982. RNA synthesis and cytoplasmic polyadenylation in the one-cell mouse embryo. Nature, 295, 342–345. | Article | ISI | ChemPort |
  8. Cui, X, Gerwin, J, Navidi, W, Li, H, Kuehn, M, and Arnheim, M. 1992. Gene-centromere linkage mapping by PCR analysis of individual oocytes. Genomics, 13, 713–717. | PubMed | ISI | ChemPort |
  9. Ding, J, Moor, R M, and Foxcroft, G R. 1992. Effects of protein synthesis on maturation, sperm penetration, and pronuclear development in porcine oocytes. Mol Reprod Dev, 33, 59–66.
  10. Doherty, P C, and Zinkernagel, R M. 1975. Enhanced immunological surveillance in mice heterozygous at the H-2 gene complex. Nature, 256, 50–52. | Article | PubMed | ISI | ChemPort |
  11. Eddy, E M, Welch, J E, and O'Brien, D A. 1993. Gene expression during spermatogenesis. In: de Kretser, D. (ed.) Molecular Biology of the Male Reproductive System, pp. 181–232. Academic Press, New York, London.
  12. Egid, K, and Brown, J L. 1989. The major histocompatibility complex and female mating preferences in mice. Anim Behav, 38, 548–550. | Article | ISI |
  13. Fellous, M, and Dausset, J. 1970. Probable haploid expression of HL-A antigens on human spermatozoon. Nature, 225, 191–193. | Article | PubMed | ChemPort |
  14. Haas, G G, and Nahhas, F. 1986. Failure to identify HLA ABC and Dr antigens on human sperm. Am J Reprod Immunol Microbiol, 10, 39–46.
  15. Halim, K, and Festenstein, H. 1975. HLA-D on sperm is haploid, enabling use of sperm for HLA-D typing. Lancet, 1255–1256.
  16. Halim, K, Wong, D M, and Mittal, K K. 1982. The HLA typing of human spermatozoa by two color fluorescence. Tissue Antigens, 19, 90–91.
  17. Hamilton, W D, and Zuk, M. 1982. Heritable true fitness and bright birds: a role for parasites? Science, 218, 384–387. | Article | PubMed | ISI | ChemPort |
  18. Hamilton, W D, Axelrod, R, and Tanese, R. 1990. Sexual reproduction as an adaptation to resist parasites (a review). Proc Natl Acad Sci USA, 87, 3566–3573. | Article | PubMed | ChemPort |
  19. Hedrick, P W, and Thomson, G. 1983. Evidence for balancing selection at HLA. Genetics, 104, 449–456. | PubMed | ISI | ChemPort |
  20. Ho, H N, Gill, T J, Nsieh, R P, Hsieh, H J, and Lee, T Y. 1990. Sharing of human leukocyte antigens in primary and secondary recurrent spontaneous abortions. Am J Obstet Gynecol, 163, 178–188.
  21. Howard, R S, and Lively, C M. 1994. Parasitism, mutation accumulation and the maintenance of sex. Nature, 367, 554–557. | Article | PubMed | ISI | ChemPort |
  22. Howlett, S K, Webb, M, Maro, B, and Johnson, M H. 1985. Meiosis II, mitosis I and the linking interphase: a study of the cytoskeleton in the fertilised mouse egg. Cytobios, 43, 295–305.
  23. Karl, A, Metzner, G, Seewald, H J, Karl, M, Born, U, and Tilch, G. 1989. HLA compatibility and susceptibility to habitual abortion. Results of histocompatibility testing of couples with frequent miscarriages. Allerg Immunol (Leipz), 35, 133–140.
  24. Klein, J. 1986. Natural History of the Major Histocompatibility Complex, John Wiley, New York.
  25. Koyama, M, Saji, F, Takahashi, S, Takemura, M, Same-Jima, Y, Kameda, T. et al. 1991. Probabilistic assessment of the HLA sharing of recurrent spontaneous abortion couples in the Japanese population. Tissue Antigens, 37, 211–217.
  26. Kuhlmann, D, Dohr, G, Pusch, H, Scherbaum, W, Schieferstein, G, Uchanska-Ziegler, B, and Ziegler, A. 1986. Absence of HLA class I and class II antigens as well as beta2-microglobulin from normal and pathological human spermatozoa. Tissue Antigens, 27, 179–184.
  27. Kurpisz, M, Fernandez, N, Witt, M, Kowalik, I, Szym-Czynski, G A, and Festenstein, H. 1987. HLA expression on human germinal cells. J Immunogen, 14, 23–32.
  28. Laitinen, T. 1993. A set of MHC haplotypes found among Finnish couples suffering from recurrent spontaneous abortions. Am J Reprod Immunol, 29, 148–154.
  29. MacAs, E, Rosselli, M, Imthurn, B, and Keller, P J. 1993. Chromosomal constitution of mouse blastocysts derived from oocytes inseminated by multiple sperm insertion into perivitelline space. J Assist Reprod Genet, 10, 468–475.
  30. Maudsley, D J, and Pound, J D. 1991. Modulation of MHC antigen expression by viruses and oncogenes. Immunol Today, 12, 429. | Article | PubMed | ChemPort |
  31. Maudsley, D J, Morris, A G, and Tomkins, P T. 1989. Regulation by interferon of the immune response to viruses via the major histocompatibility complex antigens. In: Dimmock, N. J. and Minor, P. D. (eds) Immune Responses, Virus Infections and Disease, pp. 15–33. IRL Press, Oxford.
  32. O'Neill, H C, and Blanden, R V. 1979. Quantitative differences in the expression of parentally-derived H-2 antigens in F1 hybrid mice affect T cell responses. J Exp Med, 149, 724–731. | Article | PubMed | ChemPort |
  33. Pagel, M. 1993. Honest signalling among gametes. Nature, 363, 539–541. | Article |
  34. Pomiankowski, A, and Hurst, L D. 1993. Siberian mice upset Mendel. Nature, 363, 396–397. | Article |
  35. Potts, W K, and Wakeland, E K. 1993. Evolution of MHC genetic diversity: a tale of incest, pestilence and sexual preference. Trends Genet, 9, 408–412. | Article | PubMed | ISI | ChemPort |
  36. Potts, W K, Manning, C J, and Wakeland, E K. 1991. Mating patterns in seminatural populations of mice influenced by MHC genotype. Nature, 352, 619–621. | Article | PubMed | ISI | ChemPort |
  37. Renard, J P, and Babinet, C. 1986. Identification of a paternal developmental effect on the cytoplasm of one-cell stage mouse embryos. Proc Natl Acad Sci USA, 83, 6883–6886.
  38. Reznikoff Etievant, M F, Bonneau, J C, Alcalay, D, Cavelier, B, Toure, C, Lobet, R, and Netter, A. 1991. HLA antigen-sharing in couples with repeated spontaneous abortions and the birthweight of babies in successful pregnancies. Am J Reprod Immunol, 25, 25–27.
  39. Rodríguez-Córdoba, S, and Arnaiz-Villena, A. 1985. HLA-A and HLA-B (but not HLA-C, HLA-Bw4, HLA-Bw6 or HLA-DR antigens) are expressed on purified spermatozoa. Tissue Antigens, 25, 11–18.
  40. Scofield, V L, Schlumpberger, J M, West, L A, and Weissman, I L. 1982. Protochordate allorecognition is controlled by a MHC-like gene system. Nature, 295, 499–502. | Article | PubMed | ISI | ChemPort |
  41. Sokal, R R, and Rohlf, F J. 1981. Biometry, 2nd edn. Freeman, New York.
  42. SYSTAT. 1992. Statistics, Version 52 Edition. SYSTAT, Evanston, IL.
  43. Thomas, M L, Harger, J H, Wagener, D K, Rabin, B S, and Gill, T J. III., 1985. HLA sharing and spontaneous abortion in humans. Am J Obstet Gynecol, 151, 1053–1058.
  44. Tiwari, J L, and Terasaki, P I. 1985. HLA and Disease Associations Springer-Verlag, Berlin.
  45. Wedekind, C. 1994a. Handicaps not obligatory in sexual selection for resistance genes. J Theor Biol, 170, 57–62.
  46. Wedekind, C. 1994b. Mate choice and maternal selection for specific parasite resistances before, during and after fertilization. Phil Trans, R Soc, 346, 303–311.
  47. Wedekind, C, Seebeck, T, Bettens, F, and Paepke, A J. 1995. MHC-dependent mate preferences in humans. Proc R Soc B, 260, 245–249.
  48. Wolgemuth, D J. 1983. Synthetic activities of the mammalian early embryo: molecular and genetic alterations following fertilization. In: Hartmann, J. F. (ed.) Mechanism and Control of Animal Fertilization, pp. 415–452. Academic Press, New York, London.
  49. Wright, S J, and Longo, F J. 1988. Sperm nuclear enlargement in fertilized hamster eggs is related to meiotic maturation of the maternal chromatin. J Exp Zool, 247, 155–165. | PubMed | ChemPort |
  50. Xu, K P, and Greve, T. 1988. A detailed analysis of early events during in-vitro fertilization of bovine follicular oocytes. J Reprod Fertil, 82, 127–134.
  51. Yamazaki, K, Boyse, E A, Miké, V, Thaler, H T, Mathieson, B J, Abbott, J. et al. 1976. Control of mating preference in mice by genes in the major histocompatibility complex. J Exp Med, 144, 1324–1335. | Article | PubMed | ISI | ChemPort |
  52. Yamazaki, K, Beauchamp, G K, Wysocki, C J, Bard, J, Thomas, L, and Boyse, E A. 1983. Recognition of H-2 types in relation to the blocking of pregnancy in mice. Science, 221, 186–188. | Article | PubMed | ISI | ChemPort |
  53. Yamazaki, K, Beauchamp, G K, Kupniewski, D, Bard, J, Thomas, L, and Boyse, E A. 1988. Familial imprinting determines H-2 selective mating preferences. Science, 240, 1331–1332. | Article | PubMed | ISI | ChemPort |