Trends in Immunology
Female choice and the MHC
Introduction
Following the 1976 discovery by Yamazaki and colleagues that MHC-dependent, individual-specific odours influence sexual selection in mice [1], several studies in vertebrates, including humans, have revealed that highly polymorphic genes within the MHC participate in mate choice [2]. Therefore, besides their crucial function in adaptive and innate immune responses, the products of MHC genes also have a role in behavioural contexts 3, 4, as well as in reproduction. A detailed insight into the structure–function relationships of many molecules involved in immune reactions has already been achieved, however, only limited knowledge regarding the chemical nature of MHC-dependent odours, their recognition by chemoreceptors and how ligand–receptor interactions lead to neuronal responses and finally to MHC-influenced behaviours has been obtained. This deficit is probably a result of the complexity of the problem, which can be tackled only by a multi-disciplinary approach, involving, for example, studies of behaviour, genetics, immunology, neurobiology, chemistry and structural biology.
The connection between the MHC and mate selection is presumably a consequence of the crucial importance of the MHC in immune responses, in which two classes of genotypes might be favoured: heterozygotes and rare alleles 2, 5, 6, 7. MHC heterozygotes have an advantage over homozygotes because more peptides can be presented to T cells and rare MHC alleles might prevent pathogen evasion of host immune responses or exhibit a lack of association with autoimmunity, which has been shown by studies in a few vertebrate species, including humans 8, 9, 10. These two mechanisms could select for MHC diversity but both would also lead to the evolution of preferences for mates that are MHC heterozygous and MHC distinct [5]. The avoidance of inbreeding is an added benefit that can be a consequence of choosing an MHC-heterozygous mating partner. There is also evidence that MHC heterozygosity can aid in the recognition of kin [5]. For example, in the males of many mammalian species, this leads to the avoidance of mating with their own mother [4]. Theoretical considerations indicate that, for a given individual, an optimal number of MHC alleles at an intermediate level of MHC diversity exists [11]. Recent experimental evidence supports this prediction 8, 9.
In Darwin's view, sexual selection was restricted to the precopulatory phase, during which ‘the females…select the more agreeable partners’ [12]. However, within the last three decades, has come the realization that female choice (see Glossary) operates during and after copulation as well, and it influences the behaviour, anatomy and physiology of both sexes. Evidence from diverse animal groups also indicates that females use extra-pair matings to enhance the heterozygosity and fitness of their offspring 13, 14. Sperm competition, originally defined as the competition between spermatozoa of two or more males to fertilize a given set of oocytes, might also be connected with female choice 13, 14, 15.
We have only begun recently to understand some of the mechanisms that influence mate choice in vertebrates. This has been aided greatly by the molecular identification of odorant receptors (ORs) by Buck and Axel in 1991 [16] and the subsequent description of chemoreceptors (the vomeronasal receptors V1R and V2R) expressed within the vomeronasal organ (VNO) (reviewed in Ref. [17]). In addition, these different types of chemoreceptors not only fulfil their role of recognizing distinct ligands within the nose (an important process in the initial encounter of potential partners) but are also used by spermatozoa as guidance cues 18, 19. Possibly, their expression on spermatozoa enables a female to influence sperm motility through the establishment of chemical gradients within her reproductive tract. This indicates that postcopulatory female choice might involve gene products that take part in precopulatory mating decisions as well.
This review will focus on the evidence for the involvement of polymorphic MHC genes and chemoreceptors [17] in the various stages of female choice. The role of MHC-encoded transcription factors (TFs) that might influence prezygotic control within the fertilized oocyte will then be discussed, and analogies to mechanisms that participate in mate choice in fungi, currently one of the genetically best characterized systems [20], will be pointed out.
Section snippets
Precopulatory sexual selection
Circumstantial evidence for an influence of MHC alleles on precopulatory female choice has been observed in nearly all classes of vertebrates. However, evidence for a relationship among various receptors within the main olfactory epithelium (MOE) or the VNO (Box 1), the MHC and reproductive behaviours has been obtained only in a limited number of species, particularly rodents 21, 22 (for a comprehensive review of earlier work, including that carried out with rats, see Ref. [2]). The involvement
Postcopulatory sexual selection before oocyte fertilization
As a costly investment into an embryo with potentially suboptimal genetic and immunological properties should be avoided by a female, it would seem to make sense for her to scrutinize the suitability of the genetic contribution of the male before zygote formation. This could occur by cryptic female choice in connection with sperm competition, as well as by prezygotic female choice during and after fertilization of the oocyte (see the next section). The term ‘cryptic female choice’ refers to the
Postcopulatory sexual selection during and after oocyte fertilization
The interaction of male gametes with an oocyte depends on co-evolving proteins that are present on both types of cells [50]. In vertebrates, none of the proteins involved are known to be MHC-encoded, although, similar to MHC antigens, several are highly polymorphic. This additional barrier to fertilization might participate in cryptic female choice and act on the few mammalian spermatozoa (in humans, maximally a few hundred) that reach the vicinity of an unfertilized oocyte. These
Concluding remarks
Clearly, MHC molecules have a crucial role within the immune system, however, there is also growing evidence for a role in the refinement and plasticity of neuronal connections [3] and during distinct phases of reproduction, as summarized here. Many genes that fulfil essential functions within these three systems are in tight linkage with the MHC 26, 55 and are subject to positive selection. For example, two HLA-linked OR genes, OR2W1 (olfactory receptor, family 2, subfamily W, member 1) and
Acknowledgements
We thank Stephan Beck, Manfred Milinski, Cordula Petter, Paula Stockley, Christian J. Thaler, Armin Volz, as well as three anonymous reviewers for constructive comments on the manuscript. Our work on MHC-linked OR genes is financially supported by the Volkswagen-Stiftung (I75/196, I72/740) and the Monika-Kutzner-Stiftung, Berlin.
Glossary
- Cryptic female choice:
- Possibility that sexual selection might involve hidden female effects that impact on the success of males in fertilizing ova.
- Female choice:
- Selection of a mating partner by a female. This can occur before, during and after copulation.
- Haplotype:
- Combination of alleles at several loci on a single chromosome of a given individual. For example, for a gene with alleles W and w that is linked to another locus with alleles V and v, possible haplotypes are WV, Wv, wV and wv.
References (70)
- et al.
How do major histocompatibility complex genes influence odor and mating preferences?
Adv. Immunol.
(1998) Importance of olfactory and vomeronasal systems for male sexual function
Physiol. Behav.
(2004)Parasites and individual major histocompatibility complex diversity – an optimal choice?
Microbes Infect.
(2004)Allele-dependent similarity between viral and self-peptide presentation by HLA-B27 subtypes
J. Biol. Chem.
(2005)- et al.
A novel multigene family may encode odorant receptors: a molecular basis for odor recognition
Cell
(1991) Mice (Mus musculus) lacking a vomeronasal organ can discriminate MHC-determined odortypes
Horm. Behav.
(2004)Specific repertoire of olfactory receptor genes in the male germ cells of several mammalian species
Genomics
(1997)Complex transcription and splicing of odorant receptor genes
J. Biol. Chem.
(2003)Rare congenital disorders, imprinted genes, and assisted reproductive technology
Lancet
(2003)Lack of the appropriate natural killer cell inhibitory receptors in women with spontaneous abortion
Hum. Immunol.
(2005)
Structure and function of the vomeronasal system: an update
Prog. Neurobiol.
Developing germ cells in mouse testis express pheromone receptors
FEBS Lett.
Two novel odorant receptor families expressed in spermatids undergo 5′-splicing
J. Biol. Chem.
Control of mating preference in mice by genes in the major histocompatibility complex
J. Exp. Med.
Immune signalling in neural development, synaptic plasticity and disease
Nat. Rev. Neurosci.
Wisdom through immunogenetics
Nat. Genet.
Major histocompatibility complex heterozygote superiority during coinfection
Infect. Immun.
Parasite selection for immunogenetic optimality
Science
Terminal investment induced by immune challenge and fitness traits associated with major histocompatibility complex in the house sparrow
Evolution Int. J. Org. Evolution
The optimal number of major histocompatibility complex molecules in an individual
Proc. Natl. Acad. Sci. U. S. A.
The descent of man, and selection in relation to sex
Promiscuity: An evolutionary history of sperm competition and sexual conflict
Sexual selection and the comparative anatomy of reproduction in monkeys, apes, and human beings
Annu. Rev. Sex Res.
Sperm competition in mammals
Hum. Fertil (Camb)
Genes and ligands for odorant, vomeronasal and taste receptors
Nat. Rev. Neurosci.
Identification of a testicular odorant receptor mediating human sperm chemotaxis
Science
Functional characterization of a mouse testicular olfactory receptor and its role in chemosensing and in regulation of sperm motility
J. Cell Sci.
Mate recognition in fungi
Heredity
MHC class I peptides as chemosensory signals in the vomeronasal organ
Science
Olfactory fingerprints for major histocompatibility complex-determined body odors: II. Relationship among odor maps, genetics, odor composition, and behavior
J. Neurosci.
Effect of B2m gene disruption on MHC-determined odortypes
Immunogenetics
Discrimination of MHC-derived odors by untrained mice is consistent with divergence in peptide-binding region residues
Proc. Natl. Acad. Sci. U. S. A.
Co-duplication of olfactory receptor and MHC class I genes in the mouse major histocompatibility complex
Hum. Mol. Genet.
Gene map of the extended human MHC
Nat. Rev. Genet.
Biology of chromosome 6
DNA Seq.
Cited by (93)
Spermatozoa selection in the female reproductive tract: The initiation of the battle of the sexes
2023, Principles of Gender-Specific Medicine: Sex and Gender-Specific Biology in the Postgenomic EraSelection of reproductive partners in semi-feral horses (Equus caballus) is not influenced by major histocompatibility complex (MHC): A field study
2020, Applied Animal Behaviour ScienceChemical Signaling: Air, Water, and on the Substrate
2019, Encyclopedia of Animal Behavior, Second Edition: Volume 1-5Chemical signaling: Air, water, and on the substrate
2019, Encyclopedia of Animal BehaviorSperm success and immunity
2019, Current Topics in Developmental BiologyBattle of the Sexes: How the Selection of Spermatozoa in the Female Reproductive Tract Manipulates the Sex Ratio of Offspring
2017, Principles of Gender-Specific Medicine: Gender in the Genomic Era: Third Edition