The Mechanism of MHC Odor Signaling
Manfred Milinski
Immune genes of the vertebrate MHC vary among individuals. Each individual collection is optimally diverse to provide resistance against some infectious diseases but not too diverse to cause autoimmune diseases. MHC-dependent mate choice aims for optimally complementary MHC alleles. Each potential partner signals through body odor his/her MHC alleles. Identifying the signal molecules was a long-lasting puzzle solved only recently after many deviations as described. Commensal microbiota which are controlled by the individual MHC genes differ among individuals but cannot provide the much sought after.
Immune genes of the Major Histocompatibilitdied biology and mathematics at the University Complex (MHC) are by far the most polymorphic genes in vertebrates. Only one or a few different MHC alleles provide resistance to a specific parasite [1f Bielefeld,2]. Each individual’s mix of MHC allGeles determines its specific resistance against current infectious diseases [2]. This fact invites hrmanypotheses on MHC-dependent mate choice. However, it was inconceivable until 1975 that an individual’s MHC genes organize its mate choice decisions. This year technicians at the Sloan-Kettering Institute in New York made a remarkable observation: “The technicians looking after these mice reported that the male and female of dissimilar H-2 type appeared to consort with one another to the relative exclusion of the female whose H-2 type was the same as the male’s” [3]. Staand the Ruhr-University Bochum. PhD (Drting with Yamazaki et al. [4] numerous studies, mostly with inbred strains of mice, showed that actual mate choice favors MHC dissimilar individuals e.g., [5,6,7,8,9,10,11,12,13]. MHC-dependent mate choer nat.) ice was demonstrated also in other vertebrates such as rats [14,15,16,17], birds [18,19,20,21,22,23,24,25,26,27], fish [28,29,30,31,32,33,34,35,36,37], repti Bioles [38] small mammals [39], primates [40], and humans [41,42,43,44,45,46].
This review follows the historgy of studying MHC-dependent mate choice. Because most of the early experiments were performed with mice, later followed by stickleback fish, insights and ideas focused to some extent on these models and thus had limitations for being generalized. It is, however, convenient to describe the history of understanding mechanisms and functional consequences of MHC-dependent mate choice in one or two finally well-studied and understood systems rather than including the great variation among species right from the beginning. I found it convincing how the various parts of a system made sense as predicted by immunological theory. It could be the ‘null system’ which needs to be extended to cover natural variation1978. Habilitation ( venia legend) in 1985 from Ruhr-University Bochum.
One sensory modality that transports the information aboGut an individual’s MHC was revealed again in mice: odor. The choice between urine odor from MHC similar and dissimilar mice in a y-maze favored MHC dissimilar individuals e.g., [5,47,48,49,50,51,52,53,54]. Thus, odor estransmits the MHC signal and the choosing mouse knows her own MHC otherwise she could not prefer ‘dissimilar’. At the time some MHC researchers were skeptical. ‘Some immunologists resist the idea that MHC genes could themselves specify odors. In part, this is because there has been suggested no plausible mechanism by which these genes, which code for cell-surface proteins, could also specify differential body odor’ [55Professor at the Department of Ecology,56]. A Unumber of studies revealed mate choice that was based on odor, in rats [14,15], fiversish [29,30,31,32,33,34,36], reptiles [38], birds [24,25,26], small mammals [57], and Humans [42,43,44,45,46,58]. Thus, there must be a mechanism. Because the polymorphic MHC genes of the vertebrate immune system are highly conserved and at least 450 my old [59]of Bergen, the Nolfactory signaling and recognition system may probably be similar in all jawed vertebratesrway.
The puzzle of the origin of the odor and of its composition took a long time to be solved. One possibility could be that populations of commensal microorganisms generate differential odorants whose composition eventually reflects MHC diversity [49]. The MHC claseis II gene family may be a candidate for adjusting diverse and host-specific microbiota. MHC genes may affect the composition of the microbial community of symbiotic bacteria through the elimination of specific bacterial species in an antigen-mediated fashion; thus, an individual’s MHC genotype might be able to shape the composition of symbiotic bacteria that can survive on or inside the host. The microbial communities that result potentially influence host odor [24berg Professor at the Department of Zoology,26] as well as host fitUness [60].
Bolnick et al. [61] showed that MHC IIb polymorphism is correlated with variation in gut microbiota among individuals within a single population of three-spined sticklebacks. Individuals that had more divergent MHC motifs carried less diverse microbiota. However, MHC explained roughly only 10% of microbial variation [61]. The primary source of borsity of Oxfordy odor in birds is preen oil [25,26]. SimilaFr preen secretion chemicals correlate positively with MHC-relatedness [25]. In behaviom 1987 toral discrimination tests, kittiwakes and blue petrels can assess MHC similarity on the basis of odor [25]. When song sp1999 Full Professor arrows (Melospiza melodia) were presented with preen oil from conspecifics of opposite-sex, both sexes preferred odor from MHC- dissimilar to MHC-similar birds in a two-choice design [26]. According to the authors, song sd Director of the Deparrows can discriminate MHC similarity of potential mates by using preen oil odor. Similarity at MHC is thus a predictor of similarity in the composition of preen oil [62]. Ttment of Behis relationship may be hypothesized to be mediated by symbiotic microbes. The MHC genotype, the microbial communities in preen glands, and the chemistry of preen oil was characterized in song sparrows [62]. Pairwise MHC similaritvioral Ecology predicted similarity of microbiota in preen glands. However, the overall similarity of microbes did not predict similarity in the chemistry of preen oil.
Obviously preen oil contains an MHC-dependent odor signal. nd Vertebrate Because preen oil composition was related more strongly to MHC genotype than to preen gland microbiota overall, the authors suggested the following: the effects of MHC on the composition of preen oil are not facilitated primarily through microbiota in the preen gland [62]ology at the University of Bern, Switzerland. Instead, the MHC genFrotype may affect host odor more directly [62]. Although microbiota within prem 1999 electen glands correlate with MHC, which might be just MHC’s immunological action of regulating bacteria, it is not clear whether microbiota contribute to MHC dependent odor of preen oil.
T Scientific Member of the microbiotMa hypothesis experienced almost continuous ups and downs that read similar to a fascinating criminal story: Yamazaki et al. [49] suggested that px-Planck-Sopulations of commensal microorganisms may generate differential odorants; their composition maybe somehow adjusted to MHC diversity. In the same publication, they provide a direct test of the hypothesis by excluding microbiota. If microbiota are necessary for producing the MHC-dependent odor signal, germ-free mice should not produce it. This hypothesis was tested: Mice are trained in a Y-maze system to distinguish the urinary odors from MHC-congenic mice. Mice could also easily be trained to distinguish the urines of MHC-congenic mice that had been raised germ-free. Also, mice that had learned to distinguish the urines of conventionally maintained MHC-congenic mice were shown to distinguish readily the urines of germ-free congenic mice. Thus, MHC-determined odor types do not depend on microorganisms generating odorants [49]. In the same year, Singh et aiety and founding Director of the Max-Planck Institute for Evol. [63] published the finding that rats lost their individuality odor when reared in a germ-free environment. Male rats were reared in a germ-free environment after being born by the cesarian section. A habituation-dishabituation test revealed that urine from the germfree rats was not discriminated, whereas urine from rats of the same strain that were housed conventionally could be discriminated. When urine from germfree rats was collected, after they had been moved to a conventional animal house after recolonization with commensal flora, it was discriminated against. This indicated that bacteria had an essential role in determining the urinary odors of MHC congenic rats. ‘We would predict that bacteria may control the production of MHC-specific odors in mice and other species as they do in rats’ [17]ionary Biology, Plön, Germany. From 2000 Professor of the University of Kiel, Germany.
The Fresults of Yamazaki et al. [49] and Som 2018 Dingh et al. [17] are at variance. Singh [63] offers a solution for the discrepancy. “We suspect that the differences between the results obtained lies in the methodology used, ’habituation-dishabituation’ relies on the odor stimulus being different enough for it to be interesting to the responder animal, leading to its dishabituation, while the motivation to detect a difference using the ‘training-reward’ system is much greater: the mice are thirsty and detecting the difference allows them to drink. Thus, the residual MHC-related odors (derived from normal metabolic processes, other than gut flora) that remain in germ-free urine are more likely to be detected by the trained mice, while untrained mice may not have the ‘motivation’ to discriminate between the germ-free urine samplesr Emeritus at the Max Planck Institute for Evolutionary Biology, Plön, Germany.”
Yamazaki et al. [56] cMomment on ‘this apparent contradiction’ that the clear key are differences in methods. They assume that the relevant odorants are still expressed in germ-free animals but in smaller amounts such that they fail in the habituation paradigm to motivate non-contingent investigation. ‘If thist important publications:
Reputation helps solve the ‘tragedy of the commons’
M is so, then the hypothesis that MHC genes specify odor by controlling commensal microflora cannot be true’ [56].
If the ‘microbiota signaling hypothesis’ is to be revivedilinski, someD proximate and functional questions need to be answered, for example [64]: If we consider an info-cheSemmical X that animal-A produces and which alters the behavior of animal-B, to demonstrate that the microbiota in animal-A synthesize info-chemicnn, HJ Krambeck
Nal X, three lines of evidence are required: (i) Some microbiota in animal-A can synthesize X. (ii) If the microbiota from animal A are eliminated, both the loss of X and the loss of the behavioral trait of animal-B results; and (iii) interaction with microbe-free animal-A that has been supplemented with the info-chemical X revives the behavior of animal-B.ure 415 (6870), 424-426, 2002
Cooperation through image scoring in humans
IfC these stringent conditions are fulfilled, it needs the study of the evolutionary processes that facilitate the origin and also the persistence of communication that is microbial-mediated, rather than chemical signals that the animal host synthesizes itself, avoiding conflict between microorganisms and the animal host [63,64]. Before we come bacWedekind, M Milinsk to microbiota we discuss what was proposed next.
Several ideas assumed that MHC molecules are the carriers of the specific info chemicals. After an infection, the host’s cells contain foreign proteins which are degraded by proteasomes into small pieces, aboutience 288 (5467), 850-852, 2000
Female sticklebacks use male coloration in mate choice and hence avoid parasitized males
M nine amino acMids long, called peptides. In order to inform the T lymphocytes outside the cell, the peptides need to be bound and transported through the cell membrane and presented to T lymphocytes. This is the task of MHC molecules if the peptide fits into the binding groove of an MHC molecule by its ‘anker amino acids’ in specific positions of the peptide [65]linski, T Bakker, irrespective of whether it is a foreign or
Na self-peptide. Each of an individual’s few MHC alleles has its specific binding groove to bind only specific peptides, although examples of promiscuous peptide binding exist [66,67]. To avoid autoure 344 (6264), 330-immune diseases333, T1990
M lymphocytes have been selected Min the thymus to recognize only foreign peptides to induce an immune response [68]. Thuslinski, theR broader the spectrum of one’s MHC alleles, the moHellere infectious dise
Nases can be presented to and attacked by the immune system suggesting mate choice for MHC dissimilar partners. This allows each ure 275 (5681), 642-644, 1978
Tit for tat in sticklebacks and the evolution of cooperation
MHC molecule to bind and carry only chemicals that transport information of the MHC molecule’s individuality expressed by its peptide binding groove. From collecting all the peptides transported by the MHC molecules of an Milinskindividu
Nal it would be possible to deduce the nature of that individual’s MHC alleles, i.e., its Mure 325 (6103), 433-435, 1987
The efficient interaction of indirect reciprocity and costly punishment B Rockenbach, M Milinski Nature 444 (7120), 718-723, 2006 |
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The collective-risk social dilemma and the prevention of simulated dangerous climate change M Milinski, RD Sommerfeld, HJ Krambeck, FA Reed, J Marotzke Proceedings of the National Academy of Sciences 105 (7), 2291-2294, 2008 |
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Female sticklebacks count alleles in a strategy of sexual selection explaining MHC polymorphism
TBHC genotype. Thus, peptides would be ideal info-chemicals constrained by their low volatility.
HoweverReusch, other info chemicals carried by MHC molecules were suggested. Evidence for volatiles that have distinctive patterns according to MHC type has been reported [54]. CarboxyA HaÈberlic acids have been found, in behavioral active dimethyl ether extract of acidified urine, that distinguish male mice that differ only at their MHC [55];PB Aeschlimann, M these chemicals probably have a critical role when MHC-congenic mice are discriminated by olfaction [55]. It iilins suggested that the most likely mechanism for this could be th
Nat circulating odorants are bound selectively by solublere 414 (6861), 300-302, 2001
M MHC gene products themselves; these have presumably lost their bound peptide before. Then the odorants are released to a minimal degree in serum and probably more extensively during renal processing and excretion. It is suggested that these odorants are likely the volatile acids that have been identified or precursors of them [56].
The fact that MHC class I linski, D Semmolecules can associate selectively with small molecules could also suggest a way for transporting a unique mixture consisting of volatile, endogenous metabolites to urine from the blood by MHC glycoproteins [16]. Although en, HJ Krach individual has a similar metabolic pool, this mixture would be unique to the transporting particular MHC molecule. An individual-specific odor would be impartbeck, J Marotzked to the u
Prine. The postulated volatile molecules need to be identified [16]. Maintaininceeding the microbiota hypothesis, Singh et al. [17] propose that the excretion of class I molecules has an important role in individual odor to be determined in the urine. Bacteria are considered to be an essential source of the body’s pool of odorant molecules by which individuals do not vary. A mixture of odorants is selected by an MHC molecule from the body pool. The MHC molecule acts as a carrier to deliver the cocktail to the urine. This is assumed to be analogous to the manor of MHC molecules binding and presenting immunogenetic peptides to T lymphocytes [17].f the National Academy of Sciences 103 (11), 3994-3998, 2006
Mate choice decisions of stickleback females predictably modified by MHC peptide ligands
M ‘The ‘carrMier hypothesis’ represents the simplest explanation of the mechanism whereby the MHC confers odors of genetic individuality’ [64].
Howeverlinski, Singh [69,70] dismisses the micGrobiota hypothesis: The intimate linkage of MHC genotype with the urinary odor was argued to be indirect and to reflect the immune response that responds to commensal bacterial flora causing individual MHC types to be associated with unique flora. The volatile odorants excreted were assumed to be secondary metabolites that are derived from these organisms. This hypothesis seemed unconvincing a priory because the types and relative numbers of commensal bacteria are required not to vary over time, which is not true [71]ffiths, KM Wegner, TBH Reusch, A Haas-Assenbaum, ... Acco
Prding to three studies, immune regulation of commensal flora is not needed for the determination of MHC-associated odors [49,72,73].
Singh [69,70] again supports the ceedings of the National Acarrier hypothesis in more detail. He argues that MHC molecules are not likely to be the odor components because of their size and missing vapor pressure. However, my of Sciences 102 (12), 4414-4418, 2005
Parasite selection for immunogenetic optimality
KMHC molecules might be in an allele-specific association with smaller molecules for transporting them to the urine [16Wegner,69]. Thus,M from a pool of metabolites, a unique mixture of volatiles could be selected, in which, commensal flora could take part [17]. After transport, a unique odor that is MKalbe, J Kurtz, TBHC specific would appear in the urine. A mechanism might work by which MHC molecules each pick up a unique mixture of volatiles in their binding groove to be transported to the urReusch, M Milinskine as an individuality marker.
MHC-assoSciated peptides are cleared into the circulation, undergoingence 301 (5638), 1343-1343, 2003
Volunteering leads to rock–paper–scissors dynamics in a public goods game
D furthSer fragmentation. The release of any bound peptides allows the now empty platform to bind a unique mixture of odorants, to be transported to the urine where they are further degraded to molecules that make up an odor that is MHC specific. “The nature of the specmmann, HJ Krambeck, M Milinskific odor
Nant molecules that are bound to soluble class I molecules is unknown, although carboxylic acids may be one source” [54].ure 425 (6956), 390-393, 2003
“The problem with the carrier hypothesis is that it is difficult to imagine how binding properties of MHC molecules might be converted from being hydrophilic peptides-binding molecules to hydrophobic aromatic-binding molecules” [52]. Even Eizaguif one would agree with the “empty platform” being able to bind a cocktail of volatiles, how could the released molecules of the ‘cocktail’ transport the information content of the specific sequence of amino acids mirroring the binding cleft of the MHC molecule? A receptor in the receiver animal needs to catch and reassemble the loose volatile molecules into the original sequence to extract the re, TL Lenz, M Kalbe, M Milinskindividu
Nality of the source MHC molecule. It needs the study of the mechanisms of the receptor side. We are not yet informed about the nature of the involved volatile molecules. No qualitative differences in volatile compounds have been found in association with MHC types by any investigation except one. However, for volatile metabolites, patterns or relative ratios vary in relation to MHC types, but in a way that is inconsistent and complex [74].ure communications 3 (1), 1-6, 2012
Working memory constrains human cooperation in the Prisoner’s Dilemma
SexM would not be needed for maximizing resistance if everybody has the whole spectrum of MHC variants. However, with each MHC molecule added to an individual’s repertoire, T cell lines that react to self-peptides bound by that MHC variant must be removed to avoid auto-immune diseases. Thus, an optimal number of ilinski, C Wedekindiffe
Prent MHC molecules per individual is predicted by theory, based on immunological results, instead of a maximum MHC diversity [77,78]. It could be optimal for humans and mice to have their low number of MHC loci for balancing an increased number of foreign peptides to be presented and an increased number of T cells removed from the original repertoire [68,76]. The consequence is an optimal (intermediate) number of different MHC alleles per individual, enough to defend against many natural diseases and not too many to keep a ‘reasonable’ collection of T cell clones [77–79]. The immunogenetic optimum found in nature was published first [29,85] and experimentally proven on three-spined sticklebacks [86]. This individual optimum maximizes reproductive success [87] and increases survival under natural conditions [88,89]. Also, for other vertebrates, e.g., birds [21,22,89], trout [37], and voles [39]ceedings of the National Academy of Sciences 95 (23), 13755-13758, 1998
Intra-and intergenerational discounting in the climate game
J optimal individuJal MHC diversity was demonstrated. Experimental mate choice studies found that female three-spined sticklebacks prefer the odor of a male that signals that it possesses MHC alleles that combined with the female’s come close to the predicted individual optimum [29–31,90].
Mcquet, K Hagel, C HC ligand peptides fulfil the requirement that the exact information of the sender’s MHC alleles is transmitted by his odor signal [91,92]. MHC molecules are specialized to be carriers of peptides and devices to duert, J Marotzke, T Röhl, M Milinskispl
Nay them. The binding specificity of the MHC molecule is mirrored by the composition of the peptide. The ‘MHC peptide hypothesis’ assumes that smelling the peptide ligand (‘the key’) informs about the ure climate change 3 (12), 1025-1028, 2013
The major histocompatibility complex, sexual selection, and mate choice
MHC protein (‘the lock’) [93]. An individual’s underlying MHC diversity can be derived from the peptide ligands that he emMilinskits. Peptides i
Anteract with receptors of the olfactory system [94] and activate olfactory sensory neurons even at low concentrations [95,96]. Individual neurons each respond to one specific MHC ligand peptide only. The peptide’s anchor residues that allow binding to ‘its’ MHC molecule define this specificity. The olfactory neurons react exactly to those parts of the peptide that define the MHC molecule’s specificity of binding the peptide. ‘The role of MHC peptides as signals of individuality appears to be eual Review of Ecology, Evolutionarily conserved’ [91]. As experimental mate choice studies found female three-spined sticklebacks prefer the odor of the male that signals the possession of MHC alleles that combined with the female’s approach to the individual optimum, as has been predicted [29–31,90]., and Systematics, 159-186, 2006
Gossip as an alternative for direct observation in games of indirect reciprocity
ItRD shSould be possible to manipulate the information of the signal by adding further peptides, if peptides naturally signal via odor revealing the MHC alleles of a male. A female stickleback prefers a male that offers by scent MHC alleles that optimally complement her own alleles [90,99]. Thus, a suboptimal male’s attractiveness should be increased and an optimal, as well as a super-optimal male’s attractiveness, should be decreased if the same four synthetic MHC peptides are added to either male’s natural signal. Choice between spiked and un-spmmerfeld, HJ Krambeck, D Semmann, M Milinskiked water f
Prom the tank of the same male revealed that the peptide side was preferred when the pair had a combined diversity that was below the optimum. The spiked side was, however, avoided when the pair was above or at the optimum [30]. It can well be that MHC peptides are part oeedings of the natural perfume-like signals in other vertebrates including humans.
When human participants in psychometric tests were asked their decision whether what they smelionaled was perceived as ‘like themselves’ or ‘like their favorite perfume’ [58], they preferred their modified body odor, when their own synthesized ‘self’ peptides were offered, to modification by synthesized ‘nonself’ peptides (from another participant). Thus, inacademy of sciences 104 (44), 17435-17440, 2007
S humans MHC peptide ligands may function as part of body odor. These findings remind of results showing that humans that share specific MHC alleles share also a similar preference for the same natural ingredients of perfume [100]. Diverse peptide mimics may be contained in perfumes. As revealed by a ‘functional magnetic resonance imaging’ study, self-peptides allele-specificly activated a region in the right middle frontal cortex. This demonstrates the human sensory facility to recognize odor cues that are specific to MHC [58]. As was shown in mice [96], peptides may invoke sensory neurons in the main olfactory epithelium. However, activation of the brain through exposure entorrino, E Djemai, A Hopfensitz, M Milinski, P Seabrighto peptides d
Evoes not mirror the precise chemical structure of the peptides. It rather shows their qualities of ‘self’ or ‘nonself’ in relation to the MHC genotype of the individual. An internal reference for the genotype of MHC reminds us of a similar finding in mice [94] and sticklebacks [30]. As is the case in mice and fish, the sensory evaluation of the diversity of MHC through recognizing structurally diverse MHC ligand peptides, may be part of human MHC-dependent behavior.ution and Human Behavior 36 (1), 8-16, 2015
Extortion subdues human players but is finally punished in the prisoner’s dilemma C Hilbe, T Röhl, M Milinski Nature communications 5 (1), 1-6, 2014 |
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C Hilbe, A Traulsen, T Röhl, M Milinski Proceedings of the National Academy of Sciences 111 (2), 752-756, 2014 |
Nature 325 (6103), 433-35, 1987 |
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When parasites disagree: Evidence for parasite‐induced sabotage of host manipulation
M Milinski, B Rockenbach Science 317 (5837), 464-465, 2007 |
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Tit for tat and the evolution of cooperation in sticklebacks M Milinski |
Humans choose representatives who enforce cooperation in social dilemmas through extortion M Milinski, C Hilbe, D Semmann, R Sommerfeld, J Marotzke Nature communications 7 (1), 1-9, 2016 |
IndividuN Hals of wild sticklebacks that possess more divergent MHC motifs harbored less der, M Milinski
Everse microbiota, although their MHC explained only about 10% of microbial variation [61].lution 69 (3), 611-620, 2015
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J To estimMate an optimum from microbial variation would thus be extremely vague. Furthermore, microbial variation fluctuates with diet and many other environmental influences. Preferring a mate with more diverse microbiota would allow a female to select the more MHC dissimilar mate. Thus, for choosing ‘dissrotzke, D Semmann, M Milinskimil
Nar’ using potential signals from microbiota would, in principle, suffice. For selecting the optimally MHC complementary mate, however, it needs ‘smelling’ exactly which MHC alleles a potential mate habors. A male would need to have exactly only those microorganisms that signal his mix of MHC alleles. He has, however, vastly more different microorganisms than this small number. For optimizing MHC using potential odor from microorganisms thus cannot work.ure Climate Change 10 (6), 518-525, 2020
Schubert et al. [101] reviewed 577 publications to find how the MHC might mediate social odor via the microbiota community, fonor examp
Ele, cto allow for MHC-dependent mate choice. However, none of the 577 studies found the odor to be a social signal. Their extensive review of complex immunological networks, potentially affecting microbiota and odor through various pathways, did not solve the problem of how the microbiota of an individual could signal the possession of exactly his MHC alleles to allow for optimal mate choice. The authors nevertheless “hoped that their review stimulates advances in the investigation and understanding of this key pathway for social communication” [101]. A response [102] to a commentary [103] that pointed to gaps in their argumentation neged Scientific member of the Max Planck Society.
Elected responding to the main criticisms [102]. The authors, on the contrary, reiterate that although “an established mechanism that provides allele-specificity has already been identified: peptide ligand-based odor signals” [101], “multiple signaling mechanisms that transmit the same information are useful” [101]. Two counter-arguments can be listed: (i) Microorganisms are not able to transmit the same information (see above), and (ii), if highly conserved peptide signaling would be joined by a microbiota signaling mechanism [91], if microbiota could actually do the signaling, this additional second mechanism cannot evolve because it does not increase the sender’s performance that is achieved with the primary mechanism no fitness gain to achieve, no further evolution possible. No need for “keeping alternative hypotheses on the table” [101]ember of the German Science Foundation Leopoldina.
FGuemale choice of a mate that offers a complementary whole MHC genotype allows only for a poor approach of the best match. A maternal and a paternal haplotype would be randomly combined. Resulting from meiotic segregation among oocytes and sperm, the genotype is phenotypically unpredictable. Ultimately this determines the genotype of the offspring. The lottery of random fusion of gametes can easily result in nonoptimal combinations of MHC haplotypes. If, however, the egg chooses and prefers the more complementary of the two sperm haplotypes of a male, it would have an offspring that is closer to the optimum MHC diversity. That sperm may select for MHC complementarity has been hypothesized [104–108]. MHC expression on the sperm surface was found by some studies [2,109].
How can the egg decide? Cross-talks during sperm–egg interaction, studied in mice, clearly showed expression ot fellow of the Institute of Advanced Study of MHC class II antigen on the post-acrosomal membrane of the sperm head [110,111]. The micropyle of fish eggs, which is an opening in the coat of the egg through which sperm enter the egg for fertilization, apparently carries specific molecules [113]. These are active in attracting sperm toward the opening of the micropyle [114,115]. Such observations offer a potential way to preferentially guide MHC-complementary sperm to the micropyle opening. There is still a gap to be filledthe Toulouse School of Economics, Fance.
When eggs coGuld choose between sperm derived from MHCidentical and from MHC dissimilar males, results were mixed [115–118]. When congenic laboratory strains of mice were crossed, parental MHC haplotypes combined non-randomly. The process, however, was affected by the infection with mouse hepatitis virus of the parents [119,120]. ‘Decisive experimental evidence for oocyte selection of specific sperm haplotypes is still elusive’ [121].
When eggs of a female stickleback were exposest fellow of the Hanse Institute of Ad simultaneously to equal volumes of sperm from two males, the result was four male haplotypes available for fertilization of each egg-haplotype. This mimicks a scenario with a sneaking neighbor [122]. Ranking the four sperm MHC haplotypes available for fertilization of each egg-haplotype according to their success in fertilization, the most successful of the sperm haplotypes was closer than the least successful one to the mean MHC divergence of the population, which approximates the optimal individual MHC divergence. Furthermore, only the two sperm haplotypes within each male were compared to avoid interaction with sperm traits, e.g., velocitanced Study, Delmenhorst, Germany or
Edensity. For each individual male sperm traits should be the same. Again, the zygote produced with the more successful sperm haplotype of two was closer to the MHC optimum than the zygote formed with the less successful one [122]. Again, the zygote produced with the more successful sperm haplotype of two was closer to the MHC optimum than the zygote formed with the less successful one [122]. Thus, eggs selecting MHC-compatible sperm prefer the best combination avoiding the lottery of meiosis, as shown in sticklebacks. The signal mode is not yet known, it could be odor again.
References
111. Mori, T.; Sor and Editorial Board Member of various scientific journato, E.; Baba, T.; Seiichi, T.; Mori, E. Molecular and immunological approaches to mammalian fertilizations. J. Reprod. Immunol. 2000, 47, 139–158.