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    Post major histocompatibility complex


    and mouse urine


    Variation in the genes of the major histocompatibility complex (MHC) contributes to unique individual odors

    (odortypes) in mice, as demonstrated by the ability of trained mice in a Y-maze olfactometer to discriminate nearly

    identical inbred mice that differ genetically only at the MHC (MHC congenic mice), while they cannot distinguish

    genetically identical inbred mice. Similar distinctions are possible with urine, a substance that is involved in

    many facets of mouse chemical communication. This paper reports results supporting the hypothesis that the

    MHC-determined urinary odor is composed of a mixture of volatile carboxylic acids occurring in relative

    concentrations that are characteristic of the odortype. Y-maze behavioral testing of urine fractions from anion

    exchange chromatography indicates that volatile acids are necessary and sufficient to convey MHC odortype

    information. Diethyl ether extracts, which are expected to contain the more volatile, less polar organic acids, were

    also discriminable in the Y-maze olfactometer. Ether extracts of 12 different urine samples from each of two panels

    of MHC congenic mice were analyzed by gas chromatography. No compounds unique to urine of either genotype were

    detected, but compounds did appear to occur in characteristic ratios in most of the samples of each type.

    Nonparametric statistical analysis of the gas chromatographic data showed that eight of the peaks occurred in

    significantly different relative concentrations in the congenic samples. One of the peaks was shown to represent

    phenylacetic acid, which has implications for the mechanism of the MHC specification of odortype.

    Evidence for

    MHC-correlated perfume preferences in



    Fragrances have been used since at least 5000 years ago and all traditional

    scents are found in modern perfumes. Although perfumes are obviously involved in sexual communication, the

    significance of great individual differences in preference for fragrances is an evolutionary puzzle. The major

    histocompatibility complex (MHC) is a highly polymorphic and conserved set of genes that plays an important role in

    immune function in vertebrates. Both mice and humans have been shown to prefer the body odor of potential partners

    that have a dissimilar MHC genotype, which would result in heterozygous offspring. We tested whether individual

    preferences for perfume ingredients correlate with a person's MHC genotype. The human MHC is called HLA (human

    leukocyte antigen). A total of 137 male and female students who had been typed for their MHC (HLA-A, -B, -DR) scored

    36 scents in a first test for use on self ("Would you like to smell like that yourself?") and a subset of 18 scents

    2 years later either for use on self or for a potential partner ("Would you like your partner to smell like that?").

    An overall analysis showed a significant correlation between the MHC and the scorings of the scents "for self" in

    both tests. In a detailed analysis we found a significant interaction of the two most common HLAs with the rating of

    the 36 scents in the first study as well as with the 18 scents in the second study when evaluated for self. This

    result suggests that persons who share, for example, HLA-A2, have a similar preference for any of the perfume

    ingredients. The significant repeatability of these preferences in the two tests showed that the volunteers that had

    either HLA-A1 or HLA-A2 were significantly consistent in their preferences for the perfume ingredients offered.

    Hardly any significant correlation between MHC genotype and ratings of the scents "for partner" were found. This

    agrees with the hypothesis that perfumes are selected "for self" to amplify in some way body odors that reveal a

    person's immunogenetics.

    MHC genes, body odours, and odour



    Increasing evidence indicates that the highly polymorphic genes of the major

    histocompatibility complex (MHC) influence odour and mating preferences in house mice and humans [1]. MHC genes

    encode cell-surface glycoproteins (class I and II molecules) that bind short peptides and present them to T

    lymphocytes. Through this mechanism, MHC genes control the immunological self/non-self discrimination, and

    subsequently, tissue rejection and immune recognition of infectious diseases. Thus, it is suspected that the

    extraordinary polymorphism of MHC loci is maintained by balancing selection from infectious diseases, though direct

    evidence for this hypothesis is lacking [2]. Surprisingly, the best evidence indicates that MHC polymorphisms are

    driven by sexual selection. Studies in house mice indicate that both males and females prefer MHC-dissimilar mates

    [3–5], who they apparently recognize by odour cues [6]. Studies in humans have also found MHC-associated odour [7]

    and mating preferences [8]. Such disassortative mating preference could explain the diversity of MHC genes, though

    several questions remain unanswered about how the MHC influences odour production and why MHC-dependent mating

    preferences evolved.

    There is much evidence that MHC genes influence individual odour in laboratory mice and

    rats (reviewed in [20]), and several hypotheses have been proposed to explain how. First, since MHC molecules occur

    in the urine and sweat, they may provide the odourants [21]. This is unlikely since MHC molecules are large,

    involatile proteins, and furthermore, denaturation of proteins in urine does not destroy the distinguishability of

    MHC-mediated odours by mice [22]. Second, MHC molecules bind to allele-specific subsets of peptides, and their

    volatile metabolites, such as carboxylic acids, may provide the odourants. Class I MHC molecules bind peptides that

    are hydrophilic, highly evolutionarily conserved, universally expressed and derived from hydrophobic proteins,

    whereas Class II- bound peptides are more conserved than their source proteins but less conserved than class I-bound

    peptides [23]. Singer et al. [24] found that the relative concentrations of volatile carboxylic acids were

    characteristic of the urinary odour of different MHC-congenic inbred mouse strains. Third, MHC genes may alter odour

    by shaping specific populations of microbial flora, although the evidence for this idea is inconsistent [25–27].

    Fourth, MHC molecules may change their conformation to bind volatiles, instead of peptides, and carry them to scent

    glands [28]. Finally, when taken together, the evidence suggests that MHC-bound peptides are metabolized and made

    volatile by microbes [20]).

    Odortypes: Their origin and



    Odors that distinguish one individual from another member of the species and are determined by polymorphic

    genes are called odortypes. Odortypes and their considerable societal significance have been studied intimately only

    in mice and mainly with respect to the genes of the major histocompatibility complex. Further understanding and the

    matter of human relevance have been hampered by the apparent restriction of odortype expression to urine. The

    present finding that odorants comprising prerenal odortypes are already present in blood, albeit in masked form,

    affords the basis of a comprehensive view of odortypes. Accordingly, major histocompatibility complex and other

    polymorphic genes of antiquity are seen inter alia as agents of normal variation, which entails quantitative

    variation in output of odorant metabolites. Relatively few such normal variations should suffice for a vast range of

    compound odors whose specificity is determined by combinative assortment of the same set of individual volatile


    We recently have reported (20) evidence for distinctive patterns of volatiles according to MHC type.

    In a behaviorally active dimethyl ether extract of acidified urine a series of carboxylic acids has been found that

    distinguishes male mice differing only at the MHC. Behavioral tests suggest that most or all of the signal from H-2

    resides in this active fraction although this fraction does not, itself, smell "mouse-like" (unpublished

    observations). Although mass spectrometry indicates the presence of neutral compounds as well as the acids, these

    have not yet been implicated in the chemical differences between samples of urine from congenic mice. Because these

    volatile acids are abundant (approx 1 mg/ml) and strongly odorous in mouse urine, it seems probable that they play a

    critical part in the olfactory discrimination of MHC-congenic mice.

    Because the pattern of odorants

    characterizing the MHC-determined odortype is sufficiently similar in serum and urine, it follows that the odorant

    pattern is established prerenally; one proven source is the hemopoietic system (21). A likely mechanism for

    odor-type specification may be that soluble MHC gene products themselves bind circulating odorants selectively,

    presumably after they have lost their bound peptide, and then release them mainly during the course of renal

    processing and excretion.

    Although there is then a need to account for the several independent non-MHC-odortype

    loci identified throughout the rest of the mouse genome (22), including both sex chromosomes (23), there is no

    evidence that any of these exhibit the extensive diversity that renders the MHC unique.

    Studies with H-2 mutant

    mice (24, 25) and class 1 knockout mice (26) prove that MHC genes themselves, and not adjacent odorant-coding genes,

    are responsible, at least in large part, for MHC odortypes.

    Odortype specification and communication are by no

    means alone as nonimmunological functions of the MHC, and, indeed, these may represent primordial functions of far

    greater antiquity than acquired immunity (27-31). Moreover, there is reason to believe that MHC genes specify

    odortypes in species other than mice, including humans, as indicated above. Such odortypes often may serve similar

    purposes in different species. For example, human mating choices can be influenced by MHC genes although there is no

    direct proof that body odors mediate this effect (ref. 32, but see also ref. 33). We have found that paternal MHC

    type can be recognized in the scent of pregnant mice (34), and other studies implicate a similar phenomenon in

    humans (35).

    It is not necessary to invoke natural selection to account for the presence of MHC-regulated

    odorants in body fluids; they may be natural by-products of normal MHC gene variation. Organisms as diverse as

    marine invertebrates and mice and humans may have seized these serendipitously available volatile signals of

    individual identity to identify appropriate mates, thereby avoiding inbreeding, or to recognize siblings, parents,

    or offspring.

    Finally, economy of hypothesis requires a comprehensive account of odortypes in the simplest

    terms, and this is proposed here, as follows.

    Odortypes are secondary, not primary, genetic traits, and so are

    ubiquitous, e.g., among mammals, regardless of particular members' ability to sense them; it is a question of

    olfactory ability; thus, rats distinguish the odortypes of mice with the same exquisite precision as mice themselves

    (36). Visual identification among human individuals is no doubt the polymorphic anatomical parallel, quite likely

    involving some of the same variable genes such as the MHC.

    Lewis Thomas, in 1974 (37), founded the study of

    odortypes by asking whether dogs might "sniff out our histocompatibility types for us." Whether humans can sniff out

    dogs' histocompatibility types for them is a matter of interest.



    "Electronic nose" detects major histocompatibility complex-dependent prerenal and postrenal odor

    Stefanie Montag*, Michael Frankdagger , Heiko Ulmerdagger , Dorothee WernetDagger , Wolfgang Göpeldagger

    , and Hans-Georg Rammensee*,§

    * Department of Immunology, Institute for Cell Biology, dagger Institute for

    Physical Chemistry, and Dagger Department of Transfusion Medicine, University of Tübingen, D-72076 Tübingen,


    Communicated by Edward A. Boyse, University of Arizona College of Medicine, Tucson, AZ, May 25, 2001

    (received for review August 11, 2000)

    Mice prefer to mate with individuals expressing different MHC genes from

    their own. Volatile components presenting MHC-dependent odor types are present in urine and can be detected by mice,

    as shown by extensive behavioral studies. Similar odor types are suspected to influence human behavior as well.

    Although a recent report indicates that MHC expression influences the ratio of volatile compounds such as

    phenylacetic acid, so far no other means than studying the behavior of mice or rats has been available to assess

    odor types. Here, we report the ability of a gas sensor array (referred to as "electronic nose") to detect

    MHC-dependent odor types. The electronic nose consists of an array of chemophysical detectors, in our case quartz

    crystal microbalances and semiconducting metal-oxide sensors that change frequency or conductivity upon binding of

    very small numbers of individual molecules present in the gas phase of odorous fluids. The pattern of changes is

    characteristic for a particular smell. Our electronic nose distinguishes the urine odor types of MHC congenic mouse

    strains, MHC class I mutant mice, and HLA-A2 transgenic mice. In addition, MHC-dependent odor types can be detected

    in serum. The device also clearly differentiates between individual odor types of human sera from HLA homozygous

    individuals; however, HLA expression seems to have only a secondary influence. Thus, odor-type research can now be

    carried out with an objective and fast through-put system independent of behavioral studies.

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    Last edited by oscar; 01-01-2006 at 07:15 AM. Reason: Inserting Link

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