mhc

and mouse urine odor
http://www.pnas.org/cgi/content/full/94/6/2210

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

humans
http://beheco.oxfordjournals.org/cgi...tract/12/2/140

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

preferences
http://ndt.oxfordjournals.org/cgi/co...full/15/9/1269

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

composition
http://www.pnas.org/cgi/content/full/96/4/1522

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 compounds.

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.



http://www.pnas.org/cgi/content/abstract/98/16/9249

"Electronic nose" detects major

histocompatibility complex-dependent prerenal and postrenal odor components
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, Germany

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.