IN-DEPTH STUDY OF A PARTICULAR CLAIM
Female mate choice in Homo sapiens – female humans prefer to mate with males bearing dissimiliar alleles at several MHC loci. (Claim)
Study: The original study to test this claim was done in 1995 by Claus Wedekind and colleagues at the University of Berne, Switzerland . First, 49 female students and 44 male students were typed for their three MHC class II genes HLA-A, -B and -DR. Secondly, the females were asked to rate the odors of six T-shirts each (pleasantness, sexiness, intensity), three of them worn by men who had dissimilar alleles at the MHC loci to the rating woman’s MHC and three worn by men who were more similar to it. The women did not know the degree of MHC-similarity of the men who had worn the T-shirts. The T-shirts (100% untreated cotton) were worn for two consecutive nights. The men, wearing the T-shirts, had to live as odor-neutral as possible: they used a perfume-free detergent to wash clothes and bedclothes, perfume-free soap, they had to avoid odor-producing foods and were asked to avoid any activities that could produce disturbing smells (i.e. smelly rooms, pets, alcohol, tobacco, sexual activity). The women were tested in the second week after the beginning of menstruation as women appear to be most odor-sensitive at this time [2, 3], they had been asked to use a nose spray during 14 days before the experiment, and they were each given a copy of P. Süskind’s novel „Das Parfum“ to sensitize their smell perception.
Results: The women scored male body odors as more pleasant (and sexy) when they differed from the men in their own MHC than when they were more similar.
Wedekind’s claim was confirmed by his study. Surprisingly he even found that his claim was reversed when the judging women were taking oral contraceptives (Figure 1 (b)). Steroids administered by the pill physiologically stimulate pregnancy and the pill could act as a confounding factor in this experiment, therefore each female had to report whether she was using oral contraceptives.
Furthermore, the odors of MHC-dissimilar men reminded the test women of their own actual or former mates, which backs up the claim that the MHC or linked genes influence female human mate choice today.
There were no men dominating the women’s preferences, preferable T-shirts were evenly distributed and chosen depending on the female’s own allele combination at the three loci.
Background: The major histocompatibility gene complex (MHC) plays an important role in the organismal immune system, autoimmunity and reproductive success of all vertebrates except for the jawless vertebrates . The MHC class II genes code for heterodimeric peptide-binding proteins on antigen-presenting cells. MHC sequence variants have been shown to correlate with important biological traits, such as susceptibility to infectious and autoimmune diseases, kin recognition, cooperation, pregnancy outcome and mating preferences . Most of our knowledge about this supergene complex has been derived from studies in humans or model species under experimental, laboratory conditions [4, 6-12]. The maintenance and the renewal of variation in the antigen binding sites is an important genetic component in the cascade leading to an appropriate immune response since this part of the MHC acts to prevent attacks by viruses, bacteria and other parasites . The more different alleles there are, the greater are the chances to detect and react against various pathogens [4, 14]. MHC-disassortative mating results in progeny with high heterozygosity and thus enhanced disease resistance. It has been shown that particular allele combinations in heterozygote human individuals were beneficial against HIV  and hepatitis .
Odors play an important role for vertebrates in mating preferences . It has been shown that MHC metabolites are involved in odor production [18-21], and females are especially sensitive to these odors during their recipient phases [2, 22, 23].
Female mate choice depending on the MHC has been investigated in several different species: mice and rats [24-33], lizards , fish [35-37], and birds [38, 39]. Besides Wedekind’s pioneer study in humans from Switzerland it has been applied to other human populations: other European populations [32, 33, 40-42], Hutterites  and a South Amerindian population .
There is obviously a publication bias in showing female mate choice for dissimilar alleles, I could only find three studies which show no such patterns [42, 44, 45], but see below.
Discussion: There are several main issues for discussion.
(1) How well supported is the claim?
Besides the publication bias is there only one paper which shows that there is no preference for dissimilar alleles in humans . Anyway, there are over 60 publications showing female mate choice for dissimilar alleles at different MHC loci in different species (http://apps.isiknowledge.com). Interestingly, almost all studies except one  did not test if there is only dissimilarity at the MHC locus or dissimilarity genome wide. Further odors could be produced by other parts of the genome and confound the studies based solely on odors from the MHC. The theory says that females choose males with dissimilar alleles at the MHC because this produces heterozygote offspring with a wide array of different alleles, which are better armed against parasites [4, 9, 29, 32, 47]. This can look like a form of balancing selection. The problem is that this pattern of balancing selection mathematically resembles a frequency-dependent selection with several advantageous alleles. Since these kinds of studies are highly theory-dependent through the use of applied simulation studies it would be good to know which theory is best to work with, which theory represents the truth about selection acting on MHC. It could even be that females mate with dissimilar allele-bearing males to simply avoid inbreeding, independently of all the theories about heterozygote-advantage or frequency-dependent selection.
The paper, including the claim that I am discussing, has been cited 279 times (http://apps.isiknowledge.com). It has been shown that several specific alleles confer a selective advantage associated with the resistance against HIV  and hepatitis . MHC has been shown to be involved in odor production [18-21] and the human female odor perception depends on the menstrual cycle as well as the fertility status of the women [2, 22, 23]. There are spontaneous abortions and infertility associated with the MHC similarity of mating partners in humans [48-52], which indicates that MHC similarity of two mating partners can be disadvantageous.
(2) Were the scientific studies backing it up designed to address this particular question?
Yes, all the studies in the different species that I mentioned in the background paragraph adressed speficially whether there is female mate choice for dissimilar alleles at a MHC locus.
(3) What is the general opinion regarding the claim in the scientific community?
It is generally accepted that the sequence diversity and also the diversity of binding proteins in several particular regions of the MHC are very high. It has also been shown that balancing selection as well as frequency-dependent selection are acting on these regions [10, 53, 54]. It is not clear what the relative contributions of the two forces are. Female mate choice is a third, widely accepted and mutually non-exclusive hypothesis for the high diversity, as mentioned above. Claus Wedekind himself is a prestigious scientist with an h-factor of 26 (http://apps.isiknowledge.com; he was born in 1966), including 5 publications in “Proceedings of the Royal Society of London“ (one was his Bachelor thesis), 4 in „Nature“ (one was his Master thesis) and 2 in „Science“. Wedekind has been cited 3376 times in scientific publications (http://apps.isiknowledge.com). The so-called T-shirt study is a very well-known study. Some scientists do not take it too seriously, maybe because of the small sample size and the possibility of a lot of confounding factors. It seems like Wedekind has been ridiculed, but to some extend because other scientists seem to be jealous since he managed as a very young and unexperienced scientist to become popular with a very simple and cheap study. On the other hand there are some particular flaws in his study: he used a small sample size, too many assumptions and no replications. There is the possibility that he overinterpreted his data since the standard deviations are quite large and they overlap. Additionally he does not explain the thresholds for the grouping of the statistical units into MHC-dissimilar and MHC-similar. This grouping seems quite arbitrary and could have been used to enhance the effect.
(4) What is the general opinion regarding the claim among the the general population of people?
The reaction to Wedekind’s claim and finding was very intensive in the general population. Wedekind’s media presence was high and he has since then been asked over and over again to inform about his studies. He is a quite frequent author in Swiss newspapers and magazines, such as „Facts“, „Tagesanzeiger“, „Weltwoche“, „Focus“ and „NZZ“, which are known, serious media in Switzerland, as well as Germany and Austria to some extent. The great interest can be explained by the fact that people want to find a partner who matches, and Wedekind’s study could reveal some facts to facilitate the search. This shows that Wedekind’s T-shirt study was more of a boulevard science than of hardcore science, such as we discussed it in our course. There is no clear definition of science but this scientific study is a little bit too sexy. This could also be the reason why it was not published in Nature or Science, if he ever tried to publish it there. Nature and Science do not accept such little, local studies with overlapping standard deviations and arbitrary groupings of statistical units. Additionally, this study did not please everybody. Conservatively religious people did not like it that Wedekind treats humans like animals. This verges on blasphemy and they cannot imagine that women chose males mainly with the nose. Other people take it too literally and try to sell it commercially (see below).
(5) Are there people or agencies that have any sort of „agenda“ regarding this matter, beyond finding out the „truth“? (Has it influenced the study?)
Since July 2008 there is a company in Zürich trying to sell Wedekind’s findings commercially. They state that love is no coincidence (www.GenePartner.com). This company was founded shortly after its big archetype in the US (www.ScientificMatch.com). Both provide the service of sequencing several MHC loci from a sample of saliva which you have to send in. Then they compare it with their database of all their members and select all the optimal partners based on MHC dissimilarity. They promise exciting sex, a faithful relationship and healthy children. The analysis and membership cost around 150 Euro a month. It is important to remember that females could use their noses to find optimal mating partners to produce advantageous offspring but MHC-dissimilarity does not help find a girl/boyfriend, companion or partner to get along for a longer time span. The two companies have been founded more than 10 years after the original study by Wedekind. Both companies do not use any scientific studies to back up their claims. I assume the four authors of the original study wanted to distance themselves from the companies. The companies did not influence the study or the outcome of the study. The researchers involved in the original study claimed to not want to make any profit of their findings and the people working at the company were not involved in the original study.
(6) Why is there only female mate choice based on odors investigated? Aren’t the males also smelling the females?
There has been a study in 2008 investigating exactly this question . They investigated the searching behavior of European and American people (university students) for mating partners. Women made use of the smell and taste of possible mates, and males were only optically-oriented and odors played a minor role. I could not find any paper where they tested if males prefer to mate with women bearing dissimilar alleles at the MHC loci. There are very few natural science papers about this topic. The only papers that I could find were from psychological sciences (http://apps.isiknowledge.com). In most vertebrate species it is the females who chose the mating partners and not the other way around because reproduction is much more costly for females [56, 57]. In humans this is much more complicated because it is confounded by social and economical factors.
(7) What have you learned from this example regarding how scientific knowledge is shaped? Regarding female mate choice depending on the MHC loci, we are in the middle of creating knowledge. We now have the methods and background theories available to investigate this claim. The first observations were done in mice and rats. Thereafter followed Wedekind’s study in humans and a great amount of studies in other vertebrates. The evidence has been growing during the last ten years and by now we have over 60 studies showing a correlation of female mate choice and the accumulation of new and more diverse allele combinations in the offspring. We have reached a state of scientific agreement regarding the high diversity at particular MHC loci and the involvement of female mate choice in this pattern. Now we will have to investigate the mechanisms backing up the claim by excluding and controlling all confounding factors with the use of manipulative experiments. It is not sufficient anymore to show a correlation, this would not add to additional knowledge about this claim. Finally we will have to find an universal, objective, parsimonious and testable hypothesis explaining the observed patterns. And sometime in the future we will have to admit the inescapable uncertainty of this conclusion, because this is the fact that makes the distinction between science and nonscience .
(8) Were the observations theory-dependent?
Research fields such as molecular ecology and molecular evolution are highly theory-dependent. With the advent of molecular techniques in ecology and evolution we have introduced a lot of assumptions and theories that we have to trust „blindly“ while doing research. In this particular study the authors rely on the theories about the production and perception of odors related to the MHC, the unconscious choice of optimal mating partners based on odor, the theory of DNA, and therefore the concept of alleles. There have not been any manipulative experiments performed, this is more like a descriptive study of an observation. Observations become only interesting in the light of a bigger theory, in this case about humans acting like „normal“ vertebrates, performing mate choice with the nose, based on smell, and therefore representing an exciting model of selection.
(9) How can major theories in philosophy of science be applied to this example?
All the studies on female mate choice for dissimilar alleles at particular MHC-loci in vertebrates are most probably leading to a scientific agreement, including the studies done on humans. By now we still lack manipulative experiments, generally. Through observations and experiences it has been shown in over 60 studies that females of several vertebrate species, mainly mammals, mate preferrably with males bearing dissimilar alleles at several MHC-loci. In an inductive framework, the behavior of these females and the logic behind it about a selective advantage in the offspring against parasites, represents a causal theory, explaining the world of vertebrate mating . We can use this theory to predict how females are going to mate in the future. The theory of neutrality (no female mate choice for dissimilar alleles) has been rejected in most of the studies by a falsification approach . The fittest theory, that one of female mate choice for dissimilar alleles at particular MHC-loci, has survived until now and is the best one available. It has not been proven to be true, but others have proven to be false or less universal. According to Popper, good theories cannot be falsified. There is one problem that we have discussed: observations, especially the discussed one here from Wedekind, are theory-dependent and failed predictions may arise due to a false assumption and not to the tested hypothesis itself . For me it seems as if female mate choice for dissimilar alleles at some MHC loci in vertebrates represents a program (Lakatos, 1950) or a paradigm (Kuhn, 1959)[62, 63]. This study is a further observation to back up the claim and enhance the protective belt of the core in the way of Lakatos . The explanation is objective, testable and quite simple. What we need right now are manipulative mating experiments with „strains“ of different genotypes, infected with different numbers and combinations of parasites to see if the program will still hold. As far as I know, Wedekind is working on such systems right now in whitefish, Coregoninae.
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