Is there a physiological gay trait
Most men’s sexual interests are directed towards women, and most women’s sexual interest is directed towards men. Many people consider this to be simply the natural order - the biologically appropriate, instinctively correct manifestation of the sex drive, reinforced by education, religion and law. But a considerable minority of men and women (estimated between 1 and 5 percent) feel drawn exclusively to their own gender; and not just a few people seek intimate contact with both sexes to varying degrees.
What is the reason for this diversity of hetero-, homo- and bisexuality? Is the background some diversity in genes or physical structure? Are previous experiences pointing the way? Or is an existing system being reshaped biographically and culturally? An insight into these relationships would be important because one could then weigh up to what extent the individual himself has an influence on his sexual inclinations, can choose them, or whether he is in a sense at the mercy of his body.
A property as complex and variable as sexual orientation is unlikely to be determined by just one influencing factor. But at least some of the results of more recent laboratory tests - including our own - indicate that genes and brain development also play a role in homosexuality, even if we do not yet know how this actually happens. It is possible that certain genes direct the brain's sexual differentiation and its interactions with the outside world in such a way that its already huge spectrum of responses to sexual stimuli becomes even broader and more varied.
In the search for the biological roots of sexual inclination, two paths have so far been pursued. On the one hand, one relies on findings from an initially completely different research field, the search for structural differences between female and male brains. We shall show that a peculiarity seems to occur in homosexual men: that a group of brain cells is shaped like in women and differently than in heterosexual men.
On the other hand, one searches for genes or gene complexes that are responsible for the expression of homosexuality or at least that could be involved in it.If they occur more frequently in certain families, one examines whether there is any equivalent in the genetic material - the DNA - something that the heterosexual men do not exhibit kinship.
A gender-typical brain area
Scientists have long been looking for an anatomical correlate in the brain for gender. As obvious as the difference between man and woman is outwardly and in many ways otherwise, this undertaking proved to be extremely difficult.
It is true that the brains of men are on average a little larger according to their entire physique, but another clear difference is not readily apparent at first glance. Even in the microscopic specimen, male and female brain structures look very similar. If there were any differences, it was to be concluded, they would have to be tiny and difficult to find. So it is not surprising that animal brains have been studied as an alternative and a cerebral sexual dimorphism has been demonstrated for the first time.
A study by Roger A. Gorski of the University of California at Los Angeles in 1978 on the hypothalamus of rats is particularly important. This structure lies at the base of the brain and is crucial for many bodily functions; Among other things, it participates in the regulation of the metabolism and plays a role in instinctive behavior - including sexual functions. As it turned out, a certain group of cells (a so-called nucleus) in the foremost area of the hypothalamus is several times larger in males than in females. Although the cell accumulation in the males is not even a millimeter in diameter, the difference can easily be seen in appropriately stained brain slices, even without a microscope.
Gorski's findings were instructive because the area in which the cell group is located is associated with the generation of sexual behavior, especially that typical of males. For example, male monkeys who have destroyed this medial preoptic region lose all sexual interest in females. On the other hand, an intact, just listless male can be brought to coitus by electrical stimulation of this zone.
However, we must not hide the fact that in monkeys a separate cell group, differently developed according to sex, which would correspond to that in rats, has not yet been found. The exact function of this nucleus in rats has also not yet been clarified. At least Gorski's group found that the difference occurs early in the animals' development and that androgens - the typical male sex hormones - play a key role.
Nerve cells in the group in question carry plenty of receptors for sex hormones, both for androgens - the most important of which is testosterone - and for estrogens, i.e. female sex hormones. First, male and female rat embryos have about the same number of neurons in the medial preoptic region. Around the time of birth, however, a high level of testosterone output from the testes of the male fetus causes the cell population to stabilize; in the case of females, on the other hand, who do not receive such a hormonal signal, many of the cells die prematurely - as a result, the nucleus permanently loses a considerable amount of size. Interestingly, only a few days before and after birth, the medial preoptic neurons are absolutely dependent on the androgen for their continued existence; the cell population does not subsequently shrink if you castrate an adult male and thus stop further testosterone production.
Later Gorski's group - Laura S. Allen was particularly involved - also found a gender-specific structure in the medial preoptic region in the human brain, the third interstitial nucleus of the anterior hypothalamus (third intermediate nucleus of the anterior hypothalamus) or INAH3 for short (Fig. 1 left and center left): The cell group in men is about three times as large as in women; however, the size varies considerably even among the same sex.
A sex-specific core of the brain
This finding gave me (LeVay) the idea in 1990 to investigate whether the INAH3 or another core in the same region might also be of different sizes in homosexual and heterosexual men. The thesis was daring because the prevailing view was that the orientation of sexual interest should be a personality trait shaped by the environment and cultural traditions. As far as we know, the brain processes influences of this kind on a higher level, namely mainly in the cerebral cortex and not in lower centers such as the hypothalamus.
I was able to examine the brains of 19 homosexual and 16 straight men whose bodies had been given up for autopsy. All of the homosexual and six of the heterosexual men had had the immunodeficiency disease AIDS and died from complications associated with it; the gender orientation of the rest had not been determined. If one assumes the pattern of the general population for them, however, at most one or two of them are likely to have been homosexual. In addition, I included the brains of six women in the study, about whose sexual preferences I also knew nothing.
The samples were anonymized so as not to inadvertently falsify the analyzes. As preparations, I used a series of very thin hypothalamus slices, which I stained in order to make individual groups of nerve cells visible, and determined their volume from their dimensions in the individual slices and the thickness of all slices. In addition to the INAH3 group, I checked the three cores INAH1, 2, and 4 that were close to it.
This confirmed the earlier finding that the INAH3 in heterosexual men is more than twice as large as in women. As I also found out, however, the nucleus in these men was two to three times as large as in the homosexuals in the sample, where in some cases it even seemed to be completely absent (photos in Fig. 1). That such a result is obtained by chance has a statistical probability of only about 1 in 1000. Because there was no significant difference in the size of the INAH3 between women and homosexual men, the dimorphism of this core seems to be equally pronounced in heterosexual and homosexual men to be like the gender typical.
It goes without saying that in such an analysis one must exclude influences other than those in question, which could possibly bring about just such structural differences. In this case, AIDS came into particular consideration: the virus that caused it - like some other pathogens that a weakened immune system can no longer cope with - can also seriously damage brain cells.
Against the suspicion that the INAH3 was smaller among homosexual men, who all died of AIDS for this reason, several arguments can be put forward: First, among the heterosexual men, the AIDS victims had an INAH3 as large as those who had who died of other reasons. Second, the history of AIDS victims with a small INAH3 was essentially no different from that of those with a large INAH3; so her infirmity had lasted no longer. Third, the three other cell groups examined in the same area - INAH1, 2, and 4 - were by no means smaller in those affected by AIDS than in the other deaths; if brain cells perish unspecifically as a result of this disease, this would probably also have had an effect on these nuclei.
Finally, after completing these analyzes, I was able to examine the hypothalamus of a homosexual who had not died of complications from AIDS. Again I did a blind study, this time using brain specimens from several heterosexual men of the same age for comparison. The result was as before: the homosexual man's INAH3 was not even half as large as that of all the others.
There seem to be even more anatomical differences in the brain that are correlated with sexual orientation. As Laura Allen and Gorski recently discovered, the anterior commissure - a bundle of fibers that runs across the median plane of the brain (picture 1, left) - is most inconspicuous in heterosexual men, larger in women, and most developed in homosexual men. If the values are compared with the differences in size of the brains, the structure of homosexuals is roughly the same as that of women.
What may be the background to the apparent correlation between sexual orientation and brain structure? In theory there are three options. One would be that the structural differences exist very early - perhaps even before birth - and that they participate in the sexual preferences a person later develops. The reverse version is that the anatomical peculiarities only arise in adulthood, namely under the influence of sexual sensations or behavior. And furthermore it would be possible that neither is controlled directly by the other, but that a third factor influences both the direction of sexual interest and the structural differences in the brain; this could be an event before or soon after the birth.
At the moment it is not possible to choose between the three explanations with certainty. In our opinion, however, at least the second is quite unlikely, if one considers, for example, that in rats the nuclei mentioned are still plastic and sensitive to androgens in early brain development, but apparently hardly later. We favor the first explanation, according to which the anatomical differences are already created in the phase of brain development and help determine sexual behavior in later life. We mentioned that in monkeys the medial preoptic region is important for sexual behavior. The INAH3 is located in the same area of the hypothalamus in humans. Perhaps this core actually influences individual gender orientation in some way in men. However, this is still pure speculation as long as there are no indications of a causal link.
If our idea is correct, it would have to be clarified how such an anatomical peculiarity develops in the embryo or fetus. The cause could be processes similar to those in typical gender differentiation. The gender-specific brain structures come about through interactions between the developing brain and steroid hormones of the gonads. Various scientists suggest that abnormal androgen levels in the fetus may be important for later sexuality - that it was unusually low in those male individuals who then became homosexual and especially high in women who later developed lesbian tendencies.
Perhaps the connection is not that simple after all. Perhaps - and this seems more likely to us - hormone levels can be quite the same, and yet each brain, while it is differentiating itself, responds to it in its own way. For the interactions certainly require a complex molecular apparatus, not only specific hormone receptors on the nerve cells, but also a number of proteins and genes of still unknown identity and function.
Signs of the hereditary nature of homosexuality
Genes for homosexuality - that sounds absurd at first. How should they be able to survive through the generations if their carriers feel drawn to their own sex and do not reproduce or reproduce only to a below-average extent? And aren't the parents of gay men and lesbians usually straight?
The research focuses more on indications of genes or genetic complexes, which at best give sexuality a gradual tendency towards direction, because no one is to be expected that strictly define its expression. Two methods are mainly meaningful: on the one hand, one analyzes the occurrence of homosexuality among twin siblings and in families over several generations in order to determine the statistical distribution in the population and possible inheritance patterns, and then on the other hand, searches specifically - using the method of DNA coupling analysis Gene complexes that coexist with homosexuality.
Just as other hereditary traits occur in certain family patterns, if homosexuality were genetically influenced, one would have to find characteristic distributions and inheritance patterns for them as well. The first modern study on this was published in 1985 by Richard C. Pillard and James D. Weinrich from the University of Boston (Massachusetts). This has so far been followed by five systematic studies on twins and other siblings of homosexual men and women.
If you take all the data together, the following results: In the case of men, the other twin of identical couples is also homosexual in 57 percent of the cases, that of dizygotic couples in 24 percent, and of other brothers the figure is 13 percent; in women it is almost 50 percent of identical twins, 16 percent of dizygoti and 13 percent of the other sisters. Compared to the average, these numbers are considerable - homosexuality appears to accumulate in some families, and this applies to both male and female families. The group led by J. Michael Bailey from Northwestern University in Evanston (Illinois) estimates the hereditary nature of sexual orientation - that is, the genetically determined proportion of characteristic variance - at around 53 percent for men and 52 percent for women. (The familial accumulation is most evident in the same sex, less between women and men.)
In order to be able to estimate the weight of the genetic factor and to be able to clarify the inheritance, systematically obtained data on the further relationship of homosexuals is required. One such survey is currently taking place at the US National Institutes of Health in Bethesda, Maryland; involved are Stella Hu, Victoria L. Magnuson, Nan Hu, Angela M.L. Pattatucci and I (Hamer) from the National Cancer Institute. The study is part of a larger project to identify risk factors for certain types of cancer that are higher than average in some groups of the homosexual population.
The first results - on male sexuality - confirm the earlier sibling figures. According to this, 14 percent of the brothers of homosexuals are also homosexual, brothers of heterosexual men only 2 percent.(The fact that the second value - practically an average for the entire population - is so low is due to the very strict definition of homosexuality in this study.) When we included the further relatives, an unexpected distribution emerged: brothers of the mother of a homosexual were with 7 percent chance of being equally homosexual, and 8 percent of their sisters had homosexual sons; on the other hand, there was no correlation with the father, his siblings or their children, or with the sons of the mother's brothers (box on pages 38 and 39).
Such data speak in themselves for the involvement of a genetic component. However, homosexuality would have to occur much more frequently if a single gene were responsible for it, which is passed on in one of the known simple inheritance patterns. It is possible, however, that certain genes are more pronounced in some families than in others. We came to this assumption when we examined families with two homosexual brothers each: 10 percent of the maternal uncles were homosexual and 13 percent of the female cousins. If a trait accumulates in this way, even outside the nuclear family, it is a strong indication of a genetic root.
Why is it that homosexual men of the same family are mostly related to one another in a maternal line? The first suspicion - that they are simply more familiar with this side of the kinship and are therefore more psychologically influenced by it - is unlikely to apply, because homosexual relatives of the opposite sex were statistically equally distributed among homosexual men and lesbian women to both parents Lines.
Now it could be that both parents inherit the factor, but it only appears in one gender - in this case in the male. Because homosexuals have fewer children than men on the statistical average, the hereditary disposition would have to be passed on disproportionately often by women. We do not yet know whether such a connection explains, at least in part, the unequal distribution pattern of homosexuality in families. This would only be possible with a genetic component that is not on one of the two sex chromosomes, because only then can both parents pass it on to the son.
Sex-linked inheritance is also conceivable, in our case a coupling of the potential factor to the X chromosome, of which women have two, men only one - their second sex chromosome is the Y chromosome. A man only passes on the Y chromosome to sons and the X chromosome to daughters, while the mother inherits an X chromosome for both of them. An X-linked gene that only works in the male sex therefore generally comes from the mother in the person concerned and can therefore also be expressed in their relatives. The inheritance scheme (box on pages 38 and 39) would correspond to the fact that only one's own brothers and those of the mother of a homosexual can be affected, as well as the sons of their sisters, but not other uncles and cousins. (Editor's note: In principle, a man can pass on such an X chromosome to a daughter; in the case of a homosexual, it could therefore also come from the grandfather.)
As a first test of such a mode of inheritance, we carried out a so-called linkage study of the X chromosomes of homosexual men. This is based on two facts: regardless of how important a gene is for the expression of a trait, those family members who carry the trait will share it more than randomly. In addition, the methodical use is made of the fact that genes that are close together on a chromosome are almost always inherited together - coupled - (with genes that are further apart, this is not always the case, because pieces of the same two chromosomes are sometimes interchanged).
Should there be a gene that affects sexual orientation, the closest chromosome segments would be passed on with it. These segments are used for orientation during the analysis. You only need clearly identifiable places on it, so-called markers, which you can recognize with certain tricks. In our case, it has to be markers that obviously appear at the same time as homosexuality. If a trait can be traced back to a single gene, then its position can be narrowed down quite precisely with this method. But even in the case of complex characteristics such as gender orientation, this procedure can at least help clarify whether a genetic component exists at all.
First of all, we had to have suitable markers in order to find individual chromosome areas again. Thanks to the large international undertaking to map the entire human genome, an extensive catalog of markers covering the entire X chromosome is already available. The most useful of these are short DNA segments, the sequence of which is simply repeated, with the length of the same marker at a certain position varying somewhat in individual people; the respective length of such a repetitive sequence is inherited.
In order to track down markers, the chromosome regions in question are multiplied billions of times; this happens very quickly today with the polymerase chain reaction. Then the fragments of different lengths, which move at different speeds in an electric field, are separated (Fig. 2).
We also had to find suitable families. This is not as unproblematic as in many other heredity studies, for which one simply determines in branched clans over several generations who has the trait and who does not. If a single gene is responsible, as in color blindness or sickle cell anemia, the property can usually be clearly recognized.
It is not so easy to determine the sexual orientation, if only because the information provided by the respondents is not necessarily completely reliable. Some people may falsely pass themselves off as straight because they do not dare to admit their true inclination to themselves or because they do not want to let others know about it. Because homosexuality used to be more flawed than it is today, and especially since the male was threatened with punishment, this must be taken into account especially with older generations.
But there is also a scientific objection: In models it can be shown that in the case of complex traits the chance of finding a genetic correlate decreases when one examines larger clans. Especially when different genes are involved, which also have different degrees of influence on the property, a large number of exceptions will occur which make the analysis more difficult.
We have therefore concentrated on core families with two openly homosexual sons. If someone is committed to a minority that is at least exposed to animosity, this should generally be true.
The procedure makes it possible to track down a single linked gene even if more genes or non-hereditary factors are required to develop the property. If, for example, homosexuality were based on the fact that a certain gene is present on the X chromosome as well as one on a non-sex chromosome and, in addition, a certain environmental constellation is given, then one would get a clear result if one were only homosexual on the X chromosome Brothers examined: They would carry the gene located there in any case. In contrast, heterosexual brothers of homosexual men would only have the gene sometimes; if only such pairs of siblings were taken into account, no clear statements would be possible.
A suspicious part of the chromosome
Sibling studies of this type are now considered to be the appropriate approach to identify the causes of multifactorial characteristics. We (Hamer and the aforementioned colleagues) wanted to limit ourselves to a potential genetic component that only emerges in men and is inherited by women. That is why we selected 40 families in which the fathers of the homosexual brothers were heterosexual.
We took DNA samples from the homosexual brothers and, whenever possible, from their mothers and sisters. We then typed the entire length of the X chromosomes using 22 markers. A woman has two versions of each of these markers, a different one on each of her two X chromosomes. Which of these a son inherits is coincidental. In general, there is a 50 percent chance that brothers will wear the same marker. We also had to include in the calculations the possibility that women sometimes have the same marker on both X chromosomes.
We now determined for each individual marker whether it is the same or different in the homosexual brothers. The result was exciting: over large areas of the X chromosome, two identical markers were not found more frequently than would have been expected if they were randomly distributed. The exception was a region at the very end of his long arm called Xq28 (box on pages 38 and 39). Of the 40 pairs of brothers there, 33 wore the same markers, only seven pairs were different.
Despite the small sample, the result is significant: If the distribution had been random, the chance of this would have been less than 1 in 200. As a cross-check, we examined any 314 pairs of brothers, most of whom were presumably heterosexual. As expected, they only had about 50 percent identical Xq28 markers at this point.
The simplest interpretation of the finding would be that there is actually a gene in segment Xq28 that influences sexual orientation in men. It is true that this would give us the strongest indication to date of a hereditary component in the orientation of human sexuality, if only because a direct connection with the genetic information, the DNA, has been established; however, as with all novel results, one should first be very careful with the interpretation.
To be on the safe side, other researchers have to repeat such a test. It has happened on various occasions that genes were thought to have been found which were supposed to have something to do with personal characteristics, but which later could not be reproduced.
In addition, the gene in question has not yet been isolated. The chromosome segment in question is around four million base pairs long (these bases, the building blocks of DNA, encode the genetic information). Even if that doesn't even make up 0.2 percent of the entire human genome, there could be several hundred genes there. In order to find the needle in this haystack, one would either have to examine a great number of families or break down the chromosome segment as a whole in much greater detail in order to identify all of the coding regions.
As we already know, the region Xq28 in particular has an extraordinarily large number of gene locations. Many of these are currently being researched. Presumably the area will be one of the first in the human genome, the structure of which is completely sequenced, so that one would also have the genes based on the base sequence.
We are also cautious because it has not yet been possible to say what part of the expression of sexual interest the gene component on Xq28 could have. In our study, seven of the homosexual pairs of brothers in the section had mismatched markers. In addition, because in half of the cases - i.e. for 20 couples - the same markers were to be expected by chance, there was no mathematical connection between a genetic trait in region Xq28 and homosexuality for 36 percent of the brothers. We do not know whether other genes were effective in these people or whether they were not hereditary physiological factors or living conditions. Neither can we say anything about the majority of homosexuals who do not have a brother who is also homosexual, nor about whether region Xq28 or perhaps other genetic locations are involved in the sexual orientation of women.
Conceivable genetic effects
At least we are now interested in how a genetic component could have an effect on region Xq28. On the one hand, an influence on the synthesis or metabolism of hormones is conceivable. One of the first considerations was whether the gene we are looking for is perhaps even the androgen receptor locus that has already been sequenced, the gene product of which is ultimately essential for the masculinization of the human brain. It was already known that it was on the X chromosome.
We tested this in an extensive study on 197 homosexual and 213 probably predominantly heterosexual men. Besides me (Hamer) and some members of my team, Bailey and Jeremy Nathans, Jennifer P. Macke, Van L. King and Terry R. Brown from Johns Hopkins University in Baltimore (Maryland) were also involved. In the coding sequence, however, we did not find any significant differences for the two groups, and coupling analyzes in homosexual brothers also gave no indication that the gender orientation was inherited together with this gene. Above all, however, as we now know, the locus is not at the end of the long arm of chromosome X, but in the region Xq11, i.e. somewhere completely different.
However, an indirect role for the hypothetical gene would also be conceivable, in that it favors certain peculiarities of personality or temperament, which in turn affect the choice of sexual partners. For example, someone with inherently strong self-confidence may be more likely to accept and show that they are attracted to people of their own gender than someone who is in need of social approval.
After all, after all that we have put forward here, it must be considered whether the gene product in question could have something to do directly with the formation of sex-dimorphic brain structures, perhaps even with the size of the INAH3. Then the simplest process would be that such a protein itself determined this development - for example, caused the nerve cells concerned to be preserved (in later heterosexual men) or that they die (in women and later homosexual men) already in the womb. .
According to a more complicated model, the gene product could, perhaps in the first few years of life, make a neural circuit in the hypothalamus more sensitive to environmental stimuli. It would therefore not determine the further development, but merely pave a path for it - not predetermine, but only predispose. Whether such considerations contain a grain of truth remains to be seen; however, with the current tools of molecular genetics and neurobiology, they can certainly be tested experimentally.
Our research has generated exceptional public interest. The reason for this is not a conceptual breakthrough, for the fact that genes and the brain are involved in human behavior is by no means new. Rather, they affect a deep conflict in modern Western society. We believe scientific research can help dispel misconceptions such as those that recently tarnished the image of homosexual men and women in general. But we also see the danger that, due to biological knowledge, the natural rights of individuals will be curtailed and thus humanity will be robbed of its diversity. Our society must pay much more attention to implementing and using new research findings in a humane way.
A Difference in Hypothalamic Structure between Heterosexual and Homosexual Men. By Simon LeVay in: Science, Volume 253, pages 1034-1037, August 30, 1991.
- A Linkage between DNA Markers on the X Chromosome and Male Sexual Orientation. From D.H. Hamer, Stella Hu, Victoria L. Magnuson, Nan Hu, and Angela M.L. Pattatucci in: Science, Volume 261, pages 321-327, July 16, 1993.
- Sequence Variation in the Androgen Receptor Gene Is Not a Common Determinant of Male Sexual Orientation. By Jennifer P. Macke, Nan Hu, Stella Hu, J. Michael Bailey, Van L. King, Terry R. Brown, Dean H. Hamer and Jeremy Nathans in: American Journal of Human Genetics, Volume 53, Issue 4, Pages 844 to 852, October 1993.
- Germ cells of pleasure. The nature of human sexuality. By Simon LeVay. Spectrum Academic Publishing House, Heidelberg, Berlin, Oxford 1994.
- Against nature? Homosexuality and evolution. From Volker Sommer. C.H. Beck, Munich 1990.
From: Spektrum der Wissenschaft 7/1994, page 36
© Spektrum der Wissenschaft Verlagsgesellschaft mbH
This article is contained in Spectrum of Science 7/1994
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