Friday, November 17, 2006

How Big Brother Makes You Gay

This is dry stuff; you’ve been warned. :-)

As I left off (here), having older brothers increases the chance that you will be gay (by about 33% per older brother). In fact, of those with an older brother, it’s calculated (by statistical magic ;-)) that 24% of them may attribute being gay to that fact (43% for those with two older brothers and so on) (1). Anyway, that effect is there but how does it work? (I’ll be greatly following the review in reference 1, but will deviate)

The theories here may be broken down into pre and postnatal causes.

To recap, evidence has accumulated to the extent that the hypothesis of a postnatal fraternal birth order effect is becoming relatively defunct (2). Early sexual experience (3,4,5) and any other effect of being raised with an older male child (6) has greatly and recently been ruled out. In fact, the older brother need not even be present in the home. Only a womb need be shared, strongly suggesting the womb is the place to look for a cause.

Another important indication that a prenatal cause is in play came surprisingly from measurements of birth weight (1). Blanchard and Ellis seem to have been the first to look at such a relationship in gays (7). They analyzed the birth weights of 2599 heterosexual females, 1111 heterosexual males, 125 homosexual females and 208 homosexual males some with the same biological mother. It was found that:

1. Men with older brothers weighed less at birth than men with older sisters.
2. Gay men with older brothers weighed less at birth than heterosexuals with older brothers.
3. Gay men with no older brothers weighed the same as heterosexuals with no brother.

With Zurcher, these findings were repeated (8), in part. The first finding was not found in one subsequent study, but, as the authors admit, this may be due to the fact that their controls were all suffering from clinical disorders and found from a psychiatric hospital. One has to be careful from where one picks their “average” human ;-). But that first finding was repeated by Cote (a bunch of crazy French accents on that) (9).

It may also be important in finding this mechanism to note that gays seem to run along the maternal line more frequently (10). I’ve got’em on both sides. This could indicate there’s something passed in the genes from mother to male child, but it could also be evidence that the maternal line has characteristics that cause the mother’s biology to influence her child towards homosexuality.

Regarding these findings a “single-mechanism” hypothesis has been proposed. Here there is one cause from the mother for both the low birth weight and homosexuality. So, if this mechanism isn’t present (no older brothers) there’s no effect on gayness or weight (#3 in the above findings). A bit more of this mechanism and baby boys are slowed in their growth, and made more effeminate (#1 above, along with Reference 1). Finally, a high dose of this mechanism leads to homosexuality (#2 above).

The front-runner as to what this mechanism could be seems to be the maternal immune hypothesis (11,12). That’s not to say others are not possible. Neither is that to say there aren’t other prenatal effects, such as hormone exposure (to which I’ll eventually get but I’ll limit the focus in this post to the cause of the fraternal birth order effect only).

It is known that a variety of cell types from the fetus enter the mother during a typical pregnancy, and do more so during birth and throughout abnormal pregnancies (21-23). In the maternal immune hypothesis, such wondering male cells are more readily recognized by the mother as foreign, due to their sex. With each exposure, each pregnancy, she may develop a progressive immunization. The related antibodies may then cross the placental barrier in future pregnancies to attach to the same male markers in the first child’s younger brother, thus altering his development, attacking what would have made him fully male (thus no such effect in lesbians). Importantly, in this theory each older brother would increase the chance that the next will be gay, as we see in the data.

Now, this is the prevailing theory, no one has found a smoking gun in humans, and how to do so ethically, in a simple manner, may be problematic. But such a theory is not without it’s evidence. As early as the first days of a pregnancy, a H-Y immune response (an response to molecules expressed by male but not female cells) has been shown in mice and cattle (24-26). This, of course, also means this effect may be in play even if you have no older brother, and it may be even stronger than the current data suggests, which only uses live births. Also, immunization to paternal antigens have been known to affect birth weight in rats (13), and mice (14, 15). Unfortunately, such experiments on humans would be frowned upon by anti-science fanatics ;-).

In humans, though, it’s not a theory without a real, and well-understood example: hemolytic disease or HDN. A woman who is Rh-negative and carrying a Rh-positive child (due to a Rh-positive father) develops an immune response to the child’s blood, which enters her system primarily during birth. Subsequent Rh-positive children are affected more and more by this attack, as seems to happen for the fraternal birth order effect. The first child is fine, the second may be anemic, and the third may never make it to term, as the mother’s immune system destroys their blood (16). It’s also important to note, adding strength to the maternal immune hypothesis on gays, it’s been shown the immune response in HDN is more likely to occur in male children, indicating mothers recognize and attack male cells more often as foreign than female cells, as one might expect (17-19).

But HDN affects the blood, and we’re talking about the brain. Here too there is evidence of a mother’s immune system playing a role. Serum from women who’ve produced autistic or dyslexic children, when injected into pregnant mice, produce mice with mental deficits (27,28). Also, in humans, boys with cognitive disorders show the same fraternal order effect that we see in gays, but girls do not (29, 30).

As to the specifics of this theoretical immune response, a number of H-Y antigens have been discovered. Of those, we do know of some good candidates. Of the 27 known proteins and protein families encoded on the Y chromosome, 12 are expressed throughout the body, and three are known to be specific to the brain and two of those on cell surfaces (20). Both of those are instrumental in cell-cell adhesion and thus the structure of the male brain. But who knows? It could be a protein encoded on another chromosome and only regulated by the Y chromosome. Much is to be done.

Let’s end it there. Though there are a couple of other variants on this theme involving the placenta and some hormonal effects, that’s plenty for now. To sum up, we see this fraternal birth order effect as one of the more prominent predictors of homosexuality, and it seems we are closing in on its mechanism. It will be interesting to see how it all plays out. For example, right now we have treatments for HDN, preventative injections. Maybe the question will someday be there for mothers with such antigens: Do you want to stop your infant from being gay?

I’ll take a break from the research for a while.

1. Blanchard, R. (2004). "Quantitative and theoretical analyses of the relation between older brothers and homosexuality in men." Journal of Theoretical Biology 230: 173-187.
2. Purcell, D., R. Blanchard, et al. (2000). "Birth Order in a Contemporary Sample of Gay Men." Archives of Sexual Behavior 29(4): 349-356.
3. Wellings, K., J. Field, et al. (1994). Sexual Behavior in Britain: the national survey of sexual attitudes and lifestyles. London, Penguin Books.
4. Dawood, K., R. Pillard, et al. (2000). "Familial Aspects of Male Homosexuality." Archives of Sexual Behavior 29(2): 155-163.
5. Bogaert, A. F (2003). "Number of older brothers and sexual orientation: New tests and the attraction/behavior distinction in two national probability samples." Journal of Personality and Social Psychology 84(3): 644-652.
6. Bogaert, A. F. (2006). "Biological versus nonbiological older brothers and men’s sexual orientation." Proceedings of the National Acadamy of Science 103(28): 10771-10774.
7. Blanchard, R. and L. Ellis (2001). "BIRTH WEIGHT, SEXUAL ORIENTATION AND THE SEX OF PRECEDING SIBLINGS." Journal of Biological Sciences 33: 451-467.
8.Blanchard, R., K. Zucher, et al. (2002). "Fraternal birth order and birth weight in probably prehomosexual feminine boys." Hormones and Behavior 41(3): 321-327.
9. Cote, K., R. Blanchard, et al. (2003). "THE INFLUENCE OF BIRTH ORDER ON BIRTH WEIGHT: DOES THE SEX OF PRECEDING SIBLINGS MATTER?" Journal of Biological Sciences 35: 455-462.
10. Camperio-Ciani, A., F. Corna, et al. (2004). "Evidence for maternally inherited factors favouring male homosexuality and promoting female fecundity." Proceedings of the Royal Society B: Biological Sciences 271: 2217-2221.
11. Blanchard, R. and A. F. Bogaert (1996). "Homosexuality in men and number of older brothers." American Journal of Psychiatry 153: 27-31.
12. Blanchard, R. and P. Klassen (1997). "H-Y Antigen and Homosexuality in Men." Journal of Theoretical Biology 185(3): 373-378.
13. Gentile T, Borel IM, et al. (1992). "Preferential synthesis of asymmetric antibodies in rats immunized with paternal particulate antigens. Effect on pregnancy." Journal of Reproductive Immunology 22(2): 173-183.
14. Lu, E. and W. Dawson (1986). "Paternal antigen and progesterone effects on conceptus size in laboratory mice." Biology of Reproduction 35(3): 524-530.
15. Saji, F., K. Nakamuro, et al. (1980). "Sensitized T-lymphocytes against paternal histocompatibility antigens cause intrauterine fetal death and growth retardation." Nippon Sanka Fujinka Gakkai Zasshi 32: 1853-1858.
16. Adams, M., J. Marks, et al. (1981). "Rh hemolytic disease of the newborn: using incidence observations to evaluate the use of RH immune globulin." American Journal of Public Health 71(9): 1031-1035.
17. Renkonen, K.O.,, M., 1962. The sex of the immunizing Rhpositive child. Ann. Med. Exp. Biol. Fenniae 40, 108–109.
18. Renkonen, K.O., Timonen, S., 1967. Factors in.uencing the immunization of Rh-negative mothers. J. Med. Genet. 4, 166–168.
19. Scott, J.R., Beer, A.E., 1973. Immunological factors in .rst-pregnancy Rh isoimmunisation. Lancet 1, 717–718.
20. Skaletsky, H., T. Kuroda-Kawaguchi, et al. (2003). "The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes." Nature 423: 825-837.
21. Pertl, B., Bianchi, D.W., 2001. Fetal DNA in maternal plasma: emerging clinical applications. Obstet. Gynecol. 98, 483–490.
22. Bayrak-Toydemir, et al., 2004, Are fetal cells in maternal plasma really there? We think they are, Journal of Human Genetics, 48, 12,
23. Kolialexi, A., et al., 2004, Fetal cells in maternal plasma are found in a late state of apoptosis, Prenatal Diagnosis, 24, 9, 719-721.
24. Epstein, C.J., Smith, S., Travis, B., 1980. Expression of H-Y antigen on preimplantation mouse embryos. Tissue Antigens 15, 63–67.
25. Krco, C.J., Goldberg, E.H., 1976. H-Y (male) antigen: detection on eight-cell mouse embryos. Science 193, 1134–1135.
26. White, K.L., Anderson, G.B., BonDurant, R.H., 1987. Expression of a male-speci.c factor on various stages of preimplantation bovine embryos. Biol. Reprod. 37, 867–873.
27.Vincent, A., R. Deacon, et al. (2002). "Maternal antibody-mediated dyslexia? Evidence for a pathogenic serum factor in a mother of two dyslexic children shown by transfer to mice using behavioural studies and magnetic resonance spectroscopy." Journal of Neuroimmunology 130: 243-247.
28.Dalton, P., R. Deacon, et al. (2003). "Maternal neuronal antibodies associated with autism and a language disorder." Annals of Neurology 53(4): 533-537.
29. ACKERMAN, P., C. GOOLSBY, et al. (1988). "A test of the immunoreactive theory of selective male affliction." Journal of pediatric psychology 13(13): 49-53.
30. FLANNERY, K. and J. LIEDERMAN (1994). "A test of the immunoreactive theory of the origin of neurodevelopmental disorders: is there an antecedent brother effect?" Developmental Neuropsychology 10(4): 481-492.


Foxx said...

Thank you for this research. I find it very interesting.

-L- said...

Holy crap, I love a blog post with 30 scientific papers in the footnotes! ;-)

This was so interesting to me and I loved your final teaser about intervening! It sort of does put a different spin on the consideration of whether being gay is a disease if it is shown to be the result of immunologic attack by the mother!

Thanks for spoon feeding me the research.

Scot said...

It sort of does put a different spin on the consideration of whether being gay is a disease if it is shown to be the result of immunologic attack by the mother!

Hey, immunological attacks are usually on unwanted parts, in this case, what would make people straight ;-).

Sure, it could be considered a disease, like those cited (Again, I don’t think it ethically matters). But there are reasons to not be so hasty, which I hope to get to. As in your latest post, sometimes things develop and are subsequently destroyed in an embryo for a reason. There’s no reason nature would be above using a mother’s immune system to do it’s work on a child and not all such change is bad ;-).

-L- said...

As with so many arguments on the pathological or benign status of homosexuality, one can choose the view that supports the conclusion one wants to believe.

I agree with you, but it's an interesting thought, isn't it?

Scot said...

Certainly; I'll not plant my feet and don't think it should matter (though it does to many).

One would hope we can test these hypotheses though; else we'll just keep looking at it however we prefer :-).

-L- said...

I'm saying we'll still keep looking at it however we prefer, regardless! I'm still interested in the research though.

Scot said...

I’m sure that’s true for some, but hypotheses die all the time of contrary evidence. I’ve had to abandon many a cherished (and some dreaded :-)) hypotheses, upon testing them in the lab.

The problem here is finding the tests and the lab (I think I’ll be writing more on this eventually).

Now if you mean some may prefer to believe the moon is made of cheese and will do so despite flying there themselves and tasting moon rock, on a nice piece of brochetta, then sure, people have great liberty in their minds to never surrender to the supposed outside “reality” :-).

-L- said...

What I meant (and I'm self-conscious after all the back and forth) is that whether an immunologic response is considered a normal process resulting in normal development or pathological depends on the biases of the observer. We may understand and quantify EXACTLY how it works, but whether or not you consider it to be a disease will still be somewhat arbitrary.

There's not a right answer objectively to what you do with the evidence. So, it's a lovely thought that truth will prevail, but the truth can be distractingly irrelevant a lot of the time. ;-)

Scot said...

Hey, I like the back and forth; I don’t get to discuss such things often in the real world, let alone with a guy in your line of work :-).

I don’t think we disagree much here.

I hope I didn’t come off as saying truth always wins out; that’s a whole other can of worms ;-).

If the two hypotheses are not testable, if they make no distinct predictions, then they are of no use to anyone but politicians. I was meaning that these both might be falsifiable hypotheses and given the right tests they may be bolstered or harmed. While I do this every day in my work, in this topic we’re certainly not at an answer, and, yes, confirming the maternal immune hypothesis would not do that either (unless say we found a protein who’s sole purpose, after decades of study, seemed to be to both provoke an immune response and make men straight, say, being pumped purposefully by the fetus into the mother’s system :-)).

"whether an immunologic response is considered a normal process resulting in normal development or pathological depends on the biases of the observer."

Normal? I bet we’d at best be one of nature’s minor contingencies :-), but, sure, pathology can be in the eye of the beholder. I know some see, say, their ADD as a benefit.

It seems to me the question is if there is some increase in human survival and/or fecundity found in the effect that keeps the cause from being selected out of business. This may be testable; predictions can be made as to what the data should be before we find them. I hope to get into some of these efforts eventually.