The big brother effect

New Scientist, 29 March 2003

LITTLE brothers owe a lot to their older male siblings. Historically, the eldest have been saddled with the ageing family farm - not to mention the ageing family - leaving younger boys free to pursue serious commerce or adventure. Even today, younger brothers enjoy expert skateboarding instruction, tips on how to use the family car undetected and more generous curfews. Long before the younger ones appear, older boys have broken their parents in, making life less miserable for those who come after. But can boys really also credit their older brothers with determining their sexual orientation?

The debate about whether homosexual men are born or made is hotly contested. Puritans still insist that homosexuality is a "lifestyle choice" (and a wrong one at that). Many gay men will tell you they have been sexually attracted to other men since they first noticed the difference between the sexes. Meanwhile, biologists have been fascinated by the question, not least because the observation that 2 per cent of men are attracted to members of their own sex contradicts everything that Darwin would have us believe. Science is not threatening to resolve this particular debate any time soon. But the idea that sexual orientation is fixed before birth has been strengthened with the intriguing finding that the more male babies a woman has borne, the greater the likelihood that any subsequent sons will be homosexual.

Over the decades, scientists have found evidence to support both sides of the nature versus nurture argument (New Scientist, 28 September 1996, p 32, and 28 November 1992, supplement). Twin studies suggest that homosexuality isn't all down to the genes, but they also show that there must be a genetic component, as many more identical twins than fraternal twins share sexual orientation. In 1993, Dean Hamer at the National Institutes of Health in Bethesda, Maryland, even claimed to have found a region on the X chromosome where a male gay gene might reside.

Several researchers have pointed to anatomical differences between gay and straight men. In 1991, Simon LeVay, then at the Salk Institute in San Diego, California, published evidence that a part of the brain known to vary in size between men and women was unusually small in homosexual men. In fact, in his post-mortem study, LeVay found that the region, known as the third interstitial nucleus of the anterior hypothalamus, or INAH3, was almost identical in size in women and gay men. LeVay argued it was evidence that gay men are born, not made. "It's much more than lifestyle or family processes," he insists.

For years, LeVay's findings went unreplicated. Then, at last year's meeting of the Society for Neuroscience in Orlando, Florida, Charles Roselli at the Oregon Health and Science University in Portland presented supporting evidence from work in animals. He and his colleagues studied 27 sheep - 10 ewes, 8 normal rams and 9 rams that exhibited homosexual behaviour. In nature, about 8 per cent of rams are gay, says Roselli. For reasons unknown, they never court or mate with females, preferring instead to mount males. Like LeVay, Roselli found that the analogous part of the hypothalamus in these rams resembled the female structure rather than the male.

Those on the nurture side of the debate argue that such anatomical differences are not the cause of homosexual behaviour, but the result of it. "We don't know whether the [interstitial] nucleus can be changed by experience," admits Roselli. But in other animals, such as rats and ferrets, that particular brain region is shaped in utero by the male hormones. "By inference, we'd think that differences between male and female-oriented rams could be traced back there too," he says.

Other gay signatures have also been identified, but their relevance to sexual preference remains unclear. Roger Gorski at the University of California at Los Angeles, for instance, found that the anterior commissure, a cable that connects the two hemispheres of the brain, is larger in gay than straight men. Dick Swaab at the Netherlands Institute for Brain Research in Amsterdam found that the body's timekeeper, the suprachiasmatic nucleus, is larger in homosexual men than in heterosexual men. And Doreen Kimura at Simon Fraser University in Vancouver found that gay men's fingerprint-ridge patterns, which are completely formed during gestation, were more like those of heterosexual women than heterosexual men.

Despite all this, the notion that sexual preferences are hardwired and that people are born with them remains extremely controversial. But the recent findings have convinced at least some of the experts. All the evidence points to the idea that male homosexuality is innate, says Ray Blanchard, a psychologist at the Centre for Addiction and Mental Health in Toronto. "The theory that early childhood experiences lead to homosexuality has had 100 years, and they've come up with zip," he says. Exactly what the biology behind homosexuality is remains a puzzle, he admits. But after 15 years studying what he calls the "fraternal birth order effect", he's convinced that he is onto something.

Blanchard stumbled into the arena while sifting through some data for a colleague. In his cross-tabulations, he couldn't help but notice the striking difference in sibling patterns between heterosexual and homosexual men: so many gay men had older brothers. "I had read somewhere about this. I thought it was absurd - such egregious pseudoscience," Blanchard says. He is now the principal proponent of the theory.

To test whether the apparent correlation was anything more than anecdote, Blanchard began by studying 302 gay men, all Caucasian non-twins who could identify every child born to their mother, and the same number of heterosexual age-matched controls. All the volunteers were given questionnaires about their parents' age at their birth, as well as the genders and numbers of older and younger siblings born to their mothers. The homosexual males, Blanchard found, had significantly more older brothers than the heterosexuals, 1.31 compared with 0.96. Parental age and the interval between births played no role. He calculated that the odds of being gay increased by about 33 per cent with each older male sibling.

Subsequent studies by Blanchard and other research teams confirmed the finding. John Manning at the University of Central Lancashire in Preston has found the effect in all his samples of gay men. "It's one of the few reliable correlates of homosexuality that I know of," he says. "Now, if you don't see it, you start thinking maybe you've done something wrong." Marc Breedlove, at Michigan State University in East Lansing, also found a striking preponderance of older male siblings among his gay male volunteers compared with the straight male volunteers, but no difference in the number of younger siblings.

The big brother effect has yet to be confirmed across other racial groups, but it has proven to be robust in many contexts. It seems to be true of people studied decades ago as well as today, of those in Europe, Canada and the US, of psychiatric patients and non-patient volunteers and of men who wish they were women as well as men who are perfectly content with their orientation and anatomy. Regardless of culture, demography or psychological state, having more older brothers predisposes a man to being homosexual.

Even Roselli's rams seem to demonstrate the fraternal birth order effect. "I'm seeing hints of it," he says. "But we're still collecting data." The findings aren't completely comparable, since sheep tend to be born in twins and triplets. But in the smallish sample Roselli has completed so far, the rams classed as homosexual have significantly more older or same-age male siblings than heterosexual ones. "The idea that it might show up in an animal model is worth investigating," he says.

In humans, the big questions these days are less about whether it's happening, but rather how and why. Interestingly, female sexual orientation seems to be completely unaffected by birth order. Neither older sisters nor older brothers have an influence. Likewise in males, older sisters are for all intents and purposes invisible. What is pivotal is the number of older brothers. Some people have argued that the big brother effect could be social - that having lots of older brothers makes you more prone to sexual abuse as a child. But Blanchard dismisses this, pointing out that there is no evidence that such abuse is more common in boys with older brothers, or that there is a link between abuse and sexual orientation.

But how might having older brothers affect a boy's sexual orientation before birth? Blanchard reasoned that a fetus can't "know" how many brothers have been gestated in the womb before him; only a mother's body can. And the biological system most capable of keeping track is probably the mother's immune system. Breedlove suspects this is right: "That's what immune systems are for - to remember who they've bumped into."

A mother could somehow be taking note of something specifically male, such as a Y-linked cell surface protein, Blanchard speculates. It's known that fetal cells can leak into a mother's bloodstream during gestation as well as at the time of birth. Some evidence even suggests these foreign cells might lurk in her body for decades. Blanchard conjectures that it is through just such a leakage that a male fetus might prompt his mother's immune system to produce antibodies against the fetal cells. The more male offspring she carries, the stronger her immunity and the fiercer the attack.

A possible candidate is one of the male-specific minor histocompatibility antigens, known collectively as the H-Y antigen. They are present in cell membranes in male fetuses from very early on. This means that even if the baby doesn't make it to full term, in principle the mother's body could record its existence. It also means that from before the time when sexual differentiation starts to take place, around the eighth week of pregnancy, an immune reaction can be triggered in the mother, possibly disrupting the process and affecting sexuality in some way.

The H-Y antigen almost certainly plays some role in sexual differentiation. It is present only in males and has been highly conserved throughout evolution. Blanchard notes that the antigen is strongly represented on the surfaces of brain cells. "It's unlikely it's just there for the hell of it," he says. That also makes it easy to understand how maternal antibodies against the antigen could target the baby's brain, he says, and affect its organisation. What's more, studies in mice have shown that when females were actively immunised against fetal H-Y antigen, 90 per cent of their male offspring showed "very poor reproductive performance", despite being fertile.

No one knows why some mothers might have a strong immune reaction while others mount little or no response. But Blanchard believes having some kind of reaction is much more common than we realise. The strongest evidence of that is the fact that birthweight appears to be affected by older siblings - even in straight men. A baby's weight at birth tends to vary according to birth order in any case, with second-born children usually heavier than firstborn, for example. But boys who have a lot of older brothers tend to weigh less than would be expected for their place in the family - less, for instance, than boys who have the same number of older sisters.

This is true of both heterosexual and homosexual men with older brothers, although the gay men tend to weigh even less. In one study, Blanchard found that gay men with two or more older brothers weighed on average 170 grams less at birth than heterosexual men with older sisters but no older brothers. This is larger than the typical difference between male and female birthweights, around 100 to 150 grams. But gay men who were firstborn weigh the same as straight male firstborns.

Also intriguing is the fact that, despite their lower birthweights, later-born males tend to have larger than normal placentas, according to a study of over 7500 placentas by Michel Vernier at the University of California, Berkeley. Both Blanchard and Breedlove think the fetus may be trying to fend off the attack from the mother's immune system, and that the bigger placenta is compensating in some way. Whatever the reason, the findings on birthweight and placental size are important because they show that prior pregnancies with male fetuses really do have an influence on the development of subsequent fetuses. They also support the contention that the big brother effect is not the result of living with older brothers. "It's hard to see what this has to do with social dynamics," says Breedlove.

Blanchard admits that the H-Y antigen is only one possible target. The effect could be triggered by something else entirely - but he doesn't think so. Manning, whose work concentrates mainly on hormonal effects in utero, isn't yet persuaded by the immune explanation. "I would love to see some direct evidence of it," he says. But Blanchard argues that his findings aren't easily explained by the two main models of sexual differentiation, which deal in either genes or hormones. He accepts that androgens drive most of the sexual differentiation in the brain. "But my data suggest it might not be 100 per cent," he says.

Now Blanchard and a colleague, James Cantor, have done some mathematical gymnastics to show the importance of the fraternal birth order effect. In a paper out last year, they calculate that about one gay man in seven can attribute his sexual orientation to his older brothers (Archives of Sexual Behavior, vol 31, p 63). Boys with 2.5 older brothers are twice as likely to be gay as boys with no older brothers, and a boy with four older brothers is three times as likely to be gay. If Blanchard is right, then clearly, as average family size decreases, so will the incidence of male homosexuality. It also follows that historically there have been more gay men than there are today. But even today, says Breedlove, you'd expect Catholics and Mormons to have more homosexual sons. "Groups that encourage large families would have more sons inclined to be gay than others," he says.

But why should this be? Why should mothers systematically tamper with the sexuality of their later-born sons? There are no easy answers. Breedlove warns that homosexuality might not be the selective disadvantage that some people suppose, even when it comes to reproduction. Gay men do father children. Other scientists have suggested that homosexual males help promote their genes by being unusually supportive uncles and brothers - a claim that, however appealing, hasn't been carefully tested.

Manning dismisses this idea. "It's tempting to look at the frequency of male homosexuality and say maybe it's adaptive," he says. "But I actually don't think that homosexuality has got anything to do with adaptation." Manning's own research on hormonal effects in the womb suggests that homosexuality, for whatever reason, might result in part from higher than normal exposure to testosterone. Intriguingly, some of Breedlove's data suggests the same for men who have older brothers in general, regardless of their sexual orientation. High levels of testosterone during development have been associated with greater muscle strength, protection against heart disease and faster running speeds. "There could be a need for a male who has older brothers to be more competitive," says Manning. Perhaps in some cases that extra testosterone also affects the sexuality of some men, he speculates.

Though Blanchard is hesitant to wade into this discussion, he raises the possibility that there may be advantages to the male fetus that we simply haven't thought to look at. Homosexuality could be only half the picture. "And the other half might simply be survival of male fetuses."