Whats the Evidence

The Hunt for a Gay Gene

In the summer of 1993, Twilight of the Golds, a play by 26-year-old Jonathan Tolins, took San Francisco, where it premiered, by storm. The play depicts a middle-aged Jewish couple painfully struggling to deal with the possibility that their daughter could bear a son with a gene that will make him gay. Having made an uneasy peace with the homosexuality of their only son, the couple is devastated by this threat to their hope for a grandson who will normalize the family. The play, which landed Tolins on "Nightline" and in the pages of Time, was prescient. While Tolins was writing it in California in 1992, a molecular biologist in Maryland was trying to see whether the artistic premise was scientifically valid.

During most of his distinguished career, Dean Hamer, the scientist who took on the question, has worked at the National Cancer Institute in Bethesda, Maryland. For almost 20 years he studied the ways in which genes are expressed, what turns them on and what turns them off. Even by scientific standards, his work was esoteric. He spent a decade investigating the regulation of a single gene that makes a protein which binds to toxic heavy metals such as cadmium when they get in cells. By studying what makes the protein abundant when the toxins are present, but barely detectable when they are not, he was exploring the much deeper question of how genes are regulated.

In 1991, at the peak of his scientific career, Hamer found himself at a crossroads. Despite the importance of his research on gene expression, he yearned for new projects involving scientific questions that had a more direct link to the human condition. One day while attending a meeting in Oxford, England, he picked up a copy of Charles Darwin's book, Descent of Man, and Selection in Relation to Sex. Hamer remembers that in the same book shop he also purchased a copy of Not in Our Genes, written by Richard Lewontin, in which the Harvard biologist argued that scientists do not have the tools to dissect the genetic contribution to complex human behaviors, such as homosexuality. Reading on the long flight home, Hamer was fascinated to find that Darwin had speculated at length about the possibility that human behaviors were highly influenced by hereditary factors (Darwin did not use the word gene, which was coined by the English biologist, Bateson, about 1906). Hamer was, on the other hand, unimpressed with Lewontin's book, which he saw as a political tract rather than a scientific argument. Like everyone else working in the biomedical sciences in the early 1990s, Dr. Hamer felt the pull to respond to the dramatic challenges posed by the HIV virus. His thoughts turned to the possible role of genes in homosexuality.

Over the past half century, a few scientists had studied the genetic contribution to homosexuality in twin, adoption, and family studies. Early research had shown that among identical twin pairs in which one twin was gay, the co-twin was much more likely to be gay than was the case among fraternal twins. Other studies found that the gender orientation of boys adopted away from their biological parents at birth was statistically more likely to match the gender orientation of their biological brothers than their adoptive brothers. The brothers of gay men and the sisters of gay women were also more likely than average to be themselves gay. Such findings cannot completely discount the role of subtle environmental factors, but they certainly suggest that genetic factors are at work.

When Hamer started to look into the topic, he may have been surprised to learn that even in the AIDS era there were only a handful of recent studies trying to assess whether there was a genetic basis for homosexuality. Important among them was the work of J. Michael Bailey, a young professor of psychology at Northwestern University who had studied gay twins. Among 110 gay sets of twins, Bailey found that of 56 pairs of identical twins, 52% of the co-twins were gay, whereas among fraternal twins, only 22% of the co-twins were gay. He later also showed that the brothers of gay/gay twins were more likely to be gay than were the brothers of gay/straight twins, another suggestion that genetic factors were at work. These data were generated by questionnaires; Bailey had asked gay men to report on the sexual orientation of their brothers, a methodological approach that cast doubt on the results. Hamer knew that molecular biology had tools that were much more likely than questionnaires to demonstrate a genetic contribution to homosexuality. He set to work to design a study that would resolve whether there was a "gay gene," and which, if there was one, would also show about where it was located.

In the fall of 1991, The National Institutes of Health approved a proposal and provided $75,000 for Hamer's lab (in which about 10 people worked) to use DNA linkage technology to hunt for a gene that influenced gender orientation. After months of planning and several key conversations with leading gene hunters, the team's final plan was to recruit two groups of gay men: (1) a randomly selected number who would be asked detailed questions about their family history to ascertain whether there were more than the expected number of gays among their male relatives, and (2) a carefully selected set of pairs of gay brothers whose DNA would be studied to see whether they were much more likely than not to share certain stretches of DNA, a finding that could indicate that a particular gene which they had in common had shaped their sexual orientation. Such a finding would be reinforced if later it could be shown that the stretch of DNA they shared was not present in other brothers who were not gay.

While Hamer's scientific team, which included Angela Pattatucci, a feminist interested in whether there was a genetic component to lesbianism, was conducting its research, other scientists were approaching the biology of homosexuality from a vastly different angle. On August 30,1992, Simon LeVay, a neuroscientist at the Salk Institute in San Diego, published a paper in Science claiming that among homosexual men, the shape and size of a region of the brain known as the anterior hypothalamus is indistinguishable from the shape and size in women, and distinctly different from the comparable region in heterosexual men. A year earlier, two other neuroscientists had reported that a different brain region, the suprachias-matic nucleus, was larger in homosexual than in heterosexual men. Intriguing as they are, however, these anatomical differences, even if they stand up to repeated inquiry, do not really offer any insight into a biological cause for homosexuality. They could, for example, reflect a biological consequence of homosexuality, rather than indicate a cause.

All the anatomical studies used tissue taken at autopsy. LeVay was building on an earlier research that had found two regions of the anterior hypothalamus which were twice as large in heterosexual men as in women. He looked at the same regions in 19 homosexual men who had died of

AIDS. This raises the question of whether the size of the region was influenced by having or being treated for the complications of AIDS, an unlikely, but possible, explanation. Even if the particular area of the brain is comparatively larger in healthy young homosexuals (a question that could only be studied in individuals who died young), that would not explain sexual orientation. The anterior hypothalamus could, for example, be enlarged due to the action of one or several genes, which also in completely unknown ways influence gender orientation. That is, the enlargement of a particular region may merely be a secondary effect. No matter how enticing the anatomy, such studies, entangled in the argument over cause or effect, would never fully resolve the issues. The research could realistically be done on only a few people, it was difficult to find good control groups, the methods used to measure brain region size were controversial, and even impressive differences would not indicate much about fundamental cause. Thus, Hamer's work unfolded as scientific debate was reaching a crescendo. His findings reverberated far outside the scientific world.

By placing advertisements in gay newspapers, Hamer and his team recruited 76 gay men who agreed to enter the study. The scientists compiled detailed pedigrees, carefully questioning each subject about the gender orientation of his relatives. The responses indicated that 13.5% of the gay men's brothers were homosexual, a much higher figure than the background rate of 2-3% male homosexuality currently assumed for the general population. Although this 2-3% figure is lower than the often quoted figure of 10%, it may be more accurate because the higher prevalence figure is based on studies that are old and methodologically flawed. For example, at least one early study which concluded that 10% of men had homosexual encounters in adulthood was based partly on interviews with prisoners. Hamer's assumption of a 2-3% general prevalence is in line with other recent studies.

When Hamer studied the extended families of the gay men they had recruited, he and his team found that there were significantly more gay relatives in the maternal side than in the paternal line. This was especially true for maternal uncles and for cousins who were the sons of maternal aunts. To a geneticist, such a finding sends a clear signal—there may be a gene on the X chromosome that influences sexual orientation.

To track down the hypothetical gene, the team selected 40 pairs of homosexual brothers. They took DNA from each and performed a "linkage analysis," a study that asks whether the presence of a particular condition or trait (in this case gender orientation) is strongly associated with a specific tiny bit of DNA (a marker) in each family member who has that characteristic (and absent in those who do not). Because during the formation of egg and sperm long stretches of DNA are transmitted in a block, the association of a DNA marker with a physical trait suggests that a causative gene is located on the same chromosome as, and in the vicinity of, the DNA marker. Brothers have a 50% chance of having inherited the same X chromosome from their mother. If gay brothers are gay because of a gene on the X chromosome, they should share the chromosomal region on which that gene resides much more than the random expectation of 50%. Molecular biologists have sets of DNA probes for determining which of two possible chromosomes a person inherited and whether a particular stretch thereof is present.

Using 22 sets of probes that act as markers on it, Hamer scanned the X chromosome for evidence of linkage. The team found that of the 40 pairs of gay brothers, 33 shared the same stretch of DNA in a region defined by two of the probes that map near the tip of the long arm of the X chromosome. Statistical analysis indicated that the odds of this occurring by chance were about 10,000 to 1. Put another way, if you decided to flip a nickel 40 times with the goal of getting heads 33 times, you could expect to achieve this result on average only about once in 10,000 series. The results were impressive. Nevertheless, it is was clear that the story must be complicated. For starters, 7 pairs of the gay brothers did not share a common DNA marker in the region. Furthermore, Hamer had also found other families with pedigrees that suggested a role for genetic factors on some other chromosome.

Hamer and his colleagues published their findings in Science. The paper appeared at the height of the public debate over whether the Department of Defense should amend its policy forbidding openly gay persons from being on active duty in the armed forces, a coincidence that helped generate interest in the study far beyond the academic community. Like most scientific work, the research raised a lot more questions than it answered. If there is a gay gene, how does the protein for which it codes drive this outcome? How does it differ from its corresponding version in heterosexual men? Does the gene have similar effects in women?

The answer to the last question came quickly. The Hamer team re cruited two new groups of families, one group with two gay brothers and another with two lesbian sisters, both of which also had heterosexual siblings. By late 1995, they had found that of 32 new pairs of gay brothers, 22 shared that same region at the tip of the long arm of X, whereas the 36 pairs of lesbian sisters did not disproportionately share the same region. Thus, whatever the putative gene is, it does not appear to affect sexual orientation in women. In this study the evidence for an influential X-linked gene was again present, but it was not nearly as strong as in the first study.

In April of 1999, a third paper regarding the possibility that a gene on the X chromosome predisposes to male homosexuality was published in Science. The scientific team, led by Dr. George Rice of the University of Western Ontario, reported that among 48 families with 2 gay brothers they found no evidence at all to support the existence of a "gay" gene on the X chromosome. The report set off an immediate scientific debate. Dr. Hamer argued that the failure of Rice and his colleagues to find an association between homosexuality and the long arm of the X chromosome was due to the manner in which they had selected the families for inclusion in the project. Dr. Rice and Dr. Neil Risch, the mathematical geneticist with whom he worked, disagreed, arguing that the selection of the families who ultimately participated (from a larger total) was completely random. At the least, the study from Canada suggests that one or more still unknown genetic factors contribute to male homosexuality, as well as an as-yet-unidentified gene lying among 4,000,000 base pairs of DNA on the long arm of X.

The Societal Response

The report of evidence for a gene that predisposes to male homosexuality generated and continues to generate much interest and debate. It is probably the most controversial of the hundreds of associations between human conditions and DNA markers published thus far. For example, the gay community split sharply over the news. Some saw it as proof that homosexual orientation is due to innate differences and thus normal. They argued that the Hamer paper should put to rest all discussion that homosexuality is deviant behavior that arises out of sordid childhood experiences. A T-shirt slogan, "Xq28—Thanks for the genes, Mom," captures the argument. Some gay men even argued that Hamer's work was important evidence in the battle to secure civil rights protection for gay persons. Others worried that society would label them as having a "genetic disease."

When he began the research, Hamer surely never anticipated that it would lead him to a courtroom in Colorado. On November 3, 1992, Colorado voters passed a state constitutional amendment (Amendment 2) that prohibited the state from enacting laws to give homosexuals a special means to secure their civil rights. Those who opposed the amendment, including gay activists, sued, arguing that it was unconstitutional. They reasoned that evidence that homosexuality was a genetically determined (innate) drive over which a person has no control made it arguably analogous to skin color, the condition that has been the subject of most civil rights laws. If a person cannot control his or her homosexuality and if there is an obvious pattern of discrimination against homosexuals in housing, hiring, and other matters, then, they argued, special laws should be passed to provide redress.

On October 16,1993, shortly after the publication of the article in Science, Hamer appeared in a Denver courtroom as an expert witness for those challenging the amendment. He testified that the research suggested that there was an exceedingly strong likelihood that some men were genetically influenced to be gay. His testimony may have helped the gay cause in Colorado. A few weeks later, in an opinion declaring Amendment 2 unconstitutional, Judge H. Jeffrey Bayless became the first judge in the United States to cite scientific evidence in support of the proposition that some men are innately gay. Today, as the confidence with which Hamer could make such assertions has faded, the court's reliance on such limited scientific evidence seems at best naive.

The argument over whether homosexuality is an inborn or acquired characteristic is hardly new. In early 20th century Germany, hoping that it would defuse discrimination and promote tolerance, homosexuals argued that their condition was innate. Their arguments were of course futile. The Nazis agreed that homosexuality was congenital, but also concluded that it was an incurable defect that must be eliminated from the race.

Some gay men have asked why Hamer's work was being undertaken (with taxpayers' dollars) at all. If we are seeking to build and maintain a society that tolerates gays and lesbians, what reason is there for hunting for a genetic basis for their homosexuality? As one writer put it, why don't the scientists hunt instead for a gene that causes homophobia? The implica tions of this challenge are obvious, and they recall the menacing issues in Twilight of the Golds. If we locate gene variations that predispose some young men to become homosexual, we will be able to test for it. Women who are the sisters of gay men will be able to ask whether they carry a gene that would, if passed on, predispose their sons to being gay. If a woman is found to be a carrier, she will be able, if she so wishes (unless society forbids it), to undergo prenatal diagnosis to determine whether she is carrying a male fetus with the predisposing allele.

Would some women abort a pregnancy because the fetus has a gay gene? Almost certainly. Shortly after Hamer's initial report about a gay gene on the X chromosome became public, a woman called me to ask if she could be tested to see if she "carried" the gene. Two years earlier the woman had cared for a much loved older brother as he was dying of AIDS. After hearing about Hamer's research, she had looked into her family history and learned that she had an uncle who had never openly admitted his homosexuality. Now in her early 30s and about to marry, but still grieving the loss of her brother, the woman told me frankly that if there were a carrier test she would take it, and that if she turned out to be a carrier, she would seek prenatal diagnosis. If she learned that she was carrying a male fetus with the gene, she said she would have an abortion. Why? She said that she could not bear the thought that someday she might have to watch a son die of AIDS as she had a brother.

Genetic Testing Issues

Should a woman have the right to find out whether her fetus carries a gay gene? Should a physician help her to find out? Those were the two questions that Mike Wallace really wanted me to answer when he and his crew from "60 Minutes" arrived in my office a few months after the news about a gay gene broke. When the staff at "60 Minutes" set up the interview, I had been told that it would be a wide-ranging interview about advances in human genetics. So it seemed at first. But after a first hour of "softball" questions, during which Wallace seemed to be charming me (of course not a second of this footage ever made it to television), the questions took on a confrontational tone.

Wallace knew that I supported a woman's right to find out information about her pregnancy and to terminate her pregnancy for whatever reason she wanted, even if it was morally repugnant to me. The first couple of times that he asked me, "Now, doctor, would you help a woman find out if her fetus was going to grow up gay, knowing that she might abort the pregnancy?", I dodged the question. After all, it was not and is not possible to provide such information, and it may never be. Genetics deals with statistical likelihood. I knew that further research in followup to Hamer's would most likely show that there were many men who had the "gay" allele at the tip of the X chromosome, but who were heterosexuals. Based on years of experience with other predisposing genes, the most likely possibility was that being born with this particular genetic variant did not program one to be gay. It merely increased the odds that this outcome would occur. Given that Hamer had sought out families with many gay members, it is almost certain that larger, population-based studies would show that if there is a predisposing allele on the X chromosome, it explains a much lower percentage of male homosexuality than originally seemed to be the case. Other unknown factors must play a major role in determining whether a boy with a predisposing gene grows up to be gay.

Of course, Wallace did not want to hear complex arguments about gene penetrance and the relative contribution of nature and nurture. When I said there was no such test, he made the issue unavoidable. "Doctor, suppose there was a test for a gene that research had showed absolutely that if a boy is born with it he will grow up to be gay. If you were a doctor who did amniocentesis (the procedure by which physicians use a large needle to take a sample of amniotic fluid from pregnant women, fluid which has fetal cells that can be tested) and a woman came to you asking that you arrange for DNA testing for the gay gene, would you help her?"

A moment of truth had arrived. In an instant, many thoughts careened through my brain. I thought about a gay friend. I thought about the gay community. I thought about discrimination. I thought about my views on abortion. I thought about pregnant women. I thought of how my answer might seem, especially after editing, and juxtaposed to the views of others. I realized that Wallace might be setting me up as the bad guy, the doctor who would conspire with a woman with irrational prejudices to provide information that could lead to the abortion of a healthy fetus. I had only two choices. I could dodge the question and then terminate the interview (with cameras rolling) or I could answer. "Yes," I said, and quickly continued. "Each year in this country there are about 1,000,000

abortions. In 99% of the cases, women are ending their pregnancies because they do not want to have a baby, almost certainly a baby that would be healthy. They have a legal right to do that. I think that if they have a legal right to end a pregnancy for whatever reason they want, it has to include reasons that I might find repugnant."

Prenatal testing already permits a woman to find out a few important facts about her fetus, such as whether or not he or she has Down syndrome. In the not-distant future, women will be able to find out a great deal more information about their future children. Does the fetus have a gene that predisposes to Alzheimer disease? To breast cancer? Is he or she likely to be obese? Is he or she likely to suffer from serious depression? The list of potential tests is staggering, but most of them will deal with possibilities rather than with certainties. As bioethicist Eric Juengst has put it, the genetic counselor of the future will be more like a weather forecaster than a soothsayer.

Because its use is so closely linked to abortion, our society is already bitterly split over whether prenatal testing is morally permissible. Who can draw the line that separates prenatal tests for conditions that are medically "serious" (and for which testing is defensible) and those which are not (and for which testing may be ever so much more difficult to defend)? It seems to me that more is lost than gained by making physicians moral gatekeepers of these tests. I think that a woman should be able to ask any question she wants about her fetus. In the few minutes that physicians have to counsel about such tests, it is impossible to discern what motivates the woman, nor should it necessarily matter. If her wishes are driven by erroneous understanding of medical risks, that should be addressed, but to educate, not to reshape behavior. There can be little doubt that someday prenatal tests will be available for genetic traits that predispose to conditions that few of us think should drive a decision to end a pregnancy. One study found that women would be about as interested in testing a fetus for the risk of severe obesity as they would for cystic fibrosis! The right course, I think, is not to deny access to testing, but to make sure that women who seek prenatal tests clearly understand the implications of the results before they undergo testing.

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