At each marker, a pair of gay brothers was scored as concordant if they inherited identical markers from their mother or as discordant if they inherited different ones. Fifty percent of the markers were expected to be identical by chance. Corrections were also made for the possibility of the mother's having two copies of the same marker.
The results of this study were striking. Over most of the X chromosome the markers were randomly distributed between the gay brothers. But at the tip of the long arm of the X chromosome, in a region known as Xq28, there was a considerable excess of concordant brothers: 33 pairs shared the same marker, whereas only seven pairs did not. Although the sample size was not large, the result was statistically significant: the probability of such a skewed ratio occurring by chance alone is less than one in 200. In a control group of 314 randomly selected pairs of brothers, most of whom can be presumed to be heterosexual, Xq28 markers were randomly distributed.
The most straightforward interpretation of the finding is that chromosomal region Xq28 contains a gene that influences male sexual orientation. The study provides the strongest evidence to date that human sexuality is influenced by heredity because it directly examines the genetic information, the DNA. But as with all initial studies, there are some caveats.
First, the result needs to be replicated: several other claims of finding genes related to personality traits have proved controversial. Second, the gene itself has not yet been isolated. The study locates it within a region of the X chromosome that is about four million base pairs in length. This region represents less than 0.2 percent of the total human genome, but it is still large enough to contain several hundred genes. Finding the needle in this haystack will require either large numbers of families or more complete information about the DNA sequence to identify all possible coding regions. As it happens, Xq28 is extraordinarily rich in genetic loci and will probably be one of the first regions of the human genome to be sequenced in its entirety.
A third caveat is that researchers do not know quantitatively how important a role Xq28 plays in male sexual orientation. Within the population of gay brothers studied, seven of 40 brothers did not share markers. Assuming that 20 siblings should inherit identical markers by chance alone, 36 percent of the gay brothers show no link between homosexuality and Xq28. Perhaps these men inherited diÝerent genes or were influenced by nongenetic physiological factors or by the environment. Among all gay men -most of whom do not have gay brothers- the influence of Xq28 is even less clear. Also unknown is the role of Xq28, and other genetic loci, in female sexual orientation.
How might a genetic locus at Xq28 affect sexuality? One idea is that the hypothetical gene affects hormone synthesis or metabolism. A candidate for such a gene was the androgen receptor locus, which encodes a protein essential for masculinization of the human brain and is, moreover, located on the X chromosome. To test this idea, Jeremy Nathans, Jennifer P. Macke, Van L. King and Terry R. Brown of Johns Hopkins
University teamed up with Bailey of Northwestern and Hamer, Hu and Hu of the NIH. They compared the molecular structure of the androgen receptor gene in 197 homosexual men and 213 predominantly heterosexual men. But no signiÞcant variations in the protein coding sequences were found. Also, linkage studies showed no correlation between homosexuality in brothers and inheritance of the androgen receptor locus. Most significant of all, the locus turned out to be at Xq11, far from the Xq28 region. This study excludes the androgen receptor from playing a significant role in male sexual orientation.
A second idea is that the hypothetical gene acts indirectly, through personality or temperament, rather than directly on sexual-object choice. For example, people who are genetically selfreliant might be more likely to acknowledge and act on same-sex feelings than are people who are dependent on the approval of others.
Finally, the intriguing possibility arises that the Xq28 gene product bears directly on the development of sexually dimorphic brain regions such as INAH3. At the simplest level, such an agent could act autonomously, perhaps in the womb, by stimulating the survival of specific neurons in preheterosexual males or by promoting their death in females and prehomosexual men. In a more complex model, the gene product could change the sensitivity of a neuronal circuit in the hypothalamus to stimulation by environmental cues, perhaps in the first few years of life. Here the genes serve to predispose rather than to predetermine. Whether this fanciful notion contains a grain of truth remains to be seen. It is in fact experimentally testable, using current tools of molecular genetics and neurobiology.
Our research has attracted an extraordinary degree of public attention, not so much because of any conceptual breakthrough -the idea that genes and the brain are involved in human behavior is hardly new- but because it touches on a deep conflict in contemporary American society. We believe scientific research can help dispel some of the myths about homosexuality that in the past have clouded the image of lesbians and gay men. We also recognize, however, that increasing knowledge of biology may eventually bring with it the power to infringe on the natural rights of individuals and to impoverish the world of its human diversity. It is important that our society expand discussions of how new scientific information should be used to benefit the human race in its entirety.
SIMON LEVAY and DEAN H. HAMER investigate the biological roots of homosexuality. LeVay earned a doctorate in neuroanatomy at the University of Gšttingen in Germany. In 1971 he went to Harvard University to work with David Hubel and Torsten Wiesel on the brain's visual system. He moved to the Salk Institute for Biological Studies in San Diego in 1984 to head the vision laboratory. In 1992 he left Salk to found the Institute of Gay and Lesbian Education. Hamer received his Ph.D. in biological chemistry from Harvard in 1977. For the past 17 years, he has been at the National Institutes of Health, where he is now chief of the section on gene structure and regulation at the National Cancer Institute. He studies the role of genes both in sexual orientation and in complex medical conditions, including progression of HIV and Kaposi's sarcoma.