The Scientific Journals

by : Simon LeVay and Dean H. Hamer

PINPOINTING GENES shared by gay brothers (darker brown) first involved taking DNA from subjects. Several billion copies of speciÞc regions of the X chromosome were then made using the polymerase chain reaction, and the different fragments were separated by gel electrophoresis. Gay brothers shared a marker, in this hypothetical example CA11, in the Xq28 region at rates far greater than predicted by chance.

Why are most gay male relatives of gay men on the mother's side of the family? One possibility -that the subjects somehow knew more about their maternal relatives- seems unlikely because opposite-sex
gay relatives of gay males and lesbians were equally distributed between both sides of the family. Another explanation is that homosexuality, while being transmitted by both parents, is expressed only in one sex in this case, males. When expressed, the trait reduces the reproductive rate and must therefore be disproportionately passed on by the mother. Such an effect may partially account for the concentration of gay men's gay relatives on the maternal side of the family. But proof of this hypothesis will require Þnding an appropriate gene on an autosomal chromosome, which is inherited from either parent.

A third possibility is X chromosome linkage. A man has two sex chromosomes: a Y, inherited from his father, and an X, cut and pasted from the two X chromosomes carried by his mother. Therefore, any trait that is influenced by a gene on the X chromosome will tend to be inherited through the mother's side and will be preferentially observed in brothers, maternal uncles and maternal cousins, which is exactly the observed pattern.

To test this hypothesis, Hamer and his colleagues embarked on a linkage study of the X chromosome in gay men. Linkage analysis is based on two principles of genetics. If a trait is genetically influenced, then relatives who share the trait will share the gene more often than is expected by chance, this is true even if the gene plays only a small part.  Also, genes that are close together on a chromosome are almost always inherited together. Therefore, if there is a gene that influences sexual orientation, it should be 'linked' to a nearby DNA marker that tends to travel along with it in families. For traits affected by only one gene, linkage can precisely locate the gene on a chromosome. But for complex traits such as sexual orientation, linkage also helps to determine whether a genetic component really exists.

To initiate a linkage analysis of male sexual orientation, the first requirement was to find informative markers, segments of DNA that flag locations on a chromosome. Fortunately, the Human Genome Project has already generated a large catalogue of markers spanning all of the X chromosomes. The most useful ones are short, repeated DNA sequences that have slightly different lengths in different persons. To detect the markers, the researchers used the polymerase chain reaction to make several billion copies of specific regions of the chromosome and then separated the different fragments by the method of gel electrophoresis.

The second step in the linkage analysis was to locate suitable families. When scientists study simple traits such as color blindness or sickle cell anemia -which involve a single gene- they tend  to analyze large, multigenerational families in which each member clearly either has or does not have the trait. Such an approach was unsuited for studying sexual orientation. First, identifying someone as not homosexual is tricky; the person may be concealing his or her true orientation or may not be aware of it. Because homosexuality was even more stigmatized in the past, multigenerational families are especially problematic in this regard. Moreover, genetic modeling shows that for traits that involve several different genes expressed at varying levels, studying large families can actually decrease the chances of finding a linked gene: too many exceptions are included.

For these reasons, Hamer and his coworkers decided to focus on nuclear families with two gay sons. One advantage of this approach is that individuals who say they are homosexual are unlikely to be mistaken.  Furthermore, the approach can detect a single linked gene even if other genes or noninherited factors are required for its expression. For instance, suppose that being gay requires an X chromosome gene together with another gene on an autosome, plus some set of environmental circumstances. Studying gay brothers would give a clear-cut result because both would have the X chromosome gene. In contrast, heterosexual brothers of gay men would sometimes share the X chromosome gene and sometimes not, leading to confusing results.

Genetic analysts now believe that studying siblings is the key to traits that are aÝected by many elements. Because Hamer and his colleagues were most interested in Þnding a gene that expresses itself only in men but is transmitted through women, they restricted their search to families with gay men but no gay father-gay son  pairs.

Forty such families were recruited. DNA samples were prepared from the gay brothers and, where possible, from their mothers or sisters. The samples were typed for 22 markers that span the X chromosome from the tip of the short arm to the end of the long arm.

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