Genetic Basis of Male Homosexuality: Xq28 Research Proposal

Introduction

This study aims to resolve conflicting evidence regarding whether male homosexuality is correlated with similarities in the genetic markers from region Xq28 of the X chromosome. While many studies suggest a strong genetic and biological basis to sexual orientation, there is little persuasive, compelling, causal evidence to support this claim. Specifically, attempts to find a genetic correlate to homosexuality have proven elusive, and several attempts to replicate the finding of similarities in region Xq28 of the X chromosome among male homosexuals have proven problematic. This study will attempt to correct the methodological problems that may have undermined earlier studies, including the use of self-selecting samples, small sample sizes, and inconsistent definitions of homosexuality.

The ideas and definitions surrounding human sexuality and sexual orientation can be more fluid and complex than they appear on the surface. To the outside world, primary sexual characteristics (such as a penis or vagina) determine whether an individual is male or female. Secondary sexual characteristics, such as breasts and body hair, further confirm sexual identity. We commonly speak of someone with XY sex chromosomes as being chromosomally male, although "males" may actually take other chromosomal forms. Gender identity is also an important component of sexual orientation. LeVay writes, "Most men have a deep inner conviction that they are male, and most women that they are female," thus forming their gender identity (p. 3).

However, many factors demonstrate that sexual orientation can be fluid. Transsexuals exhibit a confused sexual identity, suggesting that gender identity can exist in opposition to biological sexual characteristics. Sometimes chromosomal sexual identity can be at odds with external sexual characteristics, as in an individual who appears male externally but does not carry the usual XY chromosome pattern. In addition, many cognitive characteristics and behaviors that are commonly differentiated between the sexes — such as aggressiveness and parental behavior — can be observed in either males or females (LeVay, 1994).

Over the past century, there has been considerable debate about whether sexual orientation is a biological trait that is genetically determined, or whether it results from factors such as upbringing or environment. Religious groups tend to favor the view that sexual orientation is caused by environmental factors, while a growing body of recent studies supports the idea that it is genetically determined. While the majority of research on sexual orientation has focused on this nature versus nurture controversy, other theories have also been proposed, including hormonal influences, parental influences, and viral or bacterial factors.

Literature Review

In the general population, the rate of homosexual orientation is estimated at between 2% and 10%. This variance is due to the specific criteria used to define homosexuality. Commonly, 4–5% of males are thought to be homosexual, while 2–4% of females are homosexual (LeVay, 1994).

While male homosexuality is often the focus of familial studies, both male and female homosexuality have been shown to be familial in nature. Specifically, homosexual females have more homosexual brothers than heterosexual females do. Similarly, homosexual males have more homosexual siblings than heterosexual males (Bailey & Bell, 1993; Bailey & Benishay, 1993).

Studies of monozygotic (identical) twins reveal a strong genetic component to human sexual orientation. A study of 38 pairs of monozygotic twins (34 male and 4 female pairs) found that the twins had a concordance rate of 65.8% for homosexual orientation, while 23 pairs of dizygotic twins had a concordance rate of 30.4% (Whitam, Diamond, & Martin, 1993). Bailey and Pillard (1991) reported similar concordance rates: 52% of monozygotic co-twins, 22% of dizygotic co-twins, 11% of adopted brothers, and 9.2% of non-twin biological siblings showed a homosexual orientation. Interestingly, childhood gender nonconformity did not appear to be linked to homosexuality in adulthood (Bailey & Pillard, 1991).

A 2000 study of monozygotic twins found a 32% concordance rate for non-heterosexual orientation in monozygotic twins, compared to 13% for dizygotic twins of the same sex. That study measured 3,000 people drawn from a random national sample in the United States (Kendler et al., 2000).

Studies of the families of male homosexuals further suggest a genetic basis for sexual orientation. In Hamer et al.'s 1993 study of 114 families of homosexual men, increased rates of same-sex orientation were linked to both the male cousins and maternal uncles of homosexual men, but not to fathers or paternal relatives. In a study of 40 families with two gay brothers and no indication of non-maternal transmission, a correlation was found between the inheritance of polymorphic markers on the X chromosome and homosexual orientation, occurring in close to 64% of sibling pairs tested (Hamer et al., 1993).

Hamer hypothesized that the genetic locus of sexual orientation may reside on the X chromosome within these families. He discovered significant similarities in the genetic markers from region Xq28 of the X chromosome in 33 of the 40 families studied — specifically, 82% of sibling pairs shared DNA in this region. Given that males have one X chromosome, the probability that both brothers would inherit the same segment of the X chromosome by chance is 50%, making the 82% figure statistically significant (Hamer et al., 1993). Further research using a smaller sample found that 67% of sibling pairs shared DNA from the Xq28 region among homosexual brothers (Hu et al., 1995).

Interestingly, female homosexuals have not been shown to exhibit a similar pattern. Later studies of the Xq28 region indicated that this chromosomal similarity was specific to male homosexuals and was not observed among female homosexuals (Hu et al., 1995).

Other lines of evidence fail to support a simple genetic link to homosexuality. Biological and adopted siblings tend to have similar rates of male homosexuality. Moreover, many twin and family studies have suffered from methodological uncertainties tied to small sample sizes or potential errors in the reporting of homosexual behavior. Specifically, Hamer's identification of the Xq28 region may have resulted from a Type I (false positive) error. As such, while there is a significant body of evidence in favor of a genetic basis for homosexuality, this basis has not been conclusively established (Rice et al., 1999).

Importantly, a 1999 study of 52 gay male sibling pairs failed to link male homosexuality to the Xq28 position. Specifically, four markers at Xq28 — DXS1113, BGN, Factor 8, and DXS1108 — did not show increased similarity between homosexual brothers (Rice et al., 1999).

A number of studies have linked physical characteristics such as the number of fingertip ridges and finger lengths to homosexuality, suggesting that the occurrence of homosexuality may be connected to developmental processes before or during pregnancy, or even at conception. Androgen levels influence finger length in the womb, making finger length an indirect measure of fetal androgen exposure (Williams et al., 2000).

Sexual orientation has also been linked to hormonal changes during pregnancy. The probability that a male child will have a homosexual orientation in adulthood increases by nearly 33% for each older brother he has, while older sisters have no effect on the sexual orientation of a younger male sibling. An immune response within the mother may account for this effect: specifically, the mother may produce anti-H-Y antigens during pregnancy that affect aspects of sexual differentiation occurring during development. Furthermore, homosexual males with older brothers weigh less at birth than heterosexual males with older brothers, who in turn weigh less than heterosexual males with older sisters. This pattern suggests that when maternal production of anti-H-Y antigens is small, birth weights are only slightly reduced, while when production is large, birth weights are markedly reduced (Blanchard, 2001).

Anatomical differences in the brains of heterosexuals and homosexuals have also been reported. The third interstitial nucleus of the anterior hypothalamus (INAH1) has been reported as smaller in gay males than in heterosexual males, with higher cell density in gay males (Byne et al., 2001). Swaab and Hofman (1990) also reported that the suprachiasmatic nucleus (SCN) is larger in gay males than in heterosexual males, although the SCN is not known to play a role in sexual behavior.

Environmental factors are also likely to play an important role in the development of sexual orientation. In studies of monozygotic twins, the highest concordance rates for homosexuality approach 50%, indicating a meaningful environmental component. Further, the rate of homosexuality in adopted brothers of homosexual or bisexual twins has been estimated at 11% — significantly above the rate in the general population — suggesting a role for environment in the development of homosexual orientation (Bailey & Pillard, 1991).

A simple genetic explanation of homosexuality is also difficult to envision given evolutionary logic: the selective pressure against genes that reduce reproduction would be strong, since homosexuals are less likely to reproduce than heterosexuals. This would argue against a straightforward Mendelian gene for homosexuality (Rice et al., 1999). Despite this, several theories have been proposed to account for the persistence of such genes, including the possibility that they promote the reproductive success of the siblings of gay individuals (Bailey, 2003).

There are often significant methodological problems that undermine existing evidence for a genetic basis of sexual orientation. In samples where participants are recruited through homophile publications, concordance rates for sexual orientation among monozygotic and dizygotic twins are higher than when samples are drawn from the general population. This can be explained by the fact that individuals who read such publications and volunteer for homosexuality research may be biased. Nevertheless, studies based on random population samples also show a significant familial link for sexual orientation. As Kendler et al. (2000) note, "sexual orientation was substantially influenced by genetic factors, but family environment may also play a role" (p. 1846).

The measurement of sexual orientation has also been problematic. Sexual orientation can be assessed using a number of different scales. In some cases, homosexuality is defined by subjects answering yes to questions about same-sex thoughts; in others, it is defined by self-identification or life experiences. Rates of familial homosexuality can differ substantially depending on which criteria are used (Bailey & Benishay, 1993).

Part of the difficulty in defining sexual orientation stems from the distribution of sexuality itself. Treating homosexual and bisexual individuals as a single group contrasted with heterosexuals implies that sexuality is easily categorized. In contrast, many anecdotal and empirical reports suggest that sexual orientation occurs along a wide spectrum, making it difficult to define homosexuality or heterosexuality at a single point on the continuum. Additionally, homosexuality in men and women may reflect different traits, and the genetic influences on male homosexuality may differ from those on female homosexuality (Bailey et al., 1993).

Future research should attempt to identify other regions of DNA that may be linked to sexual orientation and to locate specific genes within the Xq28 region. Given the recent failure of Rice et al. (1999) to replicate Hamer's Xq28 finding, research investigating the reasons for this inconsistency is crucial. It is notable that both Rice et al. (1999) and Hamer et al. (1993) used homophile publications to recruit subjects and yet obtained different results, suggesting that the replication failure may relate to small sample sizes rather than sampling method alone.

In summary, current research suggests that sexual orientation is shaped early in life and that genetic factors play an important role. At an early age, biological, psychological, and social factors interact to shape an individual's sexual orientation. However, a great deal of work remains to determine the precise nature of both genetic and environmental contributions to sexual orientation.