I was born this way

Abstract

Homosexuality has been a constant throughout human evolution and civilization, and yet, science has been slow to look at the causes of sexual preferences.

Her breast is fit for pearls,

But I was not a “Diver” –

Her brow is fit for thrones

But I have not a crest.

Her heart is fit for home‐

I ‐ a Sparrow ‐ build there

Sweet of twigs and twine

My perennial nest.

Emily Dickinson

Open Me Carefully: Emily Dickinson’s Intimate Letters to Susan Huntington Dickinson

The study of human sexuality is undoubtedly one of the most interesting and complex areas of human biology, owing to the evident social and political implications. Within the wide variety of love relationships that our species displays, homosexuality is by no means an anomaly but rather a constant. It has been present and manifested in all eras and across societies of human civilization (Fig 1). No surprise then that much has been written and debated on the origin of homosexuality: Are you born gay? Or do you become gay under the influence of social and cultural factors? More surprisingly, though, is that science has been rather reluctant to explore these intriguing questions.

Figure 1. A classic view of homosexual love.

An eromenos, an adolescent boy, with his erastes, the older partner, portraited in a love scene from the frescoes on the north wall of the Tomb of the Diver in Paestum, Italy. The frescoes are painted on limestone slabs and are dated about 475–470 BC. The making and decoration of the tomb is attributed to the Greek settlement present in this part of ancient southern Italy and was likely inspired by the figurative style common in the contiguous Etruscan civilization. valtercirillo / Pixabay.

“The nature versus nurture argument about the origins of sexual orientation has been an integral part of the gay rights debate over the years, and it is clear why. Americans who believe gays and lesbians are born with their sexual orientation are much more supportive of gay rights than are those who say orientation is due to upbringing and environment”, wrote Lydia Saad, commenting the results of a 2018 Gallup poll (https://news.gallup.com/poll/234941/say‐nature‐nurture‐explains‐sexual‐orientation.aspx). It showed that the number of Americans who believe nature plays at least some role in determining sexual orientation has grown steadily since 1979 and reached 60% lately.

Within the wide variety of love relationships that our species displays, homosexuality is by no means an anomaly but rather a constant.

Unveling the biological grounds of homosexuality, however, has proved a much more challenging task, than gaining society’s acceptance. Nonetheless, research has steadily advanced since the first genetic studies in the 1980s to gain an understanding how sexuality is shaped and if personal choices matter at all. Among the many mechanisms that have been proposed to explain same‐sex attraction, exposure to “atypical endocrine conditions” during prenatal development, is probably the one that has the widest consensus. Since the development of sexually dimorphic brain regions occur under the direct influence of androgens, “homosexual men’s fetal brains were androgenized less than heterosexual men’s; homosexual women’s were androgenized more than heterosexual women’s”, summarized Bailey et al (2016) the so‐called “organizational hypothesis” of sexual orientation.

Unveiling the biological grounds of homosexuality, however, has proved a much more challenging task, than gaining society’s acceptance.

Hormonal dysbalance

The evidence comes primarily from experiments on laboratory mammals and clinical studies of human pathologies caused by alteration of the endocrine environment during embryonic development. In the case of congenital adrenal hyperplasia, for example, girls are exposed in utero to elevated levels of testosterone, which leads to “masculinization” of their genitals and frequent—but not always—homosexual orientation (Bailey et al, 2016). Other indirect evidence that homosexual people have experienced atypical early androgen exposure are morphological differences in gay men and lesbians compared to heterosexual individuals of the same sex, such as the relative length of the index to the ring finger, and the relative length of long bones in the legs, arms and hands. “These epidemiological studies indicate that homosexual and heterosexual populations differ in a number of established sex differences that are known, or at least strongly suspected, to be controlled by prenatal testosterone in animal species and often also in humans”, wrote Belgian endocrinologist Jacques Balthazart in a review of the topic (Balthazart, 2020). “This approach provides indirect information about the hormonal milieu to which an individual with a given sexual orientation was exposed during his/her embryonic life, given that it is nearly impossible, for practical reasons, to obtain this information in a direct manner”.

There is indeed compelling evidence that the brains of gay or straight people have a different organization. Classic work in this area has already suggested that patterns of amygdala connectivity and other features of brain structure in homosexual men are more similar to those of heterosexual women, while lesbian women display more male‐like features than heterosexual women. More recently, analysis of magnetic resonance imaging (MRI) and genetic data from more than 18,000 individuals in the UK Biobank has confirmed the “cross‐sex shift” proposed by small‐scale studies, finding that “[p]atterns important for classifying between males and females were less pronounced in non‐heterosexuals”, and regional brain volumes of non‐heterosexual individuals were shifted towards that of their heterosexual opposite‐sex counterpart (Abé et al, 2021). For the first time, this study also found some genetic correlation between same‐sex behaviour and brain imaging phenotypes.

The womb’s long shadow

The maternal immune hypothesis of male homosexuality is another mechanism that has been proposed to explain how sexual orientation might be somehow shaped by embryonic environment. The so‐called fraternal birth order effect—or older brother effect—is the increasing probability of homosexuality in males if their mothers gave previously birth to other sons. According to this thesis, molecules from male foetuses would enter the maternal bloodstream, causing the progressive production of antibodies that, over successive male pregnancies, would bind to foetal cells and interfere with embryonic development. The main candidates as male‐specific antigens are the Y‐linked neuroligin 4 (NLGN4Y) and protocadherin 11 (PCDH11Y), membrane proteins normally expressed on the surface of neurons. NLGN4Y, in particular, is believed to play a role in cell‐cell interactions that are at the basis of sexual differentiation of the male brain (Fig 2).

Figure 2. The older brother effect.

For each older brother born from a given women, the incidence of male homosexuality increases, suggesting that the pathway to homosexuality is initiated during prenatal life, probably as a consequence of a progressive immunization against a male antigen of the mother bearing male embryos. The figure shows the mean rank of concentration of antibodies against the candidate protein neuroligin 4Y‐linked (NLGN4Y) in different groups of women who either had no son, or only had heterosexual son(s), or had at least one gay son who had no older brother or who had one or several older brothers. The concentration of these antibodies in the mother’s blood significantly increases across these 4 categories. Numbers indicate the sequence of birth from a same mother and parentheses indicate the presence of one or more sons of a given category. Heterosexual (straight) sons are illustrated in blue and gay sons with the rainbow flag associated with homosexuality. Reproduced from (Balthazart, 2020) with permission.

The so‐called fraternal birth order effect – or older brother effect – is the increasing probability of homosexuality in males if their mothers gave previously birth to other sons.

“[R]esearch demonstrated that overall, women have a higher blood concentration of anti‐NLGN4Y antibodies than men but more importantly that, after controlling for the number of pregnancies, mothers of gay sons, especially those with older brothers, had significantly higher concentrations of antibodies against NLGN4Y levels than control women, including mothers of heterosexual sons”, remarked Balthazart (2020). Fresh support for the mother immunization postulate comes from an Australian team led by Jan Kabátek at the University of Melbourne. They browsed Dutch records of nine million people using same‐sex marriages or registered partnerships as a proxy for homosexuality. The results show the influence of sex and number of siblings. For example, a man with three older brothers is 41% more likely to enter in a same‐sex union than if he had three older sisters, and that chance increases to 80% than if he has three younger brothers (Ablaza et al, 2022). “A biological basis for human sexuality suggests harmful practices like conversion therapy can’t alter someone’s sexual orientation. It also discredits claims homosexuality can be ‘taught’, such as through sexual diversity education at schools, or ‘passed on’, such as through same‐sex couples adopting children”, the authors commented in a post on The Conversation (https://theconversation.com/research‐confirms‐men‐with‐older‐brothers‐are‐more‐likely‐to‐be‐gay‐suggesting‐same‐sex‐attraction‐has‐a‐biological‐basis‐172396).

Nature and nurture

The idea that homosexuality is rooted, at least in part, in genes has been around for a long time now, based on some observational evidence. For example, homosexuality tends to occur more frequently in some families, and sexual orientation in men seems to be transmitted down the maternal line. Given these premises, many have been allured by the quest for the “gay gene”, a trail of studies that reached a historic point in 1993, when Dean Hamer of the National Cancer Institute in Bethesda, USA, reported that a region on the X chromosome was key to men’s sexual orientation (Hamer et al, 1993). Hamer and colleagues focused on 40 pairs of gay brothers from families with gay relatives on the maternal side and found that 64% of the tested pairs shared polymorphic markers on the Xq28 region of the X chromosome. Several teams have subsequently tried to replicate these results, with mixed results. While many failed to confirm the linkage, a genome‐wide scan of 409 independent pairs of homosexual brothers published in 2015 has confirmed the existence of genes influencing development of male sexual orientation both on Xq28 and also on chromosome 8 (Sanders et al, 2015).

Genes might indeed play a significant role in determining human sexual orientation, but environmental factors are also crucial, although the relative importance of genetic and environmental origins of same‐sex behaviour remains largely unknown. In many cases where specific traits of human behaviour have been under scrutiny, twin studies can provide useful insight. Using this approach, a large Swedish study of 3,826 monozygotic and dizygotic same‐sex twin pairs estimated that genetics might explain 34–39% of homosexuality in men and 18–19% in women, respectively, with environmental factors, including prenatal exposure to sex hormones, accounting for the remainder (Långström et al, 2010).

Genes might indeed play a significant role in determining human sexual orientation, but environmental factors are also crucial…

As tiny sample size can obviously blur the results when trying to disentangle a knot as complex as sexuality genetics, Brendan Zietsch at the University of Queensland in Brisbane, Australia, and his colleagues have assembled the largest dataset ever used for this type of studies. Delving into some half million DNA profiles from the UK Biobank and the private company 23andMe, they performed a genome‐wide association study (GWAS), searching for genetic variants associated with self‐reported same‐sex sexual behaviour (Ganna et al, 2019). Overall, the results showed a limited, but clear role of genes in determining same‐sex behaviour. Indeed, five loci—none on the X chromosome—were significantly associated with same‐sex behaviour but, collectively, all tested genetic variants accounted for just 8–25% of variation in same‐sex sexual behaviour, both for males and females (Fig 3). Moreover, no single variant could account for more than 1%, indicating that same‐sex behaviour is a strongly polygenic trait and that it could be influenced by the additive effects of a large number of multiple gene variants. “[W]e acknowledge the limitation that we only studied participants of European ancestry and from a few Western countries; research involving larger and more diverse samples will afford greater insight into how these findings fare across different sociocultural contexts”, the authors remarked (Ganna et al, 2019).

Figure 3. A genome‐wide association study (GWAS) of same‐sex sexual behaviour reveals five loci and high polygenicity.

Follow‐up analyses show potential biological pathways; show genetic correlations with various traits; and indicate that sexual preference is a complex, heterogeneous phenotype. Reproduced from (Ganna et al, 2019) with permission.

Analysing the same data and those from another GWAS study on the number of opposite‐sex sexual partners in more than 350,000 individuals, other researchers have tried to find an answer to a long‐standing puzzle: why same‐sex behaviour in humans has been maintained despite the fact that, apparently, it does not offer any evolutionary advantage (Zietsch et al, 2021) (Box 1). Genetic variants associated with same‐sex behaviour were found, somewhat surprisingly, also to be associated with having more opposite‐sex sexual partners among heterosexual people, thus indicating a mating advantage of alleles linked to same‐sex behaviour. “We cannot say how much such a mating advantage would have increased overall fitness during evolutionary history”, concluded the authors, cautioning on the current lack of a feasible explanation of the genetic correlation they reported (Zietsch et al, 2021).

No conclusive epigenetic factors

If genetics is not providing all the answers, epigenetics is even more dramatically falling short. In theory, the possibility of epigenetic modifications during prenatal life fits well with the idea that environmental influences could determine sexual orientation, eventually leading to same‐sex behaviour. The problem though is to demonstrate it. Most of the work along these lines has been done at Eric Vilain’s lab at UCLA, USA, but the results have been contradictory, at best, and not replicated. The latest result goes back to 2015, when Vilain and his postdoc Tuck Ngun presented what sounded as a breakthrough at the meeting of the American Society of Human Genetics. The screening of methylation patterns in 37 pairs of monozygotic twins of which one was straight and the other gay compared to ten pairs of monozygotic twins who were both gay, indicated the existence of five epigenetic markers that were more common in gay than in genetically identical straight men (https://www.science.org/content/article/homosexuality‐may‐be‐caused‐chemical‐modifications‐dna). The report of these findings grabbed the headlines for a while, often spiced with considerable hype about the possibility that the identified markers could be used to predict homosexuality, a claim that Vilain and Ngun never supported. However, the study was never published and was criticized for the inappropriate statistical analysis supporting its conclusions.

Nonetheless, as the evidence that biological processes influence sexual orientation is growing, researchers continue to articulate new hypotheses. “These hypotheses are not necessarily mutually exclusive. Rather, they may each provide a piece of the overall puzzle. Some recent research suggests there are multiple, distinct biological pathways that result in subgroups of same‐sex oriented individuals who owe their sexual preference to different developmental processes”, commented Doug VanderLaan, an expert in gender and sexuality development at the University of Toronto Mississauga, Canada. “In my view, the next phases of sexual orientation research should further investigate the possible existence of such subgroups as well as advance understanding of the underlying mechanisms and their impacts on the brain and behavior”.

Stigmatization and mental health

As sexual minorities are also at higher risk for mental illness, researchers have examined how victimization experiences and common psychiatric disorders relate to brain structure revealed by MRI (Abé et al, 2021). “Our study demonstrates a structural neurobiological association with SSB [same‐sex sexual behavior], albeit with small effect sizes, and indicates a possible genetic influence on brain structure. The neural correlates of SSB were unrelated to mental health disparities and experience of victimization”, the authors concluded. The finding that SSB and psychiatric disorders or victimization experiences are not neurobiologically linked support the idea that social stressors such as discrimination rather than neurobiological factors are involved in mental health problems faced by sexual minorities.

Indeed and sadly, homosexuality is still stigmatized in some parts of the world, which is one of the reasons why gays and lesbians have a higher risk of mental illness, according to Christoph Abé from the Karolinska Institutet in Stockholm, Sweden, and lead author of the study. “On one hand, our study highlights the importance of improving health‐care provision for sexual minority groups aimed at reducing the burden of mental health problems. On the other hand, through a better scientific understanding, our findings may also help improve social attitudes and reduce some of the negative social perceptions surrounding sexual minorities”, he commented. “In turn, this can help contribute to de‐stigmatization efforts, promote equality, have positive impacts for the self‐perception and ultimately for the psychological well‐being of people with minority sexual orientation”.

…through a better scientific understanding, our findings may also help improve social attitudes and reduce some of the negative social perceptions surrounding sexual minorities.

The scientific evidence so far, despite all the limitations and biases that inevitably characterize this type of research, shows us that our sexual behaviour is, at least in part, grounded in our biology and does not depend only on external and environmental factors. “I don’t think I was born gay. I don’t think I was born straight. I was born the way all of us are born: as a human being with a seemingly infinite capacity to announce myself, to re‐announce myself, to try on new identities like spring raincoats, to play with limiting categories, to challenge them and topple them, to cultivate my tastes and preferences, and, most importantly, to love and to receive love”. These words of gay writer Brandon Ambrosino aptly describe this new understanding of human sexuality, one that goes much beyond the nature/nurture dichotomy, and reclaim the central stage for the borderless fluidity of human sexuality (https://www.bbc.com/future/article/20160627‐i‐am‐gay‐but‐i‐wasnt‐born‐this‐way).

Box 1. The long evolutionary history of same‐sex sexual behaviour.

From insects to sea stars, from birds to mammals, same‐sex sexual behaviour (SSB) is widespread among metazoans, much more than researchers believed. To date, SSB has been recorded in some 1,500 animal species, including at least 300 vertebrates and most major groups of invertebrates. The prevalence of SSB across species raises an intriguing question. How can the “Darwininian paradox” of SSB’s evolutionary persistence be explained since it offers no obvious reproductive or survival benefit?

A number of hypotheses have been put forward to solve the puzzle, including the idea that homosexual behaviour increases male attractiveness to females, or that SSB reinforces a cooperative bond between partners. More recently, a team led by Julia Monk from Yale University at New Heaven, USA, has proposed an alternative view, namely that SSB is an ancestral trait that has emerged at the same time as sexuality itself. Under this scenario, animal species mated indiscriminately, with individuals of all sexes, and different‐sex sexual behaviours appeared only subsequently along the evolution of the sophisticated and costly mechanisms needed for mate recognition, such as sexual polymorphism (Monk et al, 2019). “[W]e suggest that selection would only act against SSB in ecological or social contexts where its costs become prohibitive. Absent such costs in particular lineages, SSB may be retained, because reproductive fitness is likely often maximized at intermediate mixtures of sexual behaviours that balance the costs of specifically targeting fertilization‐compatible mates with the benefits of an increased number of mating opportunities”, the authors explained (Fig Box). However, the new theory has not been universally accepted at face value, with several evolutionary biologists asking that the claims by Monk and colleagues have to be tested. We are just at the beginning of a long journey that will eventually lead us to understand why SSB is so common in the animal kingdom and why it evolved in the first place.

Box Figure. Conceptual representation of the variation in same‐sex sexual behaviour (SSB) and different‐sex sexual behaviour (DSB) at the individual, population and species levels.

(A) Across their lifetimes, individuals may vary in the frequencies at which they express SSB or DSB, and populations can hypothetically be either monomorphic or polymorphic for SSB and DSB. Monomorphic populations could be comprised entirely of individuals expressing both SSB and DSB across their lifetimes (1), of individuals who all express exclusive DSB (2), or individuals who all express exclusive SSB (3). However, a population comprised entirely of exclusive SSB individuals would likely go extinct. Populations may also be highly polymorphic, with some comprised of individuals expressing greater frequencies of either SSB or DSB (4), some predominantly comprised of individuals that largely engage in DSB but some individuals that express higher frequency of SSB (5), and the reverse where most individuals exhibit higher frequencies of SSB but some are more often engaged in DSB (6). The polymorphic populations conceptualized here represent a small subset of the spectrum of possibilities that may exist within populations in nature. (B) Macroevolutionary hypotheses of the evolution of SSB and DSB can be depicted through phylogenetic representations with the current, dominant hypothesis of ancestral exclusive DSB (left) and our proposed hypothesis of ancestral indiscriminate sexual behaviours (right). For both hypotheses, the ancestral animal reproduces sexually and is anisogamous. Under the hypothesis of ancestral DSB, the most recent common ancestor to animals with sexual behaviour expressed exclusive DSB. This reproductive mode is then maintained with the exception of a few terminal nodes that have evolved greater levels of SSB. In contrast, our proposed hypothesis suggests the most recent common ancestor to animals with sexual behaviour expressed indiscriminate sexual behaviours with a mixture of SSB and DSB. This new hypothesis influences the perception of mixtures of sexual behaviours in extant species, suggesting that both those with more DSB or SSB might have been subject to selective pressures. Further, this hypothesis suggests that, on closer inspection, we will likely find most species to express a mixture of both DSB and SSB. Reproduced from (Monk et al, 2019) with permission.

EMBO reports (2022) 23: e55290.