The Gene

by Siddhartha Mukherjee

  The pattern ran generation on generation. To a seasoned geneticist, this trend meant the gay gene had to be carried on the X chromosome. Hamer could almost see it now in his mind’s eye—an inherited element passing between generations like a shadowy presence, nowhere as penetrant as the typical cystic fibrosis or Huntington’s gene mutations, but inevitably tracking the trail of the X chromosome. In a typical family tree, a great-uncle might be identified as potentially gay. (Family histories were often vague. The historical closet was substantially darker than the current sexual closet—but Hamer had collected data from occasional families where sexual identity was known for up to two or even three generations.) All the sons born from that uncle’s brothers were straight—men do not pass on the X chromosome to their children (sperm, remember, carries only the Y chromosome). But one of his sister’s sons might be gay, and that son’s sister’s son might also be gay: a man shares parts of his X chromosome with his sister and with his sister’s sons. And so forth: great-uncle, uncle, eldest nephew, nephew’s sibling, sidestepping through generations, forward and across, like a knight’s move in chess. Hamer had suddenly moved from a phenotype (sexual preference) to a potential location on a chromosome—a genotype. He had not identified the gay gene—but he had proved that a piece of DNA associated with sexual orientation could be physically mapped to the human genome.

  But where on the X chromosome? Hamer now turned to forty gay sibling pairs from whom he had collected blood. Assume, for a moment, that the gay gene is indeed located on some small stretch of the X chromosome. Wherever the stretch is, the forty siblings would tend to share that particular chunk of DNA at a significantly higher frequency than siblings where one is gay and the other straight. Using signposts along the genome defined by the Human Genome Project, and careful mathematical analysis, Hamer began to sequentially narrow the stretch to shorter and shorter regions of the X chromosome. He ran through a series of twenty-two markers along the entire length of the chromosome. Notably, of the forty gay siblings, Hamer found that thirty-three brothers shared a small stretch of the X chromosome called Xq28. Random chance predicted that only half the brothers—i.e., twenty—would share that marker. The chance that thirteen extra brothers would carry the same marker was vanishingly small—less than one in ten thousand. Somewhere near Xq28, then, was a gene that determined male sexual identity.

  Xq28 was an instant sensation. “The phone rang off the hook,” Hamer recalled. “There were TV cameramen lined up outside the lab; the mailbox and e-mail overflowed.” The Daily Telegraph, the conservative London newspaper, wrote that if science had isolated the gay gene, then “science could be used to eradicate it.” “A lot of mothers are going to feel guilty,” wrote another newspaper. “Genetic tyranny!” claimed yet another headline. Ethicists wondered whether parents would “genotype” their way out of having homosexual children by testing fetuses. Hamer’s research “does identify a chromosomal region that could be analyzed for individual males,” one writer wrote, “but the results of any test based on this research would, again, offer only probabilistic tools by which to estimate the sexual orientation of some men.” Hamer was attacked left and right—literally. Antigay conservatives argued that by reducing homosexuality to genetics, Hamer had justified it biologically. Advocates of gay rights accused Hamer of furthering the fantasy of a “gay test” and thereby propelling new mechanisms of detection and discrimination.

  Hamer’s own approach was neutral, rigorous, and scientific—often corrosively so. He continued to refine his analysis, running the Xq28 association through a variety of tests. He asked if Xq28 might encode not a gene for homosexuality, but a “gene for sissyness” (only a gay man would dare to use that phrase in a scientific paper). It did not: men who shared Xq28 did not have any significant alterations in gender-specific behaviors, or in conventional aspects of masculinity. Could it be a gene for receptive anal intercourse (“Is it the bottoms up gene?” he asked)? Again, there was no correlation. Could it be related to rebelliousness? Or a gene for bucking repressive social customs? A gene for contrary behavior? Hypothesis after hypothesis was turned over, but there was no link. The exhaustive elimination of all possibilities left only one conclusion: male sexual identity was partially determined by a gene near Xq28.

  Since Hamer’s 1993 paper in Science, several groups have tried to validate Hamer’s data. In 1995, Hamer’s own team published a larger analysis that confirmed the original study. In 1999, a Canadian group tried to replicate Hamer’s study on a small group of gay siblings but failed to find the link to Xq28. In 2005, in perhaps the largest study to date, 456 sibling pairs were studied. The link to Xq28 was not discovered, but links to chromosomes seven, eight, and ten were found. In 2015, in yet another detailed analysis of 409 additional sibling pairs, the link to Xq28 was validated again—albeit weakly—and the previously identified link to chromosome eight was reiterated.

  Perhaps the most intriguing feature of all these studies is that, thus far, no one has isolated an actual gene that influences sexual identity. Linkage analysis does not identify a gene itself; it only identifies a chromosomal region where a gene might be found. After nearly a decade of intensive hunting, what geneticists have found is not a “gay gene” but a few “gay locations.” Some genes that reside in these locations are indeed tantalizing candidates as regulators of sexual behavior—but none of these candidates has been experimentally linked to homo- or heterosexuality. One gene that sits in the Xq28 region, for instance, encodes a protein that is known to regulate the testosterone receptor, a well-known mediator of sexual behavior. But whether this gene is the long-sought gay gene on Xq28 remains unknown.

  The “gay gene” might not even be a gene, at least not in the traditional sense. It might be a stretch of DNA that regulates a gene that sits near it or influences a gene quite far from it. Perhaps it is located in an intron—the sequences of DNA that interrupt genes and break them up into modules. Whatever the molecular identity of the determinant, this much is certain: sooner or later, we will discover the precise nature of the heritable elements that influence human sexual identity. Whether Hamer is right or wrong about Xq28 is immaterial. The twin studies clearly suggest that several determinants that influence sexual identity are part of the human genome, and as geneticists discover more powerful methods to map, identify, and categorize genes, we will inevitably find some of these determinants. Like gender, these elements will likely be hierarchically organized—with master regulators on top, and complex integrators and modifiers on the bottom. Unlike gender, though, sexual identity is unlikely to be governed by a single master regulator. Multiple genes with small effects—in particular, genes that modulate and integrate inputs from the environment—are much more likely to be involved in the determination of sexual identity. There will be no SRY gene for straightness.

  The publication of Hamer’s article on the gay gene coincided with the forceful reemergence of the notion that genes could influence diverse behaviors, impulses, personalities, desires, and temperaments—an idea that had been out of intellectual fashion for nearly two decades. In 1971, in a book titled Genes, Dreams and Realities, Macfarlane Burnet, the renowned Anglo-Australian biologist, wrote, “It is self-evident that the genes that we are born with provide, along with the rest of our functional selves, the basis of our intelligence, temperament and personality.” But by the midseventies, Burnet’s conception had become far from “self-evident.” The notion that genes, of all things, could predispose humans to acquiring particular “functional selves”—possessing particular variants of temperament, personality, and identity—had unceremoniously been drummed out of universities. “An environmentalist view . . . dominated psychological theory and research from the 1930s through the 1970s,” Nancy Segal, the psychologist, wrote. “Other than being born with a general capacity to learn, human behavior was explained almost exclusively by forces outside the individual.” A “toddler,” as one biologist recalled, was perceived as a “random access memory onto w
hich any number of operating systems could be downloaded by culture.” The Silly Putty of a child’s psyche was infinitely malleable; you could mold it into any shape and force it into any dress by changing the environment or reprogramming behavior (hence the stupefying credulity that enabled experiments, such as John Money’s, to attempt definitive changes in gender using behavioral and cultural therapy). Another psychologist, entering a research program at Yale University in the 1970s to study human behaviors, was bewildered by the dogmatic stance against genetics in his new department: “Whatever back-porch wisdom we might have brought to New Haven about inherited traits [driving and influencing human behaviors] was the kind of bunk that we were paying Yale to purge.” The environment was all about environments.

  The return of the native—the emergence of the gene as a major driver for psychological impulses—was not as easy to orchestrate. In part, it required a fundamental reinvention of that classic workhorse of human genetics: the much maligned, much misunderstood twin study. Twin studies had been around since the Nazis—recall Mengele’s macabre preoccupation with Zwillinge—but they had reached a conceptual gridlock. The problem with studying identical twins from the same family, geneticists knew, was the impossibility of unbraiding the twisted strands of nature and nurture. Reared in the same home, by the same parents, often schooled in the same classrooms by the same teachers, dressed, fed, and nurtured identically, these twins offered no self-evident way to separate the effects of genes versus the environment.

  Comparing identical twins to fraternal twins partially solved the problem, since fraternal twins share the same environment, but share only half the genes, on average. But critics argued that such identical/fraternal comparisons were also intrinsically flawed. Perhaps identical twins are treated more similarly than fraternal twins by their parents. Identical twins, for instance, were known to have more similar patterns of nutrition and growth compared to fraternal twins—but was this nature or nurture? Or identical twins might react against each other to distinguish themselves from one another—my mother and her twin often self-consciously chose opposite shades of lipstick—but was that dissimilarity encoded by genes, or a reaction to genes?

  In 1979, a scientist in Minnesota found a way out of the impasse. One evening in February, Thomas Bouchard, a behavioral psychologist, found a news article left by a student in Bouchard’s mailbox. It was an unusual story: a pair of identical twins from Ohio had been separated at birth, adopted by different families, and experienced a remarkable reunion at age thirty. These brothers were obviously part of a fleetingly rare group—identical twins given up for adoption and reared apart—but they represented a powerful way to interrogate the effects of human genes. Genes had to be identical in these twins, but environments were often radically different. By comparing separated-at-birth twins against twins brought up in the same family, Bouchard could untwist the effects of genes and environments. The similarities between such twins could have nothing to do with nurture; they could only reflect hereditary influences—nature.

  Bouchard began recruiting such twins for his study in 1979. By the late eighties, he had assembled the world’s largest cohort of reared-apart and reared-together twins. Bouchard called it the Minnesota Study of Twins Reared Apart (or “MISTRA”). In the summer of 1990, his team presented a comprehensive analysis as a lead article in Science magazine.II The team had collected data from fifty-six reared-apart identical twins and thirty reared-apart fraternal twins. In addition, data from an earlier study, containing 331 reared-together twins (both identical and fraternal), was included. The twin sets came from a broad range of socioeconomic classes, with frequent discordances between two individual twins (one reared in a poor family, another adopted by a wealthy family). Physical and racial environments were also broadly different. To assess environments, Bouchard made the twins compile meticulous records of their homes, schools, offices, behaviors, choices, diets, exposures, and lifestyles. To determine indicators of “cultural class,” Bouchard’s team ingeniously recorded whether the family possessed a “telescope, an unabridged dictionary, or original artwork.”

  The punch line of the paper was presented in a single table—unusual for Science, where papers typically contain dozens of figures. Over nearly eleven years, the Minnesota group had subjected the twins to battery upon battery of detailed physiological and psychological tests. In test upon test, the similarities between twins remained striking and consistent. The correlations between physical features had been expected: the number of fingerprint ridges on the thumb, for instance, was virtually identical, with a correlational value of 0.96 (a value of 1 reflects complete concordance or absolute identity). IQ testing also revealed a strong correlation of about 0.70, corroborating previous studies. But even the most mysterious and profound aspects of personality, preferences, behaviors, attitudes, and temperament, tested broadly using multiple independent tests, showed strong correlations between 0.50 and 0.60—virtually identical to the correlation between identical twins that had been reared together. (As a sense of the strength of this association, consider that the correlation between height and weight in human populations lies between 0.60 and 0.70, and between educational status and income is about 0.50. The concordance among twins for type 1 diabetes, an illness considered unequivocally genetic, is only 0.35.)

  The most intriguing correlations obtained by the Minnesota study were also among the most unexpected. Social and political attitudes between twins reared apart were just as concordant as those between twins reared together: liberals clustered with liberals, and orthodoxy was twinned with orthodoxy. Religiosity and faith were also strikingly concordant: twins were either both faithful or both nonreligious. Traditionalism, or “willingness to yield to authority,” was significantly correlated. So were characteristics such as “assertiveness, drive for leadership, and a taste for attention.”

  Other studies on identical twins continued to deepen the effect of genes on human personality and behavior. Novelty seeking and impulsiveness were found to have striking degrees of correlation. Experiences that one might have imagined as intensely personal were, in fact, shared between twins. “Empathy, altruism, sense of equity, love, trust, music, economic behavior, and even politics are partially hardwired.” As one startled observer wrote, “A surprisingly high genetic component was found in the ability to be enthralled by an esthetic experience such as listening to a symphonic concert.” Separated by geographic and economic continents, when two brothers, estranged at birth, were brought to tears by the same Chopin nocturne at night, they seemed to be responding to some subtle, common chord struck by their genomes.

  Bouchard had measured characteristics where measurable—but it is impossible to convey the strange feel of this similarity without citing actual examples. Daphne Goodship and Barbara Herbert were twins from England. They had been born to an unmarried Finnish exchange student in 1939, and their mother had given them up for adoption before returning to Finland. The twins were raised separately—Barbara, the daughter of a lower-middle-class municipal gardener, and Daphne, the daughter of a prominent upper-class metallurgist. Both lived near London—although, given the rigidity of class structure in 1950s England, they might as well have been brought up on different planets.

  Yet in Minnesota, Bouchard’s staff was repeatedly struck by the similarities between the twins. Both laughed uncontrollably, erupting into peals of giggles with minimal provocation (the staff called them the “giggle twins”). They played pranks on the staff, and on each other. Both were five feet three inches tall, and both had crooked fingers. Both had gray-brown hair; both had dyed it an unusual shade of auburn. They tested identically on IQ tests. Both had fallen down the stairs as children and broken their ankles; both had a consequent fear of heights, and yet both, despite some clumsiness, had taken lessons in ballroom dancing. Both had met their future husbands through dancing lessons.

  Two men—both renamed Jim after adoption—had been separated from each other thirty-seven days after
birth and had grown up eighty miles apart in an industrial belt in northern Ohio. Both had struggled through school. “Both drove Chevrolets, both chain-smoked Salems, and both loved sports, especially stock-car racing, but both disliked baseball. . . . Both Jims had married women named Linda. Both had owned dogs that they had named Toy. . . . One had a son named James Allan; the other’s son was named James Alan. Both Jims had undergone vasectomies, and both had slightly high blood pressure. Each had become overweight at roughly the same time and had leveled off at about the same age. Both suffered migraine headaches that lasted approximately half a day and that did not respond to any medication.”

  Two other women, also separated at birth, emerged from separate airplanes wearing seven rings each. A pair of male twins—one brought up Jewish, in Trinidad, and the other Catholic, in Germany—wore similar clothes, including blue oxford shirts with epaulets and four pockets, and shared peculiar obsessive behaviors, such as carrying wads of Kleenex in their pockets and flushing toilets twice, once before and once after using them. Both had invented fake sneezes, which they deployed strategically—as “jokes”—to diffuse tense moments of conversation. Both had violent, explosive tempers and unexpected spasms of anxiety.