Fairfax, VA, USA. Reports of a transsexual gene? The New Scientist recently flashed a breathless headline: 'Transsexuality gene' makes women feel like men, with an accompanying article by Linda Geddes. [C1]

This inaccurate report caused quite a stir among friends and foes alike.


Skewed research and hack journalism harm acceptance of transsexuality as a bona fide medical condition. Research without rigor from the Medical University Vienna and uninformed discussion of the findings in New Scientist manage to both mislead the gullible and undermine more serious consideration of the subject. Apart from her emphasis on "men" as the starting point for comparisons, Geddes reported on newly discovered "proof" of a single genetic component (along with cultural factors) in the development of what she and the researchers call transsexuality.

The Research

Researchers at Medical University Vienna (Vienna, Austria) examined a gene variant for an enzyme called cytochrome p (CYP) 17, or more simply CYP17. [C2] It is key in androgen synthesis and the metabolism of sex hormones, with a role in regulation. Among other conditions, mutations in this gene may be associated with cancers of the breast and prostate. The research team's findings [C2] are scheduled for print publication in Fertility and Sterility, from the American Society for Reproductive Medicine (ASRM).

Testosterone is the best-known androgen, present in both females and males, but of primary importance in male development. The synthesis of testosterone in a human body follows a pathway from cholesterol and its conversion to active androgen and estrogen metabolites. Testosterone levels can vary throughout the day, but not by much. Under ordinary circumstances, males have far more testosterone in their bodies than females.

The Austrian team worked with a group of people they deemed transsexuals on the basis of their feeling they were "men" trapped in "women's" bodies. This confusion of sex and gender continues throughout their work, as does references to transsexuality as a characteristic of certain people. Even more important to this column and elucidation of transsexuality, they (and Linda Geddes) rely on dated notions of a gene having the ability to determine a particular characteristic of an organism and pass on the heritability of this characteristic all by itself.

This kind of foundational assumption has been superseded by the discovery of the human genome and the subtle interactions necessary for heritability.

Based on prior work, and their own assumptions, the research team wondered if the presence of a CYP17, a known gene variation, would lead to higher than average tissue concentrations of male and female sex hormones. This is based on the idea that while natal females do not produce much testosterone, the presence of the variant would permit them to retain more testosterone in their cells.

Because sex hormones are so important to early brain development, Dr. Clemens Tempfer and his colleagues (in the Department of Gynecologic Endocrinology and Reproductive Medicine) investigated whether the variant was present in the DNA drawn from a sample of people who were identified as Female-to-Male transsexuals [sic].

The population sample consisted of 49 female-to-male (FtM), 102 male-to-female (MtF), and 756 male and 915 female controls. Their results showed that the variant was more common in natal males than natal females, as would be expected. The could not detect implications of the variant in MtF subjects, finding that the proportion of "transsexuality" was similar between MtF transsexuals and non-transsexual men.

Their big finding, and the one that drew the New Scientist coverage, was the observation of comparisons with natal females: 31% of the baseline group of non-transsexual females carried the variant, compared with 44% of FtM transsexuals.

Their basic finding suggested to them that presence of the variant makes women more likely to feel that their bodies are of the wrong sex. They inferred this as a possible result of fetal exposure to above average testosterone levels. This is a conventional finding, but one that presupposes transsexuality has a point-specific cause that can be assigned to one genetic source well into adulthood.

In fact, Dr. Tempfer has been quoted as saying "It may increase the likelihood that people will become transsexual". [My emphasis.] In other words, he doesn't talk about a birth condition at all, but assumes a genetic predisposition, filled out by, as he stresses, cultural influences.

A call for caution

This is a relatively simple observational study without definitive findings that has been elevated to confirmational status without reference to the underlying neurobiology.

• Examination of a baseline control group suggests 31% of all natal females have some form of the gene variant. This is a large percentage as such studies go; it could be reduced if other interacting genomic components are identified that reduce the number and permit more meaningful comparisons.
  
  Just as important, we are left to wonder how the "non"-transsexual characteristics were determined. In fact, all a study participant had to do was claim membership in that group. The researchers used no other objective criteria.
  
  
• 44% of the FtM transsexuals carry the variant. This presents a large gap between the FtMs and the 31% of natal females. Except that,
  
  an ill-defined population of subjects, chosen on the basis of self-reports without regard to verifying criteria can hamper attempts to reproduce the experiment.
  
  The paper does not present rigorous criteria to validate the subjects. How many were full time? Were any of them already on hormones that could influence their brain chemistry? Did any of the subjects take actions that would increase confidence in their self-diagnosis (such as top surgery)? 

Mikael Landén is from the Karolinska Institute (Stockholm, Sweden), an institution known for more cautious and rigorous research. He says

The present study found that a mutant gene that ultimately results in higher testosterone levels is overrepresented in female-to male transsexualism. … This is in line with what we previously know about masculinisation of the brain and is therefore less likely to be a chance finding.

In other words, it is an interesting observation that qualifies as a follow-up to earlier research.

Hence, the study is important and adds to the notion that gender identity is influenced by sex hormones early in life, and that certain gene combinations make individuals more vulnerable to aberrant effects.

Here, Landén expands the discussion: … certain gene combinations make individuals more vulnerable to aberrant effects.  The reported research did not even discuss gene combinations and influences from the rest of the genome.

In other words, there is a lot more to do.

Sex steroids

Sex steroids are subject to the same patterns discussed elsewhere in this column. These substances are steroid (gonadal) hormones that interact with vertebrate receptors for androgen, estrogen, and progestin. They are crucial to the differentiation of the sexes between female and male, a near-universal pattern in humans and most other life forms. The effects of sex steroids, or hormones, are most noticeable in neurobioogical and anatomical development following conception.

For nearly all humans, these development pathways follow parallel courses, resulting in natal females and males who have unified sexual identities. In some cases, a misalignment can occur, a mismatch between the outcomes of neurobioogical and anatomical development.

Genes in perspective

A gene is a packet of information located in a region of the genome that corresponds to a unit of inheritance (but not the totality of inheritance, as discussed earlier). In common usage, the term gene refers to a heritable trait which is usually accompanied by a specific characteristic of a human (such as blue eyes or slim build). The proper scientific term for this is allele. However, a single gene seldom accounts for a specific characteristic without reference to the genome.

All things being equal, height — as just one example — is a consequence of the complex interplay of multiple genes and other regulators in the human cell. After that, the influences of diet and environmental factors further refine the outcome. A scientifically concise definition of the term gene takes all of this into account and includes referents to complex patterns of regulation and transcription, genic conservation and non-coding RNA.

Gerstein et al developed a working definition: A gene is a union of genomic sequences encoding a coherent set of potentially overlapping functional products. [C3] This definition recognizes that inheritance is a consequence of dispersed genome regulation activity. The complexities of regulation and transcription are not included in the definition because final, functional gene products group together entities associated with a single gene. Intermediate transcripts are important to the process, but are not the bottom line. So, quoting Gerstein, 

1. A gene is a genomic sequence (DNA or RNA) directly encoding functional product molecules, either RNA or protein.
   
   
2. In the case that there are several functional products sharing overlapping regions, one takes the union of all overlapping genomic sequences coding for them.
   
   
3. This union must be coherent — i.e., done separately for final protein and RNA products — but does not require that all products necessarily share a common subsequence.

Allowing for that, what is the role of a single gene? Amino acids are basic building blocks: 20 of them are commonly found in proteins. Specific genes code for proteins, translated from RNA which is transcribed from DNA (with certain exceptions, such as reverse transcription in retroviruses). The genetic code specifies the precise sequence of amino acids necessary for each protein. 

Even a single gene can vary in important ways. It is central to molecular biology that variations or mutations in genes can cause errors in certain steps in the metabolic pathways. While essentially the same, a sequence in the genetic code can differ between people, resulting in what is called a gene variant. There are well-known examples of this. Relatively benign characteristics can result, such as lengthened noses or arced eyebrows. More seriously, the presence of certain gene variants are known to heighten the risk for such conditions as autism, breast cancer, cystic fibrosis, and stroke.

Certain genes, erroneously transcribed and/or missed by our error-correction mechanisms, can exert their influence. Considered in a genomic context, the malformations can result in serious disease conditions. Tay-Sachs disease (TSD) is a rare genetic disorder. Its most common variant, Infantile TSD, is invariably fatal. Harmful quantities of ganglioside, a fatty acid derivative, accumulate in the brain's nerve cells. Research tracked Tay-Sachs to a genetic mutation on the HEXA gene on chromosome 15. A large number of HEXA mutations have been discovered (with new ones still under report). Moreover, different populations have significantly different carrier frequencies.

The desire to find a point-specific gene

The severity and type of TSD occurence is subject to a variety of genomal influences, so one would be hard-pressed to say, even with Tay-Sachs, that there is one specific culprit gene that explains everything. Notably, this is why one cannot say there is such a thing as a "stroke" gene or "cystic fibrosis gene" per se. The best we can do is say there is a genetic condition or — more properly — a genetic component to the occurence.

Similarly, we can't really say there is determination of sex based on a single gene. The common popular assumption has it that a Y chromosome with its few and fragile male-specific genes determines sex. However, the genome — the whole of DNA, both coding and non-coding — matters more than one of its parts, a single gene that depends on other actions within the genome to be viable.

There has been a popular emphasis on searching for specific genes that underly what are incorrectly perceived as behavioral conditions, such as TS, homosexuality, or even rival political opinions. Obviously, there is more to the story.

Principal Speculations

Transsexuality leads some researchers and many in our corner of the public to assume our birth condition occurs because of something that happens in the pre-natal environment, usually resolving itself into an application of the wrong hormones on a brain. In fact, there are two main branches of speculation on this subject, each of them carry implicit assumptions.

1. The brain is the thing. Since our brains and central nervous systems form first, our sex is set in the brain. The misalignment occurs because there has been a missed signal that resulted in the opposite anatomy (a variation in the body plan).
   
   Female brains wind up with anatomically male bodies; male brains wind up with anatomically female bodies. If, for example, an XY individual has a female brain, then the initiation point must lay further back in development, back where the chromosome was formed in the first place. Errors there would result in a body plan that is a mismatch with female neural development.
   
   There has been a rapid accumulation of evidentiary detail regarding the developmental pathways for human beings. The human body defaults to female at the outset, with maleness as the exception, so there is considerable strength in this idea.
   
   
2. The body is the thing. Any misalignment must be the result of opposite sex hormones released during fetal development (or later, in the case of humans who have other reasons for cross-sex transition).
   
   In this case, an anatomical female has a brain masculinized by hormones; an anatomical male has a brain feminized by hormones. If, for example, an XY individual has a female brain, then you don't have to look any further. Male characteristics are primary. A faulty body plan is the result of interference from opposite sex hormones.

Citation[C1] 'Transsexuality gene' makes women feel like men. Linda Geddes. New Scientist online. 29 July 2008.

---

[C2] A polymorphism of the CYP17 gene related to sex steroid metabolism is associated with female-to-male but not male-to-female transsexualism. Eva-Katrin Bentz, Lukas A. Hefler, Ulrike Kaufmann, Johannes C. Huber, Andrea Kolbus, Clemens B. Tempfer. Fertility and Sterility 90(1) 56-59. doi: 10.1016 / j.fertnstert.2007.05.056 PII: S0015-0282(07)01228-9

Abstract

Objective. To assess the association between transsexualism and allele and genotype frequencies of the common cytochrome P450 (CYP) 17 -34 T>C single nucleotide polymorphism ( SNP).

Design. Case-control study.

Setting. Academic research institution.

Patient(s). 102 male-to-female (MtF) and 49 female-to-male (FtM) transsexuals, 756 male controls, and 915 female controls.

Intervention(s). Buccal swabs and multiplex polymerase chain reaction on a microarray system.

Main Outcome Measure(s). Analysis of the CYP17 -34 T>C SNP.

Result(s). CYP17 -34 T>C SNP allele frequencies were statistically significantly different between FtM transsexuals and female controls (CYP17 T: 55/98 [56%] and CYP17 C: 43/98 [44%] versus CYP17 T: 1253/1826 [69%] and CYP17 C: 573/1826 [31%], respectively). In accordance, genotype distributions were also different between FtM transsexuals and female controls using a recessive genotype model (CYP17 T/T+T/C: 39/49 [80%] and C/C 10/49 [20%] vs. CYP17 T/T+T/C: 821/913 [90%] and C/C 92/913 [10%], respectively). The CYP17 -34 T>C allele and genotype distributions were not statistically significantly different between MtF transsexuals and male controls. Of note, the CYP17 -34 T>C allele distribution was gender-specific among controls (CYP17 C: males; 604 of 1512 [40%] vs. females; 573 of 1826 [31%]). The MtF transsexuals had an allele distribution equivalent to male controls, whereas FtM transsexuals did not follow the gender-specific allele distribution of female controls but rather had an allele distribution equivalent to MtF transsexuals and male controls.

Conclusion(s). These data support CYP17 as a candidate gene of FtM transsexualism and indicate that loss of a female-specific CYP17 T -34C allele distribution pattern is associated with FtM transsexualism.

---

[C3] What is a gene, post-ENCODE? History and updated definition. Mark B. Gerstein, Can Bruce, Joel S. Rozowsky, Deyou Zheng, Jiang Du, Jan O. Korbel, Olof Emanuelsson, Zhengdong D. Zhang, Sherman Weissman, and Michael Snyder. Genome Research 17(6) 669-681. [ Download PDF ]

Abstract

While sequencing of the human genome surprised us with how many protein-coding genes there are, it did not fundamentally change our perspective on what a gene is. In contrast, the complex patterns of dispersed regulation and pervasive transcription uncovered by the ENCODE project, together with non-genic conservation and the abundance of noncoding RNA genes, have challenged the notion of the gene. To illustrate this, we review the evolution of operational definitions of a gene over the past century—from the abstract elements of heredity of Mendel and Morgan to the present-day ORFs enumerated in the sequence databanks. We then summarize the current ENCODE findings and provide a computational metaphor for the complexity. Finally, we propose a tentative update to the definition of a gene: A gene is a union of genomic sequences encoding a coherent set of potentially overlapping functional products. Our definition sidesteps the complexities of regulation and transcription by removing the former altogether from the definition and arguing that final, functional gene products (rather than intermediate transcripts) should be used to group together entities associated with a single gene. It also manifests how integral the concept of biological function is in defining genes.

Ms. Sharon Gaughan is a Co-Founder, Principal, and Managing Editor of TS-Si. She also is a columnist for the TS-Si website. Sharon's signed articles contain her own opinions and do not necessarily convey an official position of TS-Si, its partners, or affiliates.

Sharon welcomes your comments. You can reach her via the public form below, her TS-Si Contact Page, or on Facebook (Sharon Sinead Gaughan).