Fairfax, VA, USA. The existence of transsexuality is beyond dispute, as evidenced by the large absolute numbers of people who are hormonally reconstituted, surgically corrected, and successfully transitioned into society.

Gender theorists obfuscate, blog posters dispute, and tradition-bound academic scientists dither in career-driven timidity. Nonetheless, research into the causes of the transsexual birth condition has moved beyond simplistic behavioral analysis, which often misconceives it as sexual behavior. The best among us keep an open mind and pioneer new tools to account for data that does not yield to easy off the shelf explanations.

Today, we can focus our efforts on the overall genomic context and — very importantly — on the pre-conception environment that influences the mispackaging of genetic data into skewed information. Progress depends on advances in many fields that examine the fundamental mechanisms of meiosis, inheritance, mutation, conception, the cell cycle, and many related processes.

Equally important are the longitudinal health studies of human families over multiple generations. However, people with a transsexual history are notably absent from the data collection and analysis.

Research opportunities offered by patients with a history of misaligned neurobiology and genitalia

Men and women who have corrected the misalignment of their anatomical sex are a unique — but virtually unutilized — resource for research studies. Men with such histories are unencumbered with long-term exposure to testosterone, while the women do not have menstrual histories and are non-menopausal.

 

Both men and women in this population group exhibit the measurable consequences of hormone therapy (HT) and related medication. Moreover, the group identification does not depend on race or other criteria susceptible to psychosocial misinterpretations. 

 

Even though the women have never been through menopause, doctors, endocrinologists and other medical practitioners still use traditional practice and deny the appropriate types of estrogen and sufficient dosages to their MtF patients when prescribing hormones.

 

This practice derives from studies of women who have been prescribed hormone combinations with known deleterious effects and projecting those effects to all estrogen-inclusive regimens. 

 

It is a biased practice based on uninformed presumptions that such patients seek pretense and can not be considered as women themselves. Much of the confusion derives from a failure by practitioners to distinguish between transsexuality and and paraphilia. 

 

However, the existence of a qualified post-op population offers the opportunity for informative baseline comparisons when studying the unique health concerns of all men and women, regardless of their birth circumstances.

Whole Genome Sequencing

A current and notable example of science on the move is the advent of finely detailed genomic analyses, made feasible following the emergence of more sophisticated, and cheaper, techniques for studying large but unrelated population groups.

But now researchers from the Institute for Systems Biology (ISB) have refined the analytical techniques even further and tightened the focus by analyzing the first whole genome sequences of a human family of four (mother, father, and two children). A report in Science describes how they found rare genetic variants while lowering error rates and identifying genes with known linkages to disease and, by implication, a wide range of developmental disorders. The research establishes a baseline that provides a firm basis for examining inheritance across generations.

The application of the techniques involved has important implications for research into transsexuality, family relationships and social disclosure. Of particular interest to people of transsexual history and the research community is the absence of transsexual-specific data in the analytical results. This absence tends to reinforce existing ad hoc evidence, and an increasing body of scientific results, that implies transsexuality is not gene-specific but the consequence of more complex genomic interactions and apparently random processes. But it also poses near-term questions susceptible to soft answers by psychosocial critics.

The Whole Family

The Science paper focuses on how much additional information can come from examining the full genomes of the same family. In the research, ISB and its partner, Complete Genomics, sequenced the genomes of a father, mother and two children.

Both of the children had two recessive genetic disorders, those that lie in wait for possible activation. One was Miller syndrome, a rare craniofacial disorder; the other was a lung disease, primary ciliary dyskinesia (PCD). Both are detectable with current knowledge. The research team sequenced the parents and children and identified four candidate genes associated with Miller syndrome.

The human intergenerational mutation rate is a measure of how much the genome changes from one human generation to the next. The researchers came up with the first direct estimate, finding that parent to child gene mutations occurred at half the most widely expected rate. The parent to child generational span could be too limited for definitive results, however, arguing for studies across longer generational spans, and/or the existence of something more fundamental at work (depending on the incidence of the actual condition).

David Galas, a corresponding author on the Science paper, says he was pleased and a little surprised at how much information they collected during the study. "Comparing the sequences of unrelated individuals is useful, but for a family the results are more accurate. We can now see all the genetic variations, including rare ones, and can construct the inheritance of every piece of the chromosomes, which is critical to understanding the traits important to health and disease." Galas is an ISB faculty member and its senior vice president of strategic partnerships.

The quality and extent of the information depends, of course, on knowledge of the known genetic interactions and how they are influenced by larger genomic influences. Near term, a negative result for transsexuality might occur because the unknowns are precisely that: unobserved and unknown. This is useful information for scientists but could lead, in turn, to a counter argument by psychosocial adversaries that transsexuality truly does not exist.

The most powerful rejoinders to this are facts on the ground: we are here (as always), albeit as yet not fully examined or explained.

Tracking Diversity

"This estimate could have implications for how we think about genetic diversity, but more importantly the approach has the potential to increase enormously the power and impact of genetic research," said Galas. "Our study illustrates the beginning of a new era in which the analysis of a family's genome can aid in the diagnosis and treatment of individual family members."

If family genome sequencing does become widespread, the results will be standard entries in our medical records. Research into transsexuality that can leverage these results would entail multigenerational studies, with full participation from all family members, including the subject individual(s) with a transsexual history. Apart from other considerations, what if genomic data implies the existence — or absence — of transsexuality or its preconditions, once found? In either case, we can expect superficial readings of the results by hasty observers to craft muddled medical prohibitions and legislation.

The post-op population, especially male-to-female, would offer the most nearly uniform study sample since it could include individuals who exhibit full hormonal reconstitution and completed surgery. Even if accidental anomalies were included, such as autogynephiliacs, the percentage of genuine transsexuals would approach a level more nearly typical of similar studies of other birth conditions. And since transsexuals are involved, it becomes possible to gather useful data that can inform other research areas, such as twin studies, birth order, and hormone receptors (to name only a few).

Trends Toward Full Disclosure

We in the post-op transsexual population comprise an important dataset which, once defined and mined, has the potential for changing current scientific expectations for mutation, inheritance, and the contents of the human genome. Once rigorous whole genome sequencing in families becomes widely available, it can be used to identify variations that are clinically relevant and provide diagnostic information to inform the care of patients. 

An important implication is that the population sample could not include post-op individuals who maintain a relatively deep level of social stealth. TS-Si, Lisa Thompson, and I maintain absolute adherence to privacy, but some people do not and will sell out transsexuals in stealth if they get a chance. However, changes on the way do not depend on the involuntary exposure of non-participants.

Combined with the medical privacy concerns noted earlier, non-participation (for whatever reasons) is bound to have many effects. Either privacy considerations or non-participation have the potential to deter funding interest and preempt detailed transsexual research of this type before it even starts, at least for a while.Many of us fail to qualify as subjects anyway because our families are not intact. One or more of our immediate family members may be out of touch or dead, or we may have lost part or all of our families as a consequence of transition.

However, the situation is changing with the gradual extension of social acceptance to post-op transsexuals. Lest any of you genuine pre-ops feel left out of this discussion, please remember that you and those that follow us are the ultimate beneficiaries of improved detection and treatment.

In time there will be whole genomic sequencing for an intact family that includes a person with a transsexual history, and then another and another. For each of those families, testing of relatives and descendents will extend a progressively richer baseline. All of this data will then be available for use as new and even more powerful tools become available for analysis and discovery.

As The Future Arrives ...

Let us remember the parameters laid out at the start of this column, where the transsexual group of interest is identified as those who are hormonally reconstituted, surgically corrected, and successfully transitioned into society. It should be obvious that merely identifying as a transsexual without demonstrated commitment would flaw the dataset and render quantitative comparisons impossible. While this seems like common sense, it may take vigorous argument to deflect incursions from the psychosocial academics who will set themselves up as gatekeepers.

Which family will be the first to volunteer?

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Transsexual Research and Whole Genome Sequencing in Families
Monday, 15 March 2010

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