When I first saw this recent publication, Male Gender Identity in Complete Androgen Insensitivity, I thought, “Hey, this case has really interesting ramifications about gender identity. I’ll make a blog post about it!”
Then, I broadcast on my blog that I was going to make a post about it. Big mistake.
As I drilled deeper and deeper into the literature and went down different tracks and tangents, I realized that I had potentially bitten off more than I could chew.
This subject, if explained correctly (my own anal definition of “correctly”) would touch on aspects of molecular biology, genetics, biochemistry, cell biology, physiology, embryology, psychology, sociology, behaviorology, and probably other “ologies” I can’t even think of.
But not being one to give up so easily on something (especially in public), I forged ahead. In doing so, I realized that in order to explain this subject in a way that would have everyone on the same page, I would need to bring in some very basic information about how genes work and how proteins are made. Why? Because Complete Androgen Insensitivity Syndrome (CAIS) is due to genetic mutations of the androgen receptor (AR), and the AR is a transcription factor in that, when androgens such as testosterone bind to it, it sits down on DNA and turns on genes.
Now all this talk about explaining DNA and genes and stuff like that always gets me thinking about one thing above all others:
That’s right, Orenthal James Simpson, “The Juice,” former star running back for the Buffalo Bills, NFL hall-of-fame inductee, actor and convicted felon, currently serving 15 years in Nevada for armed robbery and kidnapping.
What is the connection between O.J. and DNA? You might remember a case in Los Angeles in 1994 involving Mr. Simpson as the main suspect in the murder of his ex-wife, Nicole Brown, and her friend, Ron Goldman. His televised murder trial lasted nine months.
At the time of the O.J. Simpson murder trial in 1995, I was doing postdoctoral research in a lab at a university out west. My lab mates and I watched the trial when we could, especially the testimony regarding the DNA evidence against Simpson.
The DNA evidence came from blood samples taken where the bodies were found, from bloody gloves, one found at the scene of the crime and the other found at Simpson’s estate, and from bloody footprints at the scene of the crime, all containing DNA from Brown, Goldman and Simpson. The technology for DNA fingerprinting was relatively new at the time, and the prosecution took great pains to explain it to the jury. The problem was, the pains they took actually became painful to watch.
I remember that guy drawing DNA double-bonds, DNA base pairs, A, T, C, G, and droning on about how the DNA analysis was done and how DNA works and what DNA is made of and blah blah blah… He was so boring and so uninspiring and didn’t explain it all in lay-terms for the jury (I thought anyway) and I could only think, “Man, you are losing your audience!!”
In the end, after nine months of testimony and acrimony and courtroom theatrics and Johnnie Cochran’s catchy rhymes and Judge Ito’s inability to keep the court in order, and blatant mistakes by the people investigating the crime (one police scientist-in-training carried a vial of blood from the crime scene in her lab coat pocket for a day before submitting it as evidence) and the prosecution (asking O.J. to try on the bloody glove), plus ineffective explanations about the DNA evidence, the jury only needed four hours to deliberate to an acquittal.
So much of the case hung on that DNA evidence that botching it and its explanation, in my opinion, sunk the prosecution’s case.
At the time of the O.J. Simpson trial, I was part of a mixed bunch of scientists in the lab I was telling you about. There were protein biochemists, biologists (like me) and molecular biologists (the folks to play with DNA and engineer genes). A few weeks after the verdict, one of my fellow biologists, who I’ll call Kevin, was asking one of the molecular biologists, who I’ll call Artie, to explain a new DNA engineering technique.
Artie grabbed a scratch piece of paper and started enthusiastically drawing genes and sequences and DNA cuts and splices, talking a mile a minute. Kevin listened patiently for about 30 seconds to Artie’s very animated explanation and then politely stopped him by saying,
“Dude, O.J. is walkin’ …”
What am I getting at? Unlike what happened in the O.J. Simpson trial, I want to avoid unintelligible explanations about DNA and how genes work that would result in the acquittal-level confusion of my audience.
Now for all this explaining, I say, “Thank goodness for YouTube!” More on that in a little bit.
The Androgen Receptor (AR)
The AR gene, located on the X-chromosome at location Xq11-12, is one of the most mutated genes in the human genome. So much so that there is a database just for AR mutations. At the writing of this post, there are almost 400 known mutations of the AR gene. That’s alot!
Because the AR gene is on the X-chromosome, individuals with XY chromosomes (usually being natal males) carry only one copy of the gene, that which came from their mother. If that copy of the gene happens to be mutated, then a phenotype (a physical manifestation of the mutation) may be more readily noticable.
In XX individuals (usually natal females), one mutated copy of the gene inherited from one parent can be masked by a wild-type (i.e. normal) copy of the gene inherited from the other parent. In that way, XX individuals can unknowingly be carriers of a mutated AR gene that could show up with a phenotype in their XY offspring.
The structure of the AR gene and protein are shown in the diagram below:
The location of the AR gene on the X-chromosome is depicted in the top part of the diagram. The structure of the AR gene is shown in the middle, with the boxes depicting its 9 exons and the lines between the boxes depicting introns. When the DNA of genes are transcribed into RNA, the exons are the sequences that encode the mature protein (i.e. the product of the gene) whereas introns are spliced out. (I’ll provide better information about all this below.)
As I mentioned before, the AR is not only a receptor — it’s also a transcription factor, as are all steroid hormone receptors. When the ligand (an androgen such as testosterone or dihydrotestosterone) binds to the AR, it brings about a conformational change that allows other proteins to bind to the AR to form a complex. The complex becomes a functional unit that can sit down on a specific DNA sequence in different genes and initiate transcription (i.e. turn the genes ‘on’).
In order to do all those things, the AR protein has a number of specialized domains which are depicted the figure provided above.
The N-terminal domain (i.e. the front end of the protein) has sequences that encode a transactivation domain that helps the AR turn on genes, plus a coregulator binding domain that allows the AR to bind to other proteins. (See on the AR database all of the known proteins that interact with the AR.)
In the center of the protein there is another coregulator binding domain plus a DNA-binding domain that allows the AR to bind to specific sequences in the DNA of certain genes. At the C-terminal end of the AR (i.e. the back end of the protein), there is a domain that binds the ligands, which are androgens such as testosterone and dihydrotestosterone (DHT). There is also a sequence of amino acids for nuclear localization that helps the AR become transported from the cell cytoplasm, where it is made, into the cell nucleus where it does it’s work.
Now the AR is not a flat candy bar of a protein like that depicted in the diagram above. The amino acid sequences of the different domains of the protein fold into very specific 3-dimensional configurations that allow the AR to function properly.
So, a mutation in the DNA-binding domain would not allow the AR to sit down on DNA, a mutation in the ligand-binding domain would not allow it to bind testosterone or DHT, and a mutation in the coregulator binding domains would not allow the AR to bind to coregulator proteins and turn on genes.
Clear as mud, right? Well, that’s where YouTube comes in.
Here is video about DNA structure:
Here is a great PBS video that explains how DNA makes proteins, from transcription to translation. (The sound effects crack me up.) In this first part of this video, the AR and its coregulators would be the colored group of proteins that grabs the DNA chain to start the transcription.
Here is a video that describes how mutations can arise in DNA gene sequences and how two different types of mutations affect the protein gene product:
Sorry for all the homework. I hope you enjoy the videos and can understand what I’ve talked about so far regarding the androgen receptor, it’s gene and it’s protein structure. If you have any questions, please ask in the comments.
In Part 2 of this series, I’ll talk about the different AR gene mutations and their relationship with Androgen Insensitivity Syndrome, which was mentioned in a previous post with a link to an informative article.