With a switch of a letter in DNA ‘dark matter,’ Israeli scientists change sex of mouse

[IwantToRetire]

Bar-Ilan University researchers use CRISPR tool to alter Enh13 switch controlling Sox9 gene, causing XX mice to develop as males; study may help explain other genetic mutations ...

Gonen laid the groundwork of her research by saying that when people talk about sex, “many people have the tendency to confuse biological sex with gender and with sexual orientation, but those are actually three different pillars or layers.”

Sex determination is a process that is “fully biological,” and it “all happens during embryonic development, giving rise to males or females.”

"We understand much of it, but not all of it,” she said.

The next issue is gender, she said, which may have a biological trait, “but we don’t have really good tools to study that with mice.”

“No mouse will come and tell me, ‘Look, I’m a female, but I feel like I’m a male,'” she said. “Those are things that are really hard to study, but we know they are there.”

She said that one in 100 children and adults around the world, including Israel, will feel like they don’t match their biological sex.

Finally, the last pillar is sexual orientation.

“Most males are attracted to females and females are attracted to males, but you can have females attracted to females and males attracted to males. We know that this also exists in the animal kingdom, but it’s harder to study. Mice won’t say who they’re very attracted to.”

Full article https://www.timesofisrael.com/with-a-switch-of-a-letter-in-dna-dark-matter-israeli-scientists-change-sex-of-mouse/

And for those who can understand the language, this is the paper the artaicle is based on

A single-nucleotide enhancer mutation overrides chromosomal sex to drive XX male development
https://www.nature.com/articles/s41467-026-71328-9

I'm half hoping that someone can read the research report and put it into plain English!

Who knew that DNA had "dark matter"?

When will they develop the very special technology that will allow scientists to interrogate a human foetus at the stage before the critical moment to alter their sex, to ask if they feel more like a boy or more like a girl?

Because phew, imagine the lawsuit if they got it wrong!

Dark matter just means all the dna that doesnt directly have templates to make proteins. Scientiats used to call it junk dna. It makes up 98% of the actual length of the dna and obviously was important for something else but scientists are only just working out what some of it does.

The paper is talking about a bit of dna called an enhancer which basically controls whether a gene can be switched on or off.

What they have found is that if you effectively smash the switch up (by using a technology called crispr) , you cant turn the gene on any more and the person default develops as a male.

Is this just another option to choosing to an abortion if it is found the fetus is biologically female?

Instead you tweak this "dark matter".

I did wonder if in the research paper they explained why they were doing this.

They are just trying to understand which genes control the development of sexual characteristics.

You cant switch this in an actual child and if you did they would be infertile

Many thanks, most have cross posted.

I can just about grasp that.

Do they in any way explain why they want to do this?

There is lots of research into how embryos develop from a single cell into a whole person full of different types of cells. This is just part of that research. Its important for lots of reasons but in terms of obvious stuff it could enable us to help treat infertility or treat people with DSD if they wanted treatment.

@Geneticsbunny thanks for posts. In a rush now so hope to re read later, and try and understand.

Happy to answer any extra science questions you have.

Oh Frankenstein much.

I suppose one reason for doing it could be, apart from to find out if they can, is because there are conditions that can get passed on from mother to child, and maybe this could lead to a way that could be prevented in future. 🤷‍♀️

I dont think making people infertile is an ethical way of stopping genetic disease! Pretty sure the nazis tried that already and it didnt end well for anyone.
Plus gene editing human embryos and allowing them to grow is illegal worldwide because we dont have a good enough understanding of the techniques and consequenses yet. .

That’s interesting the male is default. As it’s XY you would think the Y is then important male part and the X the default. Strange

“No mouse will come and tell me, ‘Look, I’m a female, but I feel like I’m a male,'” she said. “Those are things that are really hard to study, but we know they are there.”

I want to know how they know that some male mice feel female and vice versa. Or is this badly written up, and she's acknowledging this in humans (gender dysphoria) but making no comment on mice? If it were the case in mice, that would be one hell of an argument in favour of an innate gender. But it's kind of hard to imagine it is. I mean, can they even conceive of themselves as individuals, or conceptualise sex difference, in the ways I'd assume would be necessary for this?!

Actually female is the default normally. I didnt explain that very well. Its a bit complicated because cells start as default cells which can be anything called stem cells. Then different genes are switched on and these switch on other genes which switch on other genes which turn the cells into kidney cells or testicle cells.

Basically if the gene in the paper (sox9) cant be switched on then there are more genes switched on which push the cells towards the testicle cell fate than those which would push the cells to be ovary cells.

They added or removed a small number of base pairs of DNA at a specific location and the XX mice developed visually as males but they had small testes and didn't produce sperm (so were infertile).

"Here, we show that XX mice carrying a 3 bp deletion or a 1 bp insertion within the SOX9 binding site (BS) of Enh13 present with female-to-male sex reversal. Adult XX mice appear externally and internally as males, but with small testes devoid of sperm due to the lack of the Y chromosome"

Could also be groundbreaking in switching off genes that increase cancer risk or any catastrophic genetic conditions - start with a clear yes/no result, then move on to conditions that come through most strongly via one parental line, etc, etc.

I also had a look at the reviewers comments (you can access the file at the bottom of the article). Scientists always want to over-emphasise the importance of their work but it's interesting to see what one of the reviewers picked up on from the original paper that got changed.

The authors originally said: "Here we show that XX mice carrying a 3 bp deletion or a 1 bp insertion within the SOX9 binding site (BS) of Enh13 present
complete female-to-male sex reversal."

And the reviewer commented: "The term “complete” may be misleading, since XX mutants exhibit ovotestis development (see Figure 2) and lack germ cells in adulthood." which led to the change in the final paper.

But then in the press release they're back to talking about "complete sex reversal" again
https://www.eurekalert.org/news-releases/1122852

I'm guessing that this dark matter still doesn't mean an adult female mouse can grow a penis and start producing sperm. Nor do I suspect it will mean an adult male mouse can grow ovaries and carry a baby mouse.

Nor would I suspect this to be possible with a juvenile baby mouse given when ovaries the eggs within them develop.

This story kind of created an idea of false hope. For it to be done to humans you would
A) have to break a lot of medical ethics
B) experiment on children
C) have parents of a particular strong mindset.

Basically it sounds like they've effectively created a sex chromosome developmental disorder created in the womb like a DSD but are labelling it as a breakthrough to help transpeople who transitioned later in life.

That's pretty fucked up on multiple levels.

They created a DSD in the mouse.

This might possibly prove a game-changer in some strands of genetics research, but it's nowhere near godlike control of a mammal's sex. Can't blame them for positioning their report within such a fashionably hot topic, though..

Hah, @RedToothBrush, crossposted! (I was slow to hit the button.)

It is just a primary research - adding to understanding how the DNA modification by crispr works, but published with a big fuss because it vaguely touches a hot topic.

No mouse will come and tell me, ‘Look, I’m a female, but I feel like I’m a male,'” she said. “Those are things that are really hard to study, but we know they are there.”

Maybe they've just not found the right kind of squeaks yet.

I have to admit, even without understanding the procedure exactly, I thought the comments in the newspaper article if not inappropriate not very "professional".

On one level you would think, or like to think, that if it is a breakthrough they would say how it was, and what if any application it would have.

causing XX mice to develop as males;

Aren't TW going to say this is discrimation?

What about their rights?