The Funniest Gene Name in History

The Unbelievable Story of Fucose Mutarotase

A couple of weeks ago, a post on Reddit’s r/TodayILearned brought the peculiarities of gene naming conventions back into the news; specifically, the fact that in 2020 the HGNC set some new standards for avoiding offensive or confusing abbreviations.

One priority was making sure that MS Excel (which powers an embarrassing amount of bioinformatics work) stops annihilating data by auto-formatting things as dates. Genes like MARCH1 and OCT4 got renamed, because…well, ‘‘you can’t fight city hall’’.

But this reminded me of another great story about gene names.
A story of what is either:

• an elaborate scientific hoax/prank,

• the greatest and funniest coincidence in the history of molecular biology, or

• proof that God exists, and he has a perverse sense of humor.

This is the story of fucose mutarotase.

It starts in the 1970s, with the identification of a cluster of bacterial genes that are important for handling a weird little sugar called fucose.

There are a lot of weird little sugars out there, since there are a lot of different ways you can stick together five or six carbon atoms, some oxygens, and a handful of hydrogen. You probably already know about glucose and fructose; these have the same molecular formula, but are put together slightly differently—giving them different properties.

Source

A lot of these weird little sugars aren’t typically burned for energy by cells the same way glucose is. They’re used structurally, e.g. to produce things like mucus, or they’re stuck onto proteins, where they can serve as flags that help your cells organize themselves. Little chains of these sugars on the surface of blood cells are what differentiate the various blood types, for example.

So they found the gene cluster for fucose handling, and a lot of these genes were given fantastic names—things like fuculokinase, abbreviated as fucK. But there was one gene that, when they were first characterizing these, they couldn’t quite figure out the function of. Naturally, it got the designation “fucose – unknown” FucU.

As it turns out, mammals have a similar gene.

Eventually, they figured out what the FucU gene does. See, fucose has a sort of ring shape, with carbon and oxygen atoms sticking off it at various angles. The protein encoded by FucU takes one of these oxygen atoms and flips it, so that it points the other way.

Here’s a really cool, high-resolution simulation of the enzyme in action

Enzymes that do this are called mutarotases, so—having figured this out, they renamed it: FucU became FucM, for fucose mutarotase. Seemingly a sad day for bawdy biology humor, but one that would soon be redeemed.

Knowing what a protein does at a molecular level doesn’t tell us all that much about its role in a complex system like an animal. For that, scientists use genetic manipulation techniques. “Knocking out” the gene lets you see what happens in its absence, overexpressing it lets you see what happens when you crank it up to 11.

This only works some of the time; if a gene is really critical, knockout animals fail to develop properly and die in utero. But around 2010, some scientists managed to generate some fucose mutarotase knockout (FucM-/-) mice.

What they found was frankly astounding.

Female FucM-/- mice behave like males. They refuse to be mounted; they show an olfactory preference for female urine, the way male mice do. Left alone with a female in heat, they’ll try to mount her.

So not only does this imply that some aspects of mammalian sexual behavior are regulated by this one literal molecular lever, it implies that we accidentally labeled it appropriately.

These days, people tend to jump all over anything related to the biochemistry of sexuality and gender identity, so let’s get this out of the way: you probably shouldn’t set too much store by any inferences about human behavior that you might be tempted to draw from this study.

Still, it’s an interesting finding, and not just for the coincidence of its name. The researchers did a bit of digging into what might mediate the effect, and it looks like the change happens in utero. At a certain point in development, levels of the estrogenic hormone estradiol are supposed to fall, thanks to a fucose-modified protein called alpha-fetoprotein.

This drop in estradiol is what triggers feminization in the brain of the developing fetus, by increasing the expression of dopamine-producing enzymes in certain brain regions.¹  The paper’s authors suggest that the lack of the FucM gene prevents alpha-fetoprotein from working properly, so estradiol levels stay high and the feminization never occurs.

These dopamine level differences are a primary driver of sex-based behavioral differences in mice. This is also true of humans, although human sexual behavior is (usually) a little more complicated than sniffing someone’s urine to find out whether or not they’re fertile.

Hope you’ve enjoyed this brief diversion from poop stuff. ‘til next time!

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1. If it’s confusing that lower levels of estrogen cause the fetus to develop as a female…welcome to endocrinology, where everything is topsy turvy, except when it’s not.