Tinkering with masculinity

Mr or Mrs fly?

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How does one embryo end up becoming male, and another female? Groningen biologists are trying hard to figure this out. Anyone who understands this can tinker with it, and that might come in handy.
Text and photo Christien Boomsma / Translation by Sarah van Steenderen

Surely the concept can’t be very complicated: the animal world has males and females. Together they ensure a genetic mix in their offspring, which makes the species as a whole flexible and fit to survive. Surely, a principle this fundamental must have been decided early on in evolution?

Apparently not.

The world is full of males and females, but nature has developed countless different ways to make them, geneticist and entomologist Leo Beukeboom says. In human beings, the gene that ‘makes’ a man is stored in the Y chromosome, which only men have. But this is not the case for all species.

Photo by Peter Koomen

Why is it useful? (1)

Fighting disease

Now that Sharma has his PhD, he will start working at the mosquito lab at Imperial College in London. He will work on combating the Zika virus.

Zika is transmitted by the yellow fever mosquito. People who are infected show flu-like symptoms and usually recover fairly quickly. Pregnant women, however, are at greater risk. Their unborn children are at risk of microcephaly – an extremely small skull. The problem is especially prevalent in Brazil.

Scientists are working on a way to grow sterile male mosquitoes. These males would then compete with fertile males in nature, reducing the population of harmful yellow fever mosquitoes, or even eradicating it altogether. Determining the sex beforehand and only growing male mosquitoes would make the entire process much more efficient.

‘In birds or butterflies, it’s the females that have two different sex hormones’, Beukeboom says. ‘But there are also species where the males only have one set of chromosomes, such as bees or ants. They only develop into females when the ovum is fertilised and the embryo develops a double pair.’


Beukeboom wants to know all about this. If he can learn to understand the genetics behind sex determination, he can then attempt to manipulate it. This could help in the fight against harmful insects.

In his lab at the Linnaeusborg, his PhD students Akash Sharma and Yanli Wu and he started a search for the gene that turns the embryo of the Musca domestica – the common, annoying, black house fly – into a male specimen.

‘You have to understand, four years ago, not a single insect’s male genes had been discovered’, says Beukeboom. ‘The house fly is especially interesting; within this species, there are different sex determination systems. These flies can be crossbred.’

The flies you find in your kitchen when your garbage needs taking out have a regular XY system, with their male gene on the Y chromosome. But the same flies from Spain, Italy, or Greece, could have their male gene on a completely different chromosome.

It was Sharma, from India, who finally managed to identify the gene that geneticists have been searching for for fifty years. In a laboratory full of plastic containers with buzzing, crawling black flies, he compared the transcriptome – the RNA molecules that are expressed in DNA – of male and female fly embryos. The differences he found led him to the gene he had been looking for.

Pregnant males

‘Then we injected a female embryo with the RNA of the gene we thought was the one we needed’, he says. It worked: the embryos no longer developed into normal females, but into male flies with ovaries. ‘Pregnant males’, Sharma says proudly.

He named his discovery Mdmd: Musca domestica male determiner. He could have left it at this.

But Sharma felt he could do more. While he had tried so hard to be the first person to discover the insect’s male gene, others had beat him to it. The male determiner of two types of mosquito had been discovered, and published about in top journal Science, just before he made his discovery, and he also wanted to publish an article in a top journal.

‘We used the CRISPR-cas9 technique to turn the gene off’, he says. ‘With that, the fly embryos that had started off as males turned into fertile females. We had completely reversed their sex’, says Sharma. ‘That was the most important discovery!’

It was more than enough for another article in Science, with Sharma as first author. The fact that his last experiment, where he tried to turn female embryos into males, had failed completely, was suddenly not that important anymore.


In the meantime, the research in the Beukeboom laboratory was yielding even more results. Sharma’s colleague Yanli Wu was also working on sex determination in the common house fly, but her research focused on something else. She discovered that the common house fly has only one ‘working’ Mdmd gene, but that it has copies in various locations, and that these copies strongly resemble each other.

‘It looks like flies’ sex genes have moved over the course of evolution’, Beukeboom explains the discovery. ‘It would also explain why there are so many different systems within the species.’

Why this happened is something that future research will have to find out. Beukeboom thinks it might be linked to temperatures. The closer the flies live to the equator, the less often the Mdmd gene can be found on the Y chromosome. They are still planning more experiments to figure out how this works exactly.

To Beukeboom, that’s all okay. It might be a shame that some answers seem to be beyond him, but he is fascinated by the new puzzles he has to keep solving. Time and again, things are more complex than he could have imagined.

‘Three masculinity genes have been discovered, in three different insects’, he says. ‘However, the gene works differently in each species. And there are more than a million different kinds!’

In other words, he’s not done yet.


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