Gene for behaviour turns out not to be

And now to a genetic mystery that’s taken a hundred years to solve: scientists have finally discovered why flies with the “yellow” gene aren’t very lucky in love. And it’s not, as the first geneticists thought, anything to do with behaviour. From Harvard, and speaking with Chris Smith, Jonathan Massey...

Jonathan - In the early 20th Century, in Thomas Hunt Morgan's fly lab - he was one of the first geneticists to ever work with fruit flies - he started collecting the first mutants in the lab. And the reason why he was able to find them is because they had these pigmentation malformations in the bodies of the flies. So when he would dump his fruit flies out of his bottle into the microscope he noticed about one in several thousand wouldn't have the right colour eyes or wouldn't have the right coloured body. One of the first mutants was a yellow coloured fly that he discovered. And so he took this yellow fly, bred them together with other yellow flies, and he found out they bred true, which just means that that yellow colour was heritable. And so that became what is known as the yellow mutant fly.

Chris - And did he work out roughly how many genes - it's a single gene, isn't it, that influences this - were involved? Because those breeding experiments mapped onto the numbers that Mendel had produced in his pea plant, so we know when you've got one single gene influencing a factor you get a certain proportion of different characteristics in the first generation, second generation, and so on.

Jonathan - That's right. So that's a good question. His undergrad student at the time, Alfred Sturtevant, in 1915 or so created the first genetic map ever. So Alfred Sturtevant, through genetic crosses, discovered that genes are inherited on chromosomes and chromosomes are linear pieces of genetic material. And so, through genetic crosses just like Gregor Mendel did with his pea plants, they were able to discover not only that yellow was a single gene but that yellow was a gene that was linked to the X chromosome, which is inherited from mothers just like in humans and flies.

Chris - Were they intrigued by the fact that these were pretty rare, these flies? So the fact that this gene was mutated and these mutants were cropping up, but then they didn't get an increase in numbers of them, argued that there was something wrong with yellow flies. Were they intrigued by that?

Jonathan - Yes, so Alfred Sturtevant had many broad interests. He wanted to understand the basics of genetics, how chromosomes work, how they're inherited; but he also was really interested in speciation and biodiversity. He noticed it was difficult to maintain these flies, and he wanted to understand why. And so he did a very basic experiment: he took the yellow mutant males and he put them in a chamber with normal female flies and he noticed that, while they courted the females like normal flies do, they very rarely were able to actually mate with them successfully. So he wrote a little paper in 1919 describing this result, and it wasn't until the 1950s that it was picked up again.

Chris - And what did people conclude when they revisited the work? What was their conclusion as to why these flies were not maintained in the population?

Jonathan - Yeah it's a fascinating history. Margaret Bastock, a behavioural biologist in Niko Tinbergen's lab in the 1950s, she concluded after Alfred Sturtevant's work that, indeed, the flies courted normally but they didn't mate, just like Sturtevant described. Her conclusion from a beautiful study using a tape recorder to describe the behaviour of the fly over time was that, although they courted like normal flies, they did not do so in such an excited way.

Chris - Did people think then that this gene was in some way affecting the nervous system of the animals? Because pigmentation is intrinsically tied up with other chemicals that are also employed as neurochemicals - I'm thinking of dopamine, for example, which is made from the same precursor tyrosine that you can turn into a range of different things. Did they think that the colouration was a side effect of different neurochemistry, and that's why the behaviour was wrong and that's why they weren't mating very much?

Jonathan - So in the 1950s they didn't know what yellow did as a protein and - believe it or not - in 2019 we still don't know what the yellow protein does. But it wasn't until the 1980s and the 1990s that part of that biochemical work was worked out, and as a consequence of that, like you suggest, for the most part geneticists concluded that the reason yellow mutant flies have abnormal behaviour is because they have low or abnormal dopamine levels in their brains.

Chris - And is that true? How have you gone about testing that? Because obviously you've visited this and said, right, let's take a modern look at this quite old problem?

Jonathan - Exactly. So in 2016, an undergraduate Diane Chung and I decided to team up to try to solve the problem. And I, like geneticists for the last 30 years, also believed the problem dealt with dopamine. And the way we went about asking the question was to selectively remove the yellow gene from the brain of the fly and ask, what happens to their behaviour. And what we found is the flies behaved completely normally. Not only did they court normally, but they mated normally; so they didn't behave like the yellow mutants do. From that study, we were able to conclude that, really, its function outside the nervous system is what's important for behaviour.

Chris - So what is it then?

Jonathan - We know that yellow is required to make black pigments or black melanin in the fly. That's why, when you remove the function of yellow, the fly turns yellow. What we discovered is that, specifically, yellow function in making black pigments in these structures on their legs that are called "sex combs" is required for a fly's ability to mate. So when you remove yellow protein from these very tiny structures on the front legs of the males, the males lose the ability to grab the females, and that's what disrupts their ability to mount and finish the mating sequence.

Chris - How did the earlier workers miss that?

Jonathan - It wasn't until about 15 years ago that geneticists developed tools in flies to be able to answer these targeted questions. They didn't have the ability to remove the function of the yellow gene in different tissues of the fly. The other thing that was critical for this project is we used a high speed video camera that slowed down the mating sequence to 1000 frames per second, so you could see all of the really fascinating details of how the fly is moving. And it was at that point we decided this is likely what's wrong. We noticed that, though they were courting fine, that last sequence, in which they tried to grab the female, seemed disrupted and that's what pointed us towards the sex comb hypothesis.