New, evolving genes sometimes have vital roles

Oddjob and Nicknack are genes that are prone to evolve and change. How is it they play a critical role?
17 December 2020

Interview with 

Harmit Malik, Fred Hutchinson Cancer Research Centre




One loose principle in genetics is that the oldest genes in our bodies, the ones that haven’t changed for millenia, must be like that because they do something critical for our survival. If they changed, we would die, simple as that. Whereas anything that is changing must be non-essential. Harmit Malik’s research overturns this principle, based on genes in fruit flies, and the reason why appears to be that the genes are constantly running on a treadmill; changing to effectively stay the same. Phil Sansom asked Harmit to explain...

Harmit - The dogma in the field has been for a very long time that the more conserved a gene has been in evolution, the more likely it is to encode an essential function. My lab was interested in asking what happens at the other end of the spectrum, where genes that are apparently not very well conserved: how likely is it that they encode essential functions? To address this we actually focused on one category of genes that we already knew showed some diversity. These are called ZAD-ZNF, which are the largest class of transcription factors required to turn on genes or turn off genes in a very regulated fashion in insect genomes. And we were surprised to make two discoveries. Discovery number one was that ZAD-ZNF genes that were not strictly retained were just as likely to encode an essential function. The second, more surprising finding was that ZAD-ZNF genes that were actually quite slow to evolve were actually less likely to encode essential functions.

Phil - So these genes, these ZAD-ZNF genes: a lot of them are pretty new, and despite that they're still coding for really important things; and even some of the ones that are evolving the most quickly are doing the most important stuff.

Harmit - That's exactly right Phil.

Phil - How is that possible? If they're doing such important jobs, how come they're so new?

Harmit - We were exactly puzzled by the same question, Phil. How is it that the genes that were very rapidly evolving were actually more likely to encode these essential functions? So to take a closer look at these genes, we focused on two of the dozen genes called Nicknack and Oddjob. These were genes that were named with a sort of inside joke, because these are both referring to James Bond henchmen.

Phil - Are these like henchman genes?

Harmit - Oddjob was named partly because it is a fairly odd gene, in the sense that typically if you have a transcription factor, you expect it to be localised to where all of the action is, where all of the genes are. Instead, Oddjob appeared to be localising to this essentially unmapped part of the genome which is really devoid of genes, for the most part. We refer to this as 'heterochromatin', which literally stands for 'other chromatin'. And we were really surprised to find that Oddjob and Nicknack do not localise to the gene rich, but instead to the gene poor heterochromatin part of the nucleus.

Phil - What is the gene poor part doing that is affecting the essential jobs, that are presumably part of the gene rich part, really?

Harmit - About 25 years ago, I would have told you that we know almost nothing about the gene poor part of the genome. More and more we are actually recognising that heterochromatin actually plays very important roles within the cell. Regions in the heterochromatin actually help regulate all of the other genes. So you could even imagine that they're sort of master puppeteers of the rest of the genome. It's actually becoming clear that the heterochromatin is just as important, if not a more important part of the cell.

Phil - That doesn't quite explain to me how they're in this fast evolving state, where you've got new genes coming up and the genes are changing so much.

Harmit - Yeah, so one of the really cool things about heterochromatin is because it's actually made up of repetitive elements, these elements are extremely different as you compare them between species or even between different members of the same species. So the paradox is really that they're able to carry on this master puppeteer function, but they're not actually doing so with exactly the same conserved DNA sequence. And therein I think lies the resolution of the paradox of Oddjob and Nicknack. In a way they're sort of acting as this buffer or mediator, to take all of this churn at the DNA level, and yet ensure that the conserved functions of heterochromatin are conserved over billions of years. So you have simultaneously this rapidly evolving, almost a competitor part of the genome, and yet you're dependent on this competitor for your essential function.


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