Not just genes

14 November 2016

Interview with

Wendy Bickmore, IGMM Edinburgh

This month we're reporting back from the Genetics Society Autumn meeting, held at the Royal Society in London. Over two packed days we heard a fascinating array of talks focusing on one of the biggest challenges in biology - understanding how our genes get turned on and off at the right time and in the right place. We know that we have around 20,000 human genes that encode recipes to make molecules called proteins, which are the molecular 'workhorses' that build our cells and keep our bodies functioning. We also know that when genes are read they care copied out in the form of a chemical called RNA, which is similar to DNA. But only a tiny fraction of our genome is made up of these protein-coding genes. So what's the rest? To get a flavour of the talks aimed at shedding some light on the dark matter of the genome, Kat Arney caught up with one of the meeting organisers, Professor Wendy Bickmore, director of the MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh...

Wendy - What we realised was we were in this amazing situation now where thanks to advances in technology, and our computational power to store and analyse the sequence of the genome, we can actually study the whole genome of hundreds, thousands, millions of individuals. They might be individuals from different species and compare in between species, or individuals within a species, and different members of the human population. Or even between different cells within the same individuals so comparing cancer cells to the normal cells in the same individual. So we have that ability to capture that information and then we realise that actually, for the vast majority of that information, we can't do anything with it. So it's a great "stamp collecting" exercise, but it's a little frustrating if all you can do is sit and stare at the sequence. And that we realised the problem was, for the bits of our genome that code for proteins - so the protein coding regions of the genome.

Kat - The "honest to God" genes.

Wendy - Yeah, the proper...

Kat - The real genes.

Wendy - Yeah, the workers of the genome that actually code for messenger RNA that makes a protein that does stuff. We can make a fairly educated guess that if there is a particular change in the DNA sequence - a change from an A to a T, at that position - it'll actually affect the way a particular protein works. And therefore, we can say whether that change is going to matter for the individual, for the species, for the disease. And that's because we understand the triplet genetic codes - so three letters equals one particular type amino acid. So we've kind of got a grammar that we can understand what change means. But that part of the genome is only 2 per cent of our genome. So the 98 per cent of the genome is doing other stuff and we don't have that understanding of what a sequence change means because there's no code that tells us these three letters do this. So that's a huge challenge. So, we wanted to bring together people who were thinking about this in different ways. So people who are looking at evolution and what evolution tells us about the part of the genome that doesn't code for genes, so comparing different closely related species and looking at how sequence changes outside of genes. People looking at disease states for example, people using smart computational and statistical arguments to identify change that matters. And then people that are trying to understand at the level of molecules of what these changes might mean. I think what we've been hearing today in the meeting, I would categorise them into to two kinds of studies. There's those where the DNA sequence change is affecting, not a protein coding gene, but still a bit of the DNA that makes an RNA molecule.

Kat - We would call this like the non-coding RNA?

Wendy - Non-coding RNA is exactly the term they've been given. They do lots and lots of interesting different things in the cell so we know they have functions. We are starting to see that actually single changes in these RNAs can actually affect the way these RNAs work so fantastic examples where they actually change the shape of the RNA. So these RNA molecules fold into these wonderful knotted structures and just little tweak in the sequence can make new bulges and knots in the RNA which presumably affects the way the RNAs work. So, we're making pretty good progress I think in that but the bigger challenge looks like it's the sequence changes in the bits of the genome that don't even make RNA molecules. They don't even seem to make anything.

Kat - So we'll be calling these things like the control switches, the regulatory switches that are involved in turning genes on and off.

Wendy - That's what we think, yes. That's what we think these bits of DNA are doing, proving that is turning out to be really tough I would say, but it's very exciting. There's been some fantastic studies in fish. Let's talk about fish for example that live either in seawater or freshwater and looking at the changes in the shape and the behaviour of those fish, and seeing when you sequence the genomes of those two fish, the changes are in what looks like regulatory switches that are changing the way these fish behave or look. Starting to come out from human genome sequencing projects as well, evidence that there could be changes in some of these switch elements that are causing very severe human disease. They are probably contributing to common disease as well. And people are starting to develop assays in cells, in organisms using computational approaches to try and get some understanding at least of how these changes in sequence might work. But we're obviously a long, long way away from being able to really understand what these are. So there's progress being made. It's really exciting, but we know there's a big challenge ahead.

Kat - So, when the human genome sequence first came out back in 2000, 2001, I think there was this wonderful idea that once we have the human genome sequence, we would know all the genes and then we would know how it all works. And now 15 years later, are we like "Oh crumbs!" We're only scratching the surface.

Wendy - We are but we are excited by that because we're realising now how complicated our genome was. I guess one of the other disappointments I suppose from the human genome project was, everyone was expecting that we would have many more genes than flies and worms. We were all a bit deflated when we realised we only had approximately the same number of protein coding genes as a fly.

Kat - We're just sophisticated fruit flies.

Wendy - We are sophisticated fruit flies. We are more complicated than that and it turns out the reason why we're more complicated is we have more types of cells than a fly and we use a set of genes in much more sophisticated ways in those different types of cells.

Kat - So it's not what you've got. It's what you do with it that counts.

Wendy - It's what you do with it, indeed. That's true.

Kat - I think that sums up the whole meeting, right?

Wendy - Absolutely!

Kat - Wendy Bickmore, from the University of Edinburgh.

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