Duncan Odom - Swapping switches

Kat - It's time to return to the Genetics Society autumn meeting. Every year the Society awards a number of medals to some of the leading geneticists around the world, who are invited to give a guest lecture at one of the society's meetings.

This time around there were three worthy winners - Felicity Jones from the Max planck Institute in Tubingen, Germany, who picked up the Balfour medal for 2016; Ben Lehner from the Centre for Genomic Regulation in Barcelona, Spain, who won the same award last year; and Duncan Odom from the Cancer research UK Cambridge Institute, who walked away with the society's Mary Lyon medal. I asked him to give me a run-down of the work he and his team are doing to figure out the differences in the control switches between different species and how they contribute to the incredibly diversity of life on the planet.

Duncan - The key piece that we're trying to exploit is the fact that nature has done a lot of the experiments that we in the laboratory would want to do anyway. So, there's a huge amount of sequence turnover which clearly is driving a huge amount of regulatory turnover as well. My laboratory specialises, along with our collaborators, in trying to connect these two things - by actually doing experiments in tissues from a lot of the species where we have genetic sequence information but we don't necessarily have any functional genomics data and then connect those two things.

Kat - So what kind of species are you looking at and what are you looking at when you get their DNA sequence and line it up?

Duncan - The species that we tend to focus on are often ones that the entire community has chosen in the sequencing space to be important. These include a number of species like dog and cow, rat, mouse that a number of laboratories have a long history of working on both for agricultural reasons as well as for evolutionary biology reasons - their evolutionary separation might be almost the same length as human and mouse for example. Those species, we didn't choose actually. The community chose them to sequence to the highest standards to start with. What my laboratory specialises in is adding on another layer of functional genomics data that allows us to go in and connect the sequence that the community has developed with functional data that we can then analyse to try to connect the sequence evolution with functional evolution. Does that make sense?

Kat - Let's unpack this a little bit so, if we think about just the genes that make proteins and we think about them across lots of different species of say, mammals.

Duncan - Those are largely conserved.

Kat - They're pretty much the same so that's what we know. So then you're looking at the - what is probably wrongly called the "junk DNA", the "non-coding DNA" all the other stuff of the genome.

Duncan - Yes.

Kat - So, how do you then start looking at that? What sort of things are you looking for when you're looking for these important control switches?

Duncan - It's much straightforward than you might imagine. There are very specific histone marks which are known to associate with active promoters for example. So, by simply mapping where those are in the genomes within specific tissues, we often use liver, you can identify what regions in the non-coding genome as you accurately put it, are functionally deployed or at least prepared to be functionally deployed in the cells of interest.

Kat - And by histones, these select the wrapping, the packaging proteins of DNA.

Duncan - Yes. Those are the highly positively charged proteins that DNA coils around in the nucleus to take what's 2 metres worth of genetic sequence and compress it down into the micron scale.

Kat - In your studies, was there anything particular challenging to figure out how to do?

Duncan - So, we obtained whale and dolphin material from a British cetacean stranding investigation programme. Those species have very poorly sequenced genomes. One of the challenges that we had was to try to align sequence information that we got from our functional assays back to a very fragmented genome. That was one serious challenge that a lot of the more unusual mammals that we were able to obtain post mortem tissue for posed.

Kat - What's kind of the take home message from the research that you found when you're looking at these control switches between species and comparing? I mean, we know that the genes are all roughly the same pretty much. What about the switches? Can we say they're the same too?

Duncan - That was one of the major discoveries that we've made is that most of the switches in fact are quite highly divergent and they change very, very rapidly. Even ones that are near genes that are thought to have conserved control, it turns out that oftentimes, this control is not conserved - in particular switches that have to be turned on have changed between species. It would be sort of like having one light in the centre of a room and in human, you flip the on switch from the bathroom door. But in mouse, that's migrated to the hall door. It's still the same switch. It might even be on the same side of the room but it's nevertheless in a different place.

Kat - I love the idea that we have very, very similar genes in different species of mammals, but different mammals look different - you've got things like whales, through to mole rats, to humans, to dogs, to cows - are these switches really evolution's playground I guess?

Duncan - That's a good way to put it and that's definitely true.

Kat - Here at the Genetics Society Autumn Meeting, we've heard a lot of stories about these control switches, how they work, people searching for them, people trying to define them. What do you think are really the big questions we still need to answer here?

Duncan - Ultimately, the tools that we had developed based on the very high conservation of protein coding genes are largely inadequate to understand the functional constraints and how they express themselves through non-coding DNA. That to me is one of the key messages from this meeting - that a lot of the hopeful and understandable approaches that we were thinking would naively solve some of our questions around what human genetic variation does, a lot of these tools are simply inadequate and we really have to develop a different framework for understanding them. That to me is one of the major take homes from this conference.

Kat - Duncan Odom, from the Cancer Research UK Cambridge Institute.