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Interview with Professor Nicholas Thomson – Why ACT?

Prof N Thomson explains the origins of ACT and what is it used for.
Prof Nicholas Thomson explains the value of comparative genomics in biomedicine
I’m Professor Nicholas Thomson from the Wellcome Sanger Institute, in Cambridge, and the London School of Hygiene and Tropical Medicine, in London. My research interests are bacterial genomics and the study of infectious disease transmission, and biology.
It’s a very simple concept. It’s the principle of comparing the content, structure, and orientation of elements within that structure of two or more different genomes.
Yeah. A-C-T, or ACT, stands for Artemis Comparison Tool, and it was developed because when we started to sequence genomes, we realised that if you had a very simple way of comparing them, you could identify important functions that differentiated two or more isolates. So, an example of that might be genes, which confer heightened virulence, for example. And so, by comparing them, you can identify those very easily.
The idea is that you keep all the annotations, all the gene predictions, all the information associated with function and context of the underlying DNA sequence. And it does a good job. It’s very simple. You can scroll through a genome. You can zoom in, zoom out. But what it doesn’t do is allow you to directly compare large sections of the genome with another genome. And so, ACT was conceived and developed. And, in essence, it’s actually two Artemis windows glued together. And the glue is what appears to be sort of red lines connecting regions or blocks connecting regions of similarity or high identity between two genomes.
So, it’s just a simple way of accessing genome data, which is Artemis, and then by gluing two together in A-C-T, or ACT, you can then very easily compare two different genomes.
So, there’s a beautiful story in Malawi, in 2006, cases of invasive non-typhoidal Salmonella causing disease, especially in children, with a very high mortality rate. Those strains were not responding, when that child or those children got to hospital to the recommended antibiotics. And so, by sequencing the genome of those invasive strains of Salmonella and comparing them to non-invasive strains of Salmonella, it became very clear, very quickly actually, that the invasive strains contained a large chunk of DNA, about 20 kilobases in size, so 20,000 base pairs, which encoded genes, which conferred resistant to therapeutically frontline antibiotics. And so, literally, by comparing two genomes, you could understand why those children were not responding to antibiotic therapy. And so, that’s one good example.
So, the real advantage of Artemis and ACT is that you keep all your information in the context of the underlying sequence. And that seems a little bit simple, but, in truth, the sequence, when you generate it, you can put statistics on in terms of accuracy. And so, we’re very good at doing that. And we know that for genomic sequencing these days, the technology is very accurate. And so, what Artemis and ACT do is they keep all of the information that you subsequently
add: the interpretation of that sequence in context to the underlying and the original consensus sequence, which means that no matter how sceptical or how confident you are about future predictions about gene content, you can always check by going back to the sequence that underlies it. And so, it’s simple but gives you the opportunity to go back to the data that you’re really confident about, which is the sequence.
Artemis and ACT are actually now fairly old tools, and so, they look slightly dated, but the functionality is still there. The functionality was developed actually in the days of single reference genomes, when we were trying to use that technology to annotate and to then submit different genomes to public databases. What that means is it’s menu-driven. They’re both menu-driven, and so they can be very complicated. There can be multiple different options and sometimes multiple different routes to do the same function. We always say it’s the 80-20 rule with 80% of the users using 20% of the functions. But that’s OK.
So, there might be some disadvantages in that there’s a lot of functionality that you don’t always need, especially if you’re just viewing genomes. But if you do, then the advantage is that there are many very tailored menu items, which perform relevant analyses on bacterial genomes. Some of the other softwares are much more modern and sometimes faster and sometimes give you a simplified set of methods, but it depends on what you want to do.
Modern genomic research is usually described as sequencing hundreds or thousands of different genomes. If that’s the case, then you actually do need tools that are different to Artemis and ACT, which wasn’t designed in an era where you could do that. You need different approaches to really identifying the pangenome, to identifying gains or losses of genes across, as I say, tens or thousands of genomes. So it has a role, but the role usually now is consigned to the latter stages when you’ve identified perhaps genes or regions of a genome that are of particular interest. What we tend to do then is to use those tools to look in much more detail at those regions.
And again, because you keep the connection with the underlying sequence, it allows you then to refine your view. So, it does have a role, but it’s a slightly different to the role it had before.
Well, it’s interesting because actually it’s not just research that Artemis and ACT are used in–its for all comparative genomics for that matter. They’re great tools for teaching, and we use them actually for A-level all the way through to degree level and then for research. They’re very accessible. They explain principles such as the coding frame and the idea of stop codons and the fact that you have forward and reverse strands coding genes separately - principles that sometimes are lost or not really well explained in modern genomics but are critical to understanding the biology of the organisms we’re looking at.
But, in essence, we’re using comparative approaches for real fine detail to understand how emerging pathogens might differ from closely related, less virulent versions of themselves. And it’s a really great way to home in on functions, genes, or just changes, as even base changes, that might differentiate different isolates which are, in your eyes, biologically different. And so, it’s a really great tool for doing that.
I think I’ve used it for every bacteria I’ve ever worked on so, from the Mycobacterium leprae where we compared it directly to Mycobacterium tuberculosis, and what was very evident was that Mycobacterium leprae had undergone very extensive genome decay. And so, whilst you could see the remnants, the sort of molecular fossils of genes which are still present and active and expressed in tuberculosis, you could see the remnants, the gene fragments of those very easily using ACT to compare the genomes. So, that’s one example. And that really was very early days actually. It started to write the book on a reductive evolution and an adaptation to very restricted niches.
We also looked at Bordetella pertussis and realised that the genome rearrangements in Bordetella pertussis were very unusual. And when we compared those to bronchiseptica, we realised that pertussis had recently jumped into a new niche, the human niche, or been restricted. And as a result, the genome, the constraints, which previously had kept the genome in quite a sort of a fixed pattern were relieved, and suddenly, the genome would become highly rearranged.
And then Vibrio cholerae: so some of my more recent work looking at Vibrio cholerae. We’re interested in toxins, and cholera toxin is the main virulence determinant that leads to a very acute watery diarrhoea. It’s carried on a bacteriophage. That’s a virus that infects bacteria. And that virus integrates within the bacterial genome carrying the toxin with it. And so, by very simply comparing genomes, you can see whether genome A has the toxin compared with B and so on. And we’ve learned a lot about the biology of pathogens like Vibrio cholerae from those sort of comparative approaches and realise that actually the biological story is not quite as simple as we previously thought.
So comparative genomics, in some people’s eyes, is an old-fashioned discipline, but it’s really not. It’s cutting-edge because it tells you really very important, biologically relevant differences between pathogens or even non-pathogens that have real importance both for basic science and for biomedical research.

In this step, we will hear an interview with Professor Nicholas Thomson

In this video, Professor Nicholas Thomson, Wellcome Sanger Institute and London School of Hygiene and Tropical Medicine, talks about comparative genomics, sharing his and others’ experience of using the Artemis Comparison Tool (ACT). He details research findings obtained using comparative genomics and the impact of these findings for a number of pathogens and isolates. The importance of ACT in teaching as well as research is emphasised.

Importantly, Professor Nicholas Thomson explains the value of comparative genomics in biomedicine: ‘Comparative genomics… is cutting edge because it tells you really very important, biologically relevant differences between pathogens or even non-pathogens that have real importance both for basic science and for biomedical research’.

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Bacterial Genomes III: Comparative Genomics using Artemis Comparison Tool (ACT)

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