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Episode Info: arieties, one a peloric variety with these petals that were kind of different. So when he crossed the common and the peloric, all of the offspring show the common form. When they self-fertilised, you got three common forms to one peloric form. That looks ever so Mendelian. Given that background, had Mendel been read by Darwin, it would have been just another case of what Darwin called preponderant inheritance. That is to say, cases where one parental character prevails over another. And it was in his view, something that happens sometimes, except when it doesn't happen. It was part of what he was trying to explain, but he didn't regard it as somehow the bedrock phenomenon.Kat: One of the things I know about Darwin that's always fascinated me, was that he didn't really go with this kind of concept now that we have of genes being inherited from mum and dad, in the way we understand on chromosomes. He had this idea of gemmules, these little blobs that came from the body and mixed and matched together when you made a baby. Was it more like Mendel's ideas just didn't fit in this paradigm he was thinking of?Greg: Well, it's absolutely true that for Mendel's purposes, all of the action when it comes to the passing on of parental characters, is in the production of egg cells and pollen cells. Darwin's hypothesis of pangenesis - which is the closest thing that Darwin has to a theory of inheritance - takes as its basic premise that the whole body is generative. The whole body, in Darwin's view, is involved in production and reproduction. He called it pangenesis just for that reason. Everything is making all the time.His claim, his hypothesis - which is the term he used - was that every part of the body is constantly throwing off these tiny - as you say - gemmules, nobody is entirely sure how to pronounce it. These tiny particles. And the whole body, the whole system is swarming with all of these particles. And once they're thrown off they multiply. And eventually, if the find the right attachment point, they will grow into the same part that threw them off. That's their function.Darwin thinks that he's able to explain not just inheritance, but the regrowth of parts, reproduction, really odd phenomena from our point of view of what he calls "the functional independence of body parts", the way that parts of the body seem to have a life of their own, all in terms of this single rather simple set of ideas about the body constantly throwing off these gemmules - pangenesis. So he would have explained Mendel's pattern, the same pattern as the Snapdragon pattern he got, as to do with what happens when one set of gemmules from the yellow seeded peas meets the set of gemmules from the green seeded peas, and the yellow ones just prevail. That doesn't have to happen. In other cases you get a kind of union and then the characters blend. In other cases there's actual antagonism and you'll get a kind of blotchiness. But Darwin thought he could account for those kinds of patterns and vastly more by this theory that almost no one accepted.Kat: I do love looking back at the history of science. You see how these ideas have evolved. You bring together Darwin, you bring together Mendel, you're bringing together the work of the early 20th Century geneticists, and then the molecular gene. And now we know that we have DNA and it encodes proteins, and now we have the body and all this kind of thing. Do you think we've got to a synthesis? Do you think that there is anything in the kind of ideas that we have now that are particularly right, or maybe might be proved to be wrong?Greg: Well, one of the things I think that's so instructive - and I found this today at the conference sharing Darwin's ideas on pangenesis - is that we live in a moment now when there's a lot of openness to the possibility that genes might not just be determining traits in a kind of sublimely determinist way, but might be interacting with other genes, with developmental contexts, with environmental contexts.Kat: It’s very wobbly!Greg: It's very wobbly. And in a lot of ways Darwin is more stimulating company than Mendel for being flexibly-minded about where one might look for the next instructive phenomena. So I think there's still room for both of them in the conversation.Kat: And finally, every so often I see headlines in science magazines saying, "Was Darwin wrong?" Was Darwin wrong?Greg: Well of course he was wrong. Mendel was wrong too. Most science turns out to be wrong and that's in some ways the beauty of science, the beauty of history, the beauty of knowledge. You don't expect that what people thought 150 years ago or 100 years ago is just going to be preserved in aspic. One hopes that it won't, that things will advance. Of course it isn't right, but what else would you expect? The important thing is that it proved to be fruitful. More and more I've come to appreciate that the ideas that turn out to be stimulating that spur creative work, that's a huge value in its own right not to be dismissed. Both Darwin and Mendel in their very different ways produced bodies of work which have been enormously stimulating to other investigators. So we've learned a huge amount from the two of them. We should be eternally in their debt, without by any means thinking that they got it all right.Sequence All The ThingsAt the time that Darwin was writing, there was nothing known about the nature of DNA, genes or genomes. Over the past 150 years, we’ve now got to a point where it’s simple and cheap enough to sequence the genomes of tens, hundreds or even thousands of species, all around the world. Leading these efforts to Sequence All the Things is the Wellcome Sanger Institute outside Cambridge in the UK - which played a leading role in sequencing the first human genome. I spoke to Dan Mead, who’s involved in co-ordinating the Sanger’s 25th birthday present to itself - reading the DNA of 25 iconic British species - as well as a larger project to sequence the entire tree of life. The first question I have to ask is why?Dan: The main idea is that if you can understand the genome for everything, you can essentially understand all of life. Which is ridiculously ambitious, but that's kind of what it boils down to. And in that sense, when you understand how everything has evolved and co-evolved over the four billion years that the planet has been around, you should be able to get a greater understanding not just of the natural world, but of us as well as humans. We've obviously evolved in the same way, we've been around for the same amount of time, we've all come from, in theory, one common ancestor back in the day. I don't know if that's actually true or not, but it's certainly an idea. And it also opens up a myriad of opportunities for drug discovery and material science and all of these other really exciting things.Loads of drugs and things come from plants and stuff. We don't know what we could get more from fungi or from animals, all of these things. Everything has co-evolved, so there's lots of interactions which have been playing out, chemical warfare races and all these sorts of things. You could look into the genetics of that and how you can produce these things. So the possibilities for science are just mind-boggling when you think about what we could do with all this information.Kat: I love that quote, what is it - Orgel's law, evolution is cleverer than you are?Dan: Absolutely! It's been working on it for billions of years, and we've only just started tinkering around the edges, looking at things that have been largely confined to laboratories for 50 years. So actually, exploring the natural world is just a phenomenal idea, I think.Kat: Apart from just the interest of knowing what's in all these species' genomes and how they might be related and how they might have evolved, what's the purpose of knowing this kind of information? What can we do with it?Dan: If you know what's there, you can use that to kind of help maintain it. So for instance, if you know what all of the species are and what all the genomes are in a particular country, you can then set up bio-monitoring stations which can essentially sample environmental DNA, to check to see what species are present.They do this thing for monitoring rare species in other countries. They go around and you can swab a paw-print for a snow leopard, for instance, and see if it is actually a snow leopard. In theory you can use the same sort of techniques to check to see that species aren't declining or if any new species are coming into areas. All this is very useful not just for conservation, but also for agriculture and monitoring effects of climate change and all of these sorts of things. So the first step is knowing what's there.Kat: I think that this is also interesting, given the people that I've talked to in zoos who are trying to do conservation and work out what are our breeding stocks, who is related to who, how close can we breed these species?Dan: Yes, absolutely. When you produce a genome sequence you can actually use certain computational methods to work out how fit a species is, in terms of what is its effective population size. One of the problems is when species get into trouble and they lose a large percentage of their individuals, the genetic diversity goes down, which makes them a lot more susceptible to disease and the effects of in-breeding and cancers and all these sorts of things. So you can find this information out from doing the genome sequencing.Kat: In the 1990's, we had projects like the human genome project and then there were a number of model organisms that researchers here at the Sanger and at other places were sequencing as well. I think it was like a mouse, and the tiny nematode worm C. elegans. How then over the past decade has that idea to sequence all the things changed and grown?Dan: I think actually it's largely driven by the technology itself. Now we have the actual physical capability of doing it, whereas I don't think even maybe two years ago, people would have been like, ooh, I'm not sure we could actually do that. But now, the rate of technology is such and has been such for a number of years now, that it exceeds Moore's Law in terms of the actual capacity, which is one of the few things that does. So the fact that we can do it, I think is almost a good enough reason to say why we should do it. And the economy is actually working out quite well, relatively speaking. The Earth Biogenome project, which is an even bigger idea to do everything on earth…Kat: All the things!Dan: Literally all the things. With an asterisk saying, "All the things we know about", which isn't very much as a species in total, but a million and a half species is still a lot. They've worked out that they think it would be cheaper to sequence all of the species on earth that we currently know about than it was to do the first human genome.Kat: Wow! That is absolutely incredible.Dan: I know, it's ridiculous. It's somewhere in the region of it cost $5 billion in today's money to do the human genome and it took 13 years. And now we can churn out genomes even today, without extrapolating cost reductions - the 25 Genomes Project, we reckon it cost about £10,000 to do a genome to the same standard that it did to do the human genome.Kat: Tell me a bit about the 25 Genomes Project. What was that all about?Dan: Sanger actually turned 25 last year. So we thought, what does Sanger do best? Sanger sequences things. That's our legacy, our history. So we thought well, we'll do 25 novel species from the UK, to celebrate our 25th anniversary.Kat: What kind of things are we talking about? You think about the UK and I think about, I don't know, pigeons and foxes and holly. What's in that list?Dan: There are some things which are very UK. We had a long discussion about what we should actually do. There was talk about doing stuff from just around Cambridge, around the actual Sanger Institute itself, and just going out and finding species here. We thought about doing things from specific countries, like doing something Scottish, something Welsh, something Northern Irish, something like that. So these discussions raged on in the steering group for a while. Eventually we just narrowed it down to five different categories. We picked an iconic category, so we did do things which you think would be a very British thing to do. Robins, for example, that's a typical thing. We've got golden eagles. That was our first one that we completed actually, really well. It's a bird, birds are good because they have reasonably small genomes and they're vertebrate so they're quite similar to humans, which makes them a little bit easier to work with in terms of the actual computational side of things. So we've done iconic things. We've got five in each category. We've got iconic, we've got floundering, which are things which are in a little bit of trouble. We've got flourishing, which are the opposite to floundering funnily enough, things that are doing quite well. We've got cryptic, which are species which you may not be able to see or you can see them but you might not know that there's more than one type of species.For instance, one of those is the pipistrelle bat, which is also quite an iconic species, but there's actually two or arguably three different pipistrelle bat species that look basically the same. There's the common pipistrelle and the soprano pipistrelle. It's called soprano because it calls at a slightly higher pitch.Kat: Not just because it's a bit of a diva?Dan: Well, it could very well be, it's enigmatic enough that nobody actually realised that it was a separate species until 1999.Kat: So maybe.Dan: Exactly.Kat: And what's your final category, then? Dan: What have I said? Floundering, flourishing, iconic, cryptic and… dangerous. Dangerous I'd forgotten and it's almost one of the most exciting ones. So that's things which could be either dangerous to us or dangerous to the ecosystem or potentially dangerous. So that latter one is the Asian hornet.Kat: Da-da-da.Dan: It's dramatic, isn't it? The hornet community would argue that actually, they're not that bad. But the honeybees would probably disagree. They've been on a steady march across Europe at the moment. There's been two or three nests found in the South West of England and obviously, as soon as they're found they are rapidly destroyed, because what Asian hornets do is they hunt and eat honeybees.Kat: OK, that's bad.Dan: That is bad. Especially with the trouble that honeybees are under at the moment anyway. And because they're not native, the honeybees have no defence, essentially. In Asia where they're from, the bees defend themselves by doing this thing called the bee-ball, I think it's called. I know, it's amazing. What they do is, they basically just get hundreds of bees, just all jump onto this hornet…Kat: A bee bundle!Dan: A bee bundle, yes exactly. And they beat their wings really, really fast to heat themselves up, and they essentially cook the hornet alive to kill it. It's pretty gruesome but it's very effective.Kat: Wow. OK, so it strikes me it would be interesting to know more about these animals. But then scaling up from that, we've got the 25 species that you did as part of the 25 genomes. What's the next stage then, the tree of life?Dan: So that is the idea over the next sort of ten to fifteen years, is to do all of the species in the UK. Which is around about 70,000. Kat: When I think of species, I think of animals and plants, but is it bacteria and fungi and other things as well? What comes under that banner of species?Dan: Under that banner is all of the eukaryotes, essentially. We won't be doing bacteria, we won't be doing viruses, but we'll be doing pretty much everything else. And I'll caveat by saying that's everything else that we know about. So we know of around about 70,000 species in the UK. The chances are that we'll probably find more because there's various estimations about the number of species that there are in the world, and it could be that we only know ten percent of the species, it could be that we only know one percent of the species in the world. So there's a good chance that we'll find some in this country whilst we're actually doing this.Kat: My favourite story about this was the recent thing about placozoa, which are these tiny little blobs, basically. I think they're the simplest animal you can get, it's just like a blob of cells. And then they did some genetic analysis and it was like, hang on, this is two different species that just look like exactly the same blob of cells.Dan: Yes, that's the sort of thing that we might have problems with. Kat: Oh, no!Dan: Absolutely. The actual identification of species is going to be one of the trickiest things to do. Even things which are known, some things you can't tell them apart by looking at them. There are certain species of flies which you actually have to inspect the genitals to be able to tell what species they are. I know, interesting. You find these things out when you go to the Natural History Museum and talk to entomologists and they're like, "Oh, did you know this?"Kat: Yes, I spend my life looking at flies’ underparts.Dan: Yes, exactly. So these sorts of things are going to be tricky, I think. And then there's stuff which is going to be symbiotic, like the placozoa. We've got the lichens, which are basically fusions of fungi and algae. All of this stuff is going to be fascinating to find out, and also really challenging at the same time.Kat: And that's another question, is how do you go about gathering all of these species? You know, I imagine you out with a butterfly net or a little Longworth trap trying to get hold a mole. How are you going to go about getting hold of all these samples to put through your sequencers? Dan: Yes. The logistics are going to be challenging, we recognise that. It's actually one of the major things that we need to plan detail for. There's also a licensing issue as well, because a lot of species are going to be protected or they live in protected areas, so we've got to work quite closely with the government and landowners and what not to be able to actually get access to them in the first place.One of the ideas we have is, if we're going to target an area and then sample everything that we can find in that area, so we build up an entire ecosystem, that way we should be able to get thousands of species that are all in the same place. We can collect them all from one place, which makes everything kind of logistically easier. That way we don't have to like you said, randomly walk around with butterfly nets trying to get things. One thing we're going to need to do is, we're going to need a lot of help from taxonomists. Obviously at Sanger we know sequencing, but I couldn't tell you the difference between two different earthworm species.Kat: You've got to look at their genitals.Dan: Exactly! That's it, isn't it?Kat: And how does this kind of thing fit into the broader perspective? Because obviously you've got 70,000 species in the UK, you've got many, many more in the rest of the world, so how are your efforts here fitting into maybe other efforts going on in other parts of the world? Dan: Yeah, like you said, there's 1.5 million known species which have been identified. It could be 10, it could be 100 million actual species. I think the important thing with the UK effort will be to blaze a trail for actually how this can be done. So, develop the technology, develop the collection methods and the logistics trains and the sequencing methods and the informatics, which is also going to be another really hard challenge to do at this sort of scale. And then we can use the knowledge that we gain here to inform other countries of how they could do a similar thing. Because all of this information that we're going to be generating is all going to be open source, it's still going to be free for everybody to use. All the methodologies and everything will also be freely available and published where we can. So yeah, we just want to enable everybody else to do the same science that we want to do.Kat: And finally, I've got two questions for you. The first thing is, what's your favourite species? And the second one is; is there any genome that you've looked at where you've just been like, woah, that is bizarre!?Dan: I think my favourite species that we've done so far is probably the golden eagle, because it's cool, because it's a golden eagle.Kat: Yeah, they’re cool.Dan: And also because it's the first one we did and it worked really well. And it was kind of a false dawn on how easy things would be. But you know, it gave us hope that these things can be done and so that's I think my favourite so far. We've had some interesting things. We've done a cricket, which is the Roesel's bush cricket. Just a nice, normal looking cricket. We expected a reasonable sized genome, slightly less than humans. And then we sequenced it and it's not, it's massive. The genome is two or three times bigger than what we expected it to be, which makes everything much more difficult. That was a bit of a shock and surprise. Also costly as well, because you need to do a lot more sequencing when the genomes are a lot bigger.Kat: I bet most people don’t have a bush cricket messing up their budgets! That’s Dan Mead from the Wellcome Sanger Institute. And if you’d like to find out more about the Sanger’s efforts to Sequence All The Things, take a look at their website:66,000 UK species to be sequenced25 Genomes for 25 YearsSnails and supergenesSince the days of Darwin and Mendel, studies on colouration have played a vital role in deciphering the mechanisms of natural selection and genetic heredity. While this work has encompassed many species from all branches of the tree of life, a particularly noteworthy one is the grove snail, Cepaea nemoralis, which comes in more colours than a Farrow and Ball paint chart.In the latest episode of the podcast from Heredity, the Genetics Society journal, James Burgon discusses two recent papers on grove snail genetics by Angus Davison and his colleagues at the University of Nottingham, investigating the so-called supergenes responsible for giving these molluscs their colourful shells.Angus: There are some individuals which are almost impossible to class by one colour or another. I suppose you might say, well, so what? Why is that interesting? Well, one of the weird things about this is that genes that determine the differences in these colours, we don't know what they are, but we know they are inherited in the supergene - that's a group of linked units. Traditionally, the theory behind supergenes is that they originate to produce distinct phenotypes, and that's absolutely what we haven't got in this system. I'm still a bit puzzled by that, and I think that maybe illustrates how ignorant we are of how natural selection and maybe also random genetic drift are acting in this system.Kat: You can hear the full interview in the latest Heredity podcast - just search for Heredity in your favourite podcast app, or got to the Heredity podcast page.That’s all for now. Thanks to my guests Dan Mead and Greg Radick, and also Emily Mobley at the Wellcome Sanger Institute. We’ll be back next time looking at some more of the top 100 ideas in genetics, as part of our special series celebrating The Genetics Society’s centenary year.You can find us on Twitter @geneticsunzip or email us at podcast@geneticsunzipped.com with any questions and feedback. Genetics Unzipped is presented by me, Kat Arney, and produced by First Create the Media for the Genetics Society - one of the oldest learned societies in the world dedicated to supporting and promoting the research, teaching and application of genetics. You can find out more and apply to join at genetics.org.uk  Our theme music was composed by Dan Pollard, and the logo was designed by James Mayall. Thanks to Hannah Varrall for production, thank you for listening, and until next time, goodbye.References:Discrete or indiscrete? Redefining the colour polymorphism of the land snail Cepaea nemoralis. Angus Davison, Hannah J. Jackson, Ellis W. Murphy & Tom Reader. Heredity (2019)Recombination within the Cepaea nemoralis supergene is confounded by incomplete penetrance and epistasis. Daniel Ramos Gonzalez, Amaia Caro Aramendia & Angus Davison. Heredity (2019)......
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