The origin of Europe's MS disease, and South Pole sequencing
This episode of Naked Genetics, the origins of multiple sclerosis markers in northern Europe is revealed, and why it might have helped more people than it hindered; we also look at organisms surviving in Earth’s most extreme conditions; and ask just why might a bunch of organisms be turning into crabs?
In this episode
00:43 - The genetic reason for high rates of MS in Northern Europe
The genetic reason for high rates of MS in Northern Europe
Shivani Shukla
First up this week, let’s look at a big story in the genetics sphere, and what might be some of the deeper questions being asked by geneticists. It’s time to venture back down into Cambridge and link up with one of my genetics gurus, Shivani Shukla.
Will - Lovely to be back in Cambridge. Shivani, you're flying solo this month. How do you feel?
Shivani - Very exciting. Thank you for having me.
Will - How does it feel to know that 99.9% of all the genetic knowledge in this room is currently in your head?
Shivani - Are you sure It's not a hundred percent <laugh>
Will - Well, I guess we'll find out. Anyway, let's jump into the story. It's a seemingly huge story and has generated not one but four papers in the journal Nature. Spearheaded by several universities including the University of Copenhagen, but also the University of Cambridge, where we are sitting right now. Researchers have created the world's largest ancient human gene bank by analysing the bones and teeth of almost 5,000 humans who lived across Western Europe and Asia up to 34,000 years ago. The new study has found that genes that significantly increase a person's risk of developing multiple sclerosis were introduced into Northwestern Europe around 5,000 years ago by sheep and cattle herders migrating from the East. Shivani, first and foremost, before we get into the genetic side of things, what is multiple sclerosis?
Shivani - Multiple sclerosis is an autoimmune disorder, which means your immune system is overactive and essentially starts attacking things that it shouldn't. So in this case, it's the myelin sheath that's found on the outside of nerves and once you attack that, the nerves don't function properly. You get things like motor disorders, sensory disorders, and it can have quite an impact on someone's quality of life.
Will - Stuff like this is definitely worth then finding out where something like multiple sclerosis came from. And this is seemingly what they've done. They've said here in the paper, that they've taken samples of bones and teeth from 5,000 individuals. But then how do you go from that to a genetic map of the past that you can use to track diseases?
Shivani - There were already a lot of specimens sitting in museums across Europe and beyond the DNA of those 5,000 specimens were then sampled to create the first of its kind actually, which is an ancient gene bank. And then to translate that to seeing how that impacts multiple sclerosis in the present day population, they took data from the UK Biobank. So then you just compare and contrast the two using statistics and that allows you to trace backwards and forwards.
Will - And now that we found this seemingly this nexus point of about 5,000 years ago where multiple sclerosis has been introduced into Northwestern Europe, and you've said that it's a bad thing in terms of being a neurodegenerative disease, but the paper seems to allude to the fact that it wasn't necessarily bad for the people that had this genetic marker at that time.
Shivani - That's true. And I think it's important to point out that biogenetic marker, we are not saying that multiple sclerosis was advantageous to those people. What actually happened was the genes that code for advantageous things 5,000 years ago, which in this case was protection against certain diseases, were actually pleiotropic. So that one gene coded for multiple proteins or multiple traits and it just so happened that that also conferred a higher probability to get to multiple sclerosis.
Will - I hate to use words like ‘trade off’ because it implies choice or sentience, but the fact that it is seemingly worth risking MS to be able to stave off these diseases.
Shivani - I suppose so, and you have to think the lifestyles of the people at the time who were raising cattle probably didn't live much beyond thirties anyways, so they didn't really run into the troubles of multiple sclerosis later on. They were just trying to stay alive and eat and live. So in this study they also found that hunter gatherers there were many genes that conferred protection against similar diseases as these cattle herds. But actually even more specific diseases like viral haemorrhagic fever and mosquito carried infections, but those genes gave them a higher risk of things like rheumatoid arthritis, which is another autoimmune condition. So that's another example of that gene was protective at that time and was probably positively selected for, and now we are not staving off viral haemorrhagic fever, but we have the remnants for that gene and unfortunately that gives those people or descendants of those people a higher risk of autoimmune conditions.
Will - I suppose then that kind of leads us to the present day and knowing this and knowing what we know now, is there anything we can do with this in terms of treatment?
Shivani - I think it's an interesting way of looking at a disease because you can kind of think about the advantages of a disease. And that's true for things like sickle cell anaemia, which disproportionately affects African-American population and it's advantageous to protect them against malaria. So when you start to see things from a different perspective, perhaps that can kind of guide the pathways in which you take. And perhaps those inflammatory markers or those chemicals that are associated with fighting off pathogens might be the ones that we want to start targeting for MS because there's an underlying link, which perhaps we didn't know about before.
Will - As with every good scientific paper, they are always going about what they want to achieve in the future. And their plans are to look at the genetic markers of stuff like ADHD, schizophrenia, bipolar disorder. What would you personally be most interested in finding the origins? If you could pick any neurodegenerative disease, what would be the most interesting you think to find the origins of?
Shivani - That's a very interesting one. <laugh>. I think for things like ms, because we know it's autoimmune, you'd think there's an immune advantage of it at some point, so that's less surprising. But perhaps Parkinson's, which is a movement disorder and degeneration of the dopamine neurons over time lead to quite shaky movements and the symptoms we associate. And it makes me wonder what could be the advantage of a movement disorder because that's less obvious than something immune related. And it's really hard to hypothesise, do you have any ideas about something that controls movement might be advantageous. And especially its coordinated movements.
Will - Unless it is simply tied to something else that is advantageous and it was deemed worth it then that you could therefore survive long enough to procreate and, whoopsie, you got Parkinson's, but at the end of the day you still managed to reproduce. It's all a mystery. And I for one, am very interested to see where this paper goes in future.
Genetic sequencing at the end of the world
Melody Clark, BAS
In the UK, we are experiencing something of a cold snap. And that got me thinking. Whilst it’s no effort for us humans to chuck on a coat and hat, that luxury isn’t afforded to pretty much every other living organism out there. I’d assume. So, when the temperature drops, it often falls on an organism’s genetics to keep them alive and kicking. So what does that look like, and how is our understanding of such genetics changing? Well, it's worth finding out, but there’s no point in half measures when looking into this kind of stuff. So that’s why I’m joined by the British Antarctic Survey’s Melody Clark...
Will - Melody, where are you right now?
Melody - I'm actually sat in an office in the Bonner Lab, which is the marine biology laboratory at Rothera research station, which is about halfway along the Antarctic peninsula.
Will - You are at the South Pole. Marvellous <laugh>. We've really outdone ourselves. What's the weather like there today?
Melody - It's very south poley actually. It's blowing about 40 knot winds and it's absolutely freezing. And that's a very good reason for staying inside. Thank you very much.
Will - I do not blame you at all for that, but it presumably means that certain organisms, particularly in the waters around you, have a bit of a problem when it comes to low temperatures.
Melody - They do, but it is actually much more stable in the water than it is on land. So where I am at rather at the moment, the water temperatures throughout the year vary between about minus 1.86 degrees Celsius, which is when seawater freezes, up to the giddy heights of plus one degree Celsius, which it reaches briefly in the summer. If you go to the other side of Antarctica to McMurdo, which is by the Ross Sea, which is permanently ice covered, the animals only experience about half a degree temperature difference in the year. But essentially all the animals in the sea live almost permanently below zero degrees, which is pretty cold. Contrasted with that is the variability of the environment. So we have 24 hour light in the summer, 24 hour dark in the winter and in the summer you get these huge phytoplankton blooms, which is the kind of green stuff, the algae and diatoms in the water between about November and February. And then also we have the sea ice here, which doubles the size of the continent every year.
Will - All of this put together it sounds like a not ideal set of conditions for organisms to survive. But you've been looking at a group in particular. Would you mind talking our audience through what this latest genetic study looked at?
Melody - We've been looking at the notothenioid fish, which are the dominant group in the Southern ocean. The project was to sequence the genomes of these animals, to identify the genes in them and really to develop a resource to start to understand how these animals survive in such extreme conditions. And we sequence 24 of these fish species. And the idea of that was to, if you want to look at cold adaptation, you want to sequence as many animals that live in the cold as possible. So you can identify species specific variation, but also you want to compare them as closely as possible to ones that don't live in the cold. So you can identify the difference between cold specific adaptation species, specific adaptation. And yes, those genomes are readily available to the whole community and anybody can look at them. And the important thing is that now we have this information for these fish, we can start to use techniques that we're using to investigate model organisms such as mice, rats, and zebra fish in more detail in these fish species.
Will - Is there a potential idea then that someone takes all of this genetic data and they can find a gene or a genome or a cluster that might be able to explain how certain fish manage to survive such cold temperatures?
Melody - Exactly. And with 24 genomes, that's a huge amount of data. So by making it publicly available, people can then go in and investigate their favourite gene, their particular pathway or maybe do some large scale studies to try and identify in general how these species have adapted to the cold. So there's a whole raft of possibilities that people can research into now that these sequences are publicly available.
Will - This is almost a call to arms then, isn't it? If someone's out there and has a favourite gene, which I love the idea of someone having a favourite gene, you can go out and get stuck into this. Taking this up to sort of a more phenotypic level, we know several of the adaptations as to how fish can survive the cold. Is it then a case of us trying to work backwards into seeing which genes are responsible?
Melody - Yeah, so we know some very common adaptations that have been known for a long time. So all of these fish have a particular sort of antifreeze. They wouldn't be able to survive without antifreeze in their body. And it's an antifreeze glycoprotein and that they all have it. Bizarrely this identical molecule also is present in the polar cod. And this is one of these quirks of evolution where nature comes up with the same answer to the same problem in completely different areas of the globe in a slightly different way. So it's an example of convergent evolution. So they all have this antifreeze molecule that they produce all year round to help them survive the cold. And there are also some more weird adaptations. So we have about 16 species of fish called ice fish. They're called ice fish because they look completely transparent and when you cut them, their blood runs clear. It's not red. So it doesn't have the haemoglobin molecule, the red molecule that we all have in our body that carries oxygen around. And so these fish survive without haemoglobin. They only carry about 3% of the oxygen that a normal fish would. And they managed to do that because it is so cold in the southern ocean and as you cool water down, the amount of oxygen it increases. So it's heavily oxygenated. So they survive in this environment because it's heavily oxygenated and also they really do nothing much at all. I mean, they are the ultimate couch potato. So if food comes past their nose, they'll eat it, but they don't really go hunting for food. And this is a very peculiar adaptation that's only been possible because it's so cold in this environment. And in terms of other adaptations, yes, then we really need to understand what the other ones are. These are the common ones we know about, but there are bound to be plenty of others.
Will - And as you say, some of these adaptations are only possible due to the cold nature of the environment. Which brings me to the inevitable topic, whenever anyone mentions Antarctica, which is climate change, how might the shift in climate affect these fish and the future studies on them?
Melody - Okay, well, I'm afraid to say for the ice fish, it's really not looking good because they don't have haemoglobin. As the waters warm up, the oxygen amount will get less and they are not able to make haemoglobin. They've completely deleted it from their genomes, which is one of the interesting genetic discoveries. In terms of the other fish, they really don't like being warmed up very much at all. And neither do the marine invertebrates. The marine invertebrates like sea cucumbers, sea stars and sea urchins. So it's not looking good for them in terms of their temperature tolerances, but also we don't know how that affects their reproduction, their immune system. And also when things warm up, you may get more diseases that affect these animals. We simply don't know. But I would say on balance it's not looking great, which is a rather depressing thing to say isn't it. But I mean, if we have the genomes of these animals, we should be able to understand a bit more about how they perform and how they survive. If that's a more promising note to end on.
15:24 - Extreme conditions leave universal mark on extremophiles
Extreme conditions leave universal mark on extremophiles
Lila Kari, University of Waterloo
There are plenty of extremes out there: high and low temperatures, high acidity, high pressure, and surviving in them also requires some seriously specialised genetic adaptations. And it turns out that the wide range of these extremophiles, microorganisms capable of making a living in hot springs or deep sea trenches, might have more in common with each other than previously realised. The University of Waterloo’s Lila Kari explains...
Lila - We are looking at extremophiles, which are organisms that not only habit but thrive in environments characterised by extremes. They are found in the most inhospitable places on earth, including volcanoes, underneath polar sea ice, hydrothermal vents on the seafloor, and even in the presence of radiation and toxic waste.
Will - So to find out just what makes them so hardy, you've been having a look at their genomes. How exactly did you do that?
Lila - So we looked at the genome of extremophiles, organisms in generals, in terms of a language to clarify. In the same way we use the letters of the Latin alphabet to write text and bits zero and one to write computer code, the four basic DNA units used by nature to write genetic information as DNA sequences. And what we studied is what is called the genomic signature of DNA, which is obtained by counting the occurrences of DNA words in a DNA sequence randomly selected from an organism. And here by a DNA word, I mean a sequence of DNA letters, for example, cat is a three letter DNA word consisting of the letter CAT. So it turns out that word frequencies are important and contain taxonomy information about the organism, species, family, genus class, and so on. And this is akin to being able to tell apart an English book from a French book by the fact that the English book is going to have a very high count of the word 'the', and the French book is gonna have a very high count of the word 'les'. So you can tell them apart by counting words and looking at the word usage profiles without knowing a single word of English and French. And in the same way we can study DNA in the genome by counting frequencies without needing to know anything about genes, proteins, or anything like that. So this method has been proved very successful for biodiversity species identification and species classification. Just look at the word counts.
Will - This seems like an extraordinarily large amount of data you had to sift through. Presumably you had help from cutting edge technology.
Lila - Actually, no, we don't need the entire genome. Remarkably you can take any short DNA fragment. The human genome is 3 billion letters. But we can look at a segment that is maybe 5,000 letters and by word counts of this short fragment, we can determine the species. And this genomic signature is so stable that it doesn't matter where you expect it from, from the beginning, the middle, the end, chromosome one, chromosome five, gene, non gene, long sequence, short sequence, they all have the same pattern. So this is one of the strengths of the method. You do not need to sequence the entire genome, you just need that tiny little fragment.
Will - So what did you do once you'd found this out?
Lila - So this has been used very successfully for taxonomic classification. But we looked to see if this genomic signature contains other information, for example, environmental information. And we knew that if there was any hope to find an environmental signal, we would have to look at extremes. And this is why we decided to look at the genomes at extremophiles.
Will - Does that mean then that if the environment in which something lives in is so extreme, it will leave a mark on the genetic information of the thing that's living in it?
Lila - Yes. That was our hypothesis, and it turned out that we confirmed that, as unlikely as it seems. And for that, we used the machine learning methods, both supervised machine learning and unsupervised machine learning.
Will - So does that mean then that if two organisms that may be unrelated live in similar conditions, that their genetics might be the same?
Lila - Their genomes certainly are the same. So what we found is that, as unlikely as it sounds, as unlikely as is, two organisms, a bacteria and archaea that are more distantly related than ebola is from a lichen, were grouped together as similar in terms of word usage because they are both adapted to high temperatures, for example. And this environmental signal, it's pervasive, it's everywhere, sprinkled everywhere along the genome, and you can detect it everywhere. No matter where you take a DNA fragment in the genome. It's a little bit like finding a new dimension of the genome. You know, we thought it was only text and actually it's songs and it has also a musical signal besides the lyrics and the text in it.
Will - So if you flip that on its head, then if you were to just look at a genome in abstract, you might be able to tell where it lives just by the frequency of certain areas of it.
Lila - Absolutely. Yes.
Will - That's quite extraordinary. So does that mean that we could potentially use this in a way of mapping organisms throughout the world?
Lila - Yes. However, I would say I am not sure that this applies to normal environmental conditions. Remember, we looked at really extremes like organisms that are very, very hardy and they have to live under very harsh conditions for a very long time. Probably for like more normal conditions, the signal is more faint and more work needs to be done in order to be able to see whether we would be able to detect. I'm sure the signal is there, but whether it is too faint to detect for normal environmental conditions, that remains to be seen.
Will - But that could well be where you'd hope to go next in this study then.
Lila - Yes, actually it's very interesting. We are also interested in this because people are interested in space missions and Mars missions and outer space. So some of these extremophiles, for example, Deinococcus radiodurans, with a radio tolerant organism, it survives vacuum radiation, desiccation, cold temperature, you name it. It was proved not by us, by other scientists, to be able to survive outer space for one to three years. So very interesting questions arise regarding what it takes to be able to survive out in space. And as it turns out, it's not enough to change this gene here or this protein here. What you need is like a pervasive change along the entire genome. So it's not as simple as you think it is.
Will - I would never assume it would be anything close to simple when it comes to sequencing genomes. So throughout this, were there any highlights or any organisms that you'd love to shout out as your favourite?
Lila - Well, I have to mention my favourite extremophile, which is Pyrococcus furiosus. You've got to love the name. Pyrococcus means ball of fire and furiosus means furiously. And it's called that because a little bowl of fire swims furiously in a hot aquatic event of 100 degrees temperature, which is its optimal growth temperature.
22:47 - Why is everything turning into crabs?
Why is everything turning into crabs?
In this month's 'quirks of evolution', and a very unusual convergence occurring in the animal kingdom. Let me take you far back in time to the prehistoric year of 2018...
It’s morning at the mouth of the River Tamar in the south west of England. Conditions are quiet and still. Cutting through the fog that is hanging just above the water is a small fishing vessel, and aboard it are 4 doe-eyed wannabe marine biologists including yours truly because, whilst this boat is used to fish, it is also used to teach.
But it is also used to fish, and a net full of the river's occupants is slowly drawn up the back of the boat. The irony that, to preserve marine species you must kill some of them in a net, is not lost on us. The unlucky landing this time around features fish, rays, and, in adjacent pots, crabs.
This abundance and diversity was noted by one of the marine biologists on the boat as he remarked to another ‘I didn’t know we had so many crabs.’
‘Yes,’ came a disembodied voice. ‘And there’ll be even more soon.’
Enter stage right, the captain of the boat. White wispy hair, a face like stained oak, and a woolly hat older than most religions. Strolling past the children masquerading as scientists, and with all the whimsy of an abattoir, he muttered, ‘we’ll all be crabs one day’.
That memory will stay with me beyond any heartbreak, endeavour, or achievement in my life. What on Earth did he mean by that? At the time, in all honesty, I thought it was just an offhand comment about how we shall all die and become food for crabs. You know, classic ship banter amongst friends.
It was only years later that I discovered the truth.
Carcinisation, later dubbed the ‘return to crab’ phenomenon by strange parts of the internet, was a term coined in 1916 by zoologist Lancelot Alexander Borradaile. It refers to a case of convergent evolution, involving the process of non-crab-like animals evolving crab-like features over time. Or, in Lancelot’s words: "the many attempts of Nature to evolve a crab".
The theory suggests that over generations, a bunch of distant crab relatives, like lobsters or shrimp, decided to ditch their disgusting, non-crab-like body plans and start resembling crabs. There are lobsters and hermits out there masquerading as crabs, indeed 5 separate groups of non-crab crustaceans have been exhibiting this phenomena.
So why do this? Why go to all this trouble? Well, because crabs are perfect.
Crabs have a hard exoskeleton that protects them from predators. This also helps them retain water, which is handy when you live in the salty ocean. Their bodies are broad and flat, making them efficient swimmers, and their legs are adapted for both walking and swimming. If you’re a shoreline creature, it really pays to be able to live on land and in sea. Crabs also have specialised claws for grabbing food and defending themselves. Even the small ones can pack a noticeable nip. It makes sense, then, that other organisms have taken note of their bauplan and followed suit.
But the extent to which they have done so is remarkable. Convergent evolution, when two or more organisms evolve the same thing, is very common. Sometimes there is one way of doing things that is both effective and worth the energy expenditure to develop. But to assimilate an entire other organism really is something special. But is it all surprising? Well, perhaps not. Crabs have been around for over 200 million years in one form or another, surviving a couple of extinction level events along the way. There are over 7000 species of true crab alive today, that’s more than all of mammals combined. They’re schooling us. This is a winning formula that we are sleeping on, arrogant as we are in our soft fleshy prisons. There is one man with the requisite to understand what is necessary for us to survive as long as 200 million years, and he might still be operating a boat near Plymouth. Maybe, it was like 7 years ago, I don’t know. What I do know is that the past was crab, the present is crab, and you would be simply naive, a gormless rube, to think the future is anything other than crab.
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