Slave Trade, Neanderthals, & COVID
This week: a risk factor for severe COVID that comes from Neanderthals; using genes to track the millions transported as slaves across the Atlantic; a doctor runs through the list of what coronavirus mutations are worth watching out for; and learning population genetics from a video game...
In this episode
00:32 - Neanderthals & COVID-19: a genetic risk factor
Neanderthals & COVID-19: a genetic risk factor
Hugo Zeberg, Max Planck Institute for Evolutionary Anthropology
Scientists have discovered that a piece of genetic code in some people that makes them more likely to get severe COVID-19 actually comes to us directly from Neanderthals. This genetic variant is about 50,000 letters of DNA long, and a study across the whole human genome identified it as the only major genetic risk factor for serious coronavirus infections. And when Hugo Zeberg at the Max Planck Institute for Evolutionary Anthropology heard about it, he discovered the Neanderthal link...
Hugo - This is a variant on chromosome 2, and there's a lot of genes in this region. So we don't really know what gene it is, but we see the effects. People carrying this variance are more likely to end up in the hospital with Covid-19 and end up in the intensive care unit.
Phil - Oh, really? Do we know how much more likely?
Hugo - Yeah. So the latest studies put this risk at 100% risk increase.
Phil - A hundred percent?
Hugo - Yes. So for a genetic variant, this is a quite strong effect.
Phil - How many people have got this?
Hugo - In Europe, one in six. Or people with European ancestry, that's one in six. And people in South Asia, one in two. It's missing in East Asia and it's missing in Africa.
Phil - So this gene variant comes to us directly from Neanderthals?
Hugo - Yes. That's true.
Phil - Not to question you of course Hugo, but how do you know?
Hugo - We have three really good genomes from Neanderthals. So we extract DNA from bones. And then we have the genome of people living today and we can just compare the genome to the Neanderthal genome.
Phil - And that's what you did. You saw this variant and you just looked through the Neanderthal genome and then you saw, "Oh my God, they're exactly the same".
Hugo - Yes. I fell off my chair when I saw it! I should say that the finding of this risk variance is not my doing, but what I did was to see that, "Oh gosh, this is a Neanderthal variant."
Phil - Tell me how unlikely do you think this is. Because obviously we're not, we don't come from Neanderthals. So what are the chances of us having this gene that's from them?
Hugo - Yes, that's a very good question. Each individual with ancestry outside Africa carry 1 to 2% Neanderthal variant. So it's not super likely that it would be a Neanderthal variant. But I think that in terms of pandemics, they might be more important. So if you separate groups, they develop their immune system to the local environment. And Neanderthals and modern humans were separated for half a million years. And then they met. So the immune system might be somewhat different.
Phil - You seem to be sort of hinting at what this gene variant might do. Are you suggesting there's a chance it might have something to do with the immune system?
Hugo - Yes. Yes. There are several receptors that modulate the immune system in this region. And we know that some of the people who have gotten very sick with Covid-19, they are characterized by an overactive immune response. So this is one hypothesis. There is also another good hypothesis. And there's another gene in this region that encodes a protein that forms a complex with the receptor for the virus. So how the virus gets into the cell. So that's another good hypothesis. We're trying to figure that out, but it probably modulates the immune response somehow. I should say, it's also striking that it is so common in some parts of the world that we believe that it couldn't have been that bad for 50,000 years. Almost like it must have been quite good because it's more common than the other Neanderthal genetic variants.
Phil - So, so it's possible then maybe if this is something that helps your immune system react more strongly, that's something that's previously been good. And it's just backfiring now.
Hugo - Exactly. One can think that it might protect against some pathogens, and now you get a too good response and this overactive immune response.
04:60 - The slave trade's genetic impact
The slave trade's genetic impact
Steven Micheletti, 23andMe
We're discussing history’s largest ever forced migration, the transatlantic slave trade: hundreds of years of ships stealing people from Africa across to the Americas. Steven Micheletti, a geneticist who works for the company 23andMe, has been part of a team looking for hints of this enormous upheaval in the genes of people in the Americas today, and checking to see if records of the slave trade really paint the full picture; as he told Phil Sansom...
Steven - To study a huge impactful event like this you really need global representation of study participants. And so fortunately we have a huge database of individuals that want to be part of our research.
Phil - How many people have you got in this study then?
Steven - In this study we have just over 50,000 individuals.
Phil - And that adds up to how many genes, or how many bits of DNA? Just so I can get it in my head...
Steven - In general we're looking at around a million different genetic variants.
Phil - Now what does that tell you? Because this is just the genes that people have today.
Steven - Right, but people today inherit those genes from their ancestors that existed long ago. So that's how we make the connection: we're essentially looking at the common ancestors between people that are currently in Africa and people that are currently in the Americas. One of the largest analyses that we focused on is called 'identity by descent', and like the name implies we're looking at identical sections of your genome that are shared with somebody else. And the reason those segments are shared with another person is because you have a common ancestor.
Phil - And can you be absolutely sure that it's not just a coincidence, you've ended up with the same genes by accident?
Steven - Yes, we do have different criteria that we apply to these analyses to give us a lot of confidence. For instance, we're looking at basically portions of the genome that are at least 3 million base pairs long, which is a large chunk of the genome.
Phil - Okay, that'd be a pretty big coincidence if you both had that same 3 million chunk by accident!
Steven - Absolutely.
Phil - You also have genes from people in Africa today that you're comparing these sequences to?
Steven - Correct. We have people in Africa that associate with over 24 different ethnolinguistic groups along the Atlantic coast of Africa; and these groups were heavily impacted in the past by the slave trade.
Phil - Right, so you've got then 50,000 people's gene, and you're finding the ancestors that are in common that may have come over on the slave trade. But these are untold millions of people transported against their will; how many actual common ancestors could you get with 50,000 people's samples?
Steven - Yeah, as you point out, there were so many people impacted by the slave trade; but people would have had to have reproduced for there to be any genetics to compare whatsoever. And what we're finding in this study is that there's cases where enslaved people simply weren't reproducing, and we're probably not able to capture that signal.
Phil - How many ancestors have you got then?
Steven - Quite a bit. The vast majority of people in the Americas have a genetic connection back to Africa. And one of the unique things about the transatlantic slave trade is that it was pretty well documented. Each shipping voyage from Africa to the Americas has shipping manifests associated with it, so we're actually able to compare these genetic results with the historical shipping estimates.
Phil - And what did you find?
Steven - In large, the shipping records match the genetic results. For instance, in the Congo region of Africa about 5.7 million people were enslaved, and we find that the most genetic connections are with the Congo region. However, that's not the full story; when we start to look in more detail at certain regions of the Americas we do find discordances between the shipping records and the genetic results. For instance, in the United States we tend to see an overrepresentation of genetic connections to Nigeria, and an underrepresentation of genetic connections to Senegal and the Gambia.
Phil - Why?
Steven - The overrepresentation of Nigerian ancestry, we believe to be caused by these other slave trades that were going on simultaneously with the transatlantic slave trade, generally forcing people out of the Caribbean into different regions of the Americas. And what we believed happened is that people with Nigerian ancestry in the Caribbean were being forced into the United States. Another piece of literature that supports this is that people from present day Nigeria were often forced into these breeding programs in the United States.
Phil - Oh, dear...
Steven - And there's evidence that this typically happened more in people with Nigerian ancestry.
Phil - Wow. Now you're getting this data from people who sign up to your database. Are these people who want to know the results of what you found, who might be interested; or are those people who don't want to know; or is it by necessity anonymous?
Steven - By necessity it is anonymous. One of the goals of this study though was to give back to people who might be interested in this topic. So we're hoping that study participants will read this and gain further insight into the slave trade. There might be personalised results that come out of this study as well.
11:07 - Coronavirus mutations: which are important?
Coronavirus mutations: which are important?
Wesley Long, Houston Methodist Hospital
Whenever the term 'mutation' gets mentioned in the context of the coronavirus, there’s usually confusion, because it sounds like it’s coming out of either a zombie movie or a Spiderman one. But the coronavirus - like all viruses - mutates all the time in tiny, often insignificant ways, whenever little parts of its genetic code get copied badly or otherwise change. We talked about this in a previous episode called the Coronavirus Mutation Situation. So the question is: among the flood of unimportant mutations, which ones are actually relevant or concerning? Phil sansom asked Wesley Long from Houston Methodist Hospital in Texas, one of many scientists tracking the virus as it spreads...
Wesley - The two genes that we've focused on the most, that many people are focused on: one is the spike protein, that's the large protein on the surface of the virus that, when you see the pictures of the viruses on the news, are the spikes that stick off of the coronavirus that really give it its name. And the other protein that we've been studying is a gene known as NSP12 or RDRP. That's really the protein that allows the virus to make copies of itself after it's infected a cell. And the reason we're really interested in both of those proteins is they affect treatments and therapies. The spike protein is particularly important for how the virus gains entry into cells; it's also the target of our immune system, our immune response; and then the RDRP is the site of action of antiviral drugs like remdesivir.
Phil - I guess then to figure out if these things are changing, you've got to track the virus over time. Where and when have you been looking at it?
Wesley - We've really been sequencing the virus now since March. So it's been about six months for us in Houston, in terms of having patients infected with COVID-19.
Phil - Over those six months, have you found anything important? Any big mutations?
Wesley - We have; we've found a wide variety of mutations. In particular there's one mutation, which has gotten a lot of press globally, in the spike protein; the resultant strains contain an allele that's often referred to as just G614, or "these are the G614 strains". They're really now the predominant strains in Europe and North America. And then we've found other mutations in the spike protein; and then also in the RDRP protein, some of which are concerning because they're near the active site for remdesivir. The possibility exists that the virus might be able to perhaps mutate to become more resistant to remdesivir or other antivirals.
Phil - Let's go back to the big change that you have seen then, which is this G614 you talked about. Describe what's happened there.
Wesley - It's just a single amino acid, this one single building block of that spike protein, that's changed. And for reasons that are still being investigated, it appears that that single change may have made it easier for the virus to infect host cells. There's still some debate about what the exact effect of the mutation is; however, the one thing that we can say is certainly in areas where this mutation has been found, strains with this mutation seem to become the predominant strains rather quickly over time. For instance in Houston, about 70% of the strains that we were seeing in early March had this G614 mutation. By the time we had our second wave, really June/July, essentially 99% of all the viruses that we were seeing were G614 mutation containing viruses.
Phil - Is that a one time thing, or is it likely that that might happen again?
Wesley - It is possible that it could happen again. It's another reason that we need to keep tracking the virus and sequencing it. It's also possible that there may be mutations that affect it negatively, that make it less fit. There is an example of a mutation that was found in Singapore in a different gene called ORF8, a rather large deletion of that gene, that appears to cause a virus that's much less severe. So the mutations can go either way in terms of changing viral behaviour, or increasing and decreasing severity. It's worth noting in our samples from Houston that although we have the G614 mutation, which seems to affect the ability of the virus to spread in populations, we didn't identify any mutations which affected outcomes in patients, positively or negatively.
16:46 - Niche: a population genetics video game
Niche: a population genetics video game
Philomena Schwab, Stray Fawn Studios
In the final part of the programme, we’re talking about population genetics: the study of genes not in a single living thing, but in a group of living things. There are lots of factors influencing the frequencies of genes in populations, including whether the genes are dominant or recessive, whether they get helped or hindered by evolution, or in many cases, whether strange things happen thanks to random chance. Studying this usually requires a lot of quite dry maths, so I’ve found a better alternative. I’ve been trying out a new video game - and speaking to that game’s creator...
Philomena - Hi everybody, I'm Philomena Schwab, I'm a game designer from Switzerland; and me and my team made a game that is called Niche: a Genetics Survival Game, which is a simulation game about population genetics. You are in charge of a population of animals - kind of like mammal-fox-like, but they can also have other animals' traits - and you're trying to keep them alive against all kinds of different odds, such as temperature changes or predators.
Phil - Okay, let's start this up. I'm going to hit play...
Philomena - So now we're going into story mode, so you will be playing as the little guy Adam who is a baby animal. While he and his sister are digging around looking for food, suddenly there's a big shadow on the ground, and a bird of prey swoops down and grabs Adam and carries him off into the distance. Adam wakes up and he's like, "oh my God, where am I?" And Adam is fending off and fighting back and scratches the bird of prey, so the bird of prey lets him go and he falls down. Luckily he survives the fall, but he's now in an environment that he has never seen before, far away from his family, and he has no idea what is going to happen next. And that's you!
Phil - So I'm this almost tiger-like little model sitting in this hexagonal grid.
Philomena - And the game now tells you you have to go and collect some food, so you go next to that berry bush and then you just hit the collect button. Depending on your ability to actually collect food you get a different amount: so you could have an animal that is absolutely horrible because it doesn't really have any fingers, or you can have animals with very nimble fingers that are very good at plucking out all these berries from the bush.
Phil - Am I doing okay?
Philomena - You're doing okay!
Phil - Okay, and now I can leave my first island.
Philomena - Yes. So here on the second island, you arrive and you smell the presence of another member of your species.
Phil - Oh, and I can see... because my hearing is so good, I've got these big ears, I can see another animal across this island.
Philomena - Exactly. And you can offer her five food that you have collected previously to come join your group.
Phil - Now I can control Adam and Eve...
Philomena - And you could even go ahead and try to control a third animal if you decide to go ahead and get Eve pregnant.
Phil - I can do that?
Philomena - You can do that! You're sitting next to Adam now, and you can see the little love icon...
Phil - Oh my God, I'm going to do it. I'm going to hit 'mate'.
Philomena - Do it! So now you're pregnant. You can see all the little hearts bubbling around. It's very child-friendly.
Phil - I took four days to get across the last Island and I just got pregnant in the morning. I'm amazing.
Philomena - And when you end the day...
Phil - I'll end the day.
Philomena - And then you get your first offspring!
Phil - Wow! And the next day, there's my little baby!
Philomena - You can see that when you select the baby...
Phil - I can go to a skill menu in the bottom left, and it's giving me a bunch of different skills: how well I can walk, how well I can swim, how well I can fly, collect resources, how strong I am... oh my God, how well I can crack things? There's a lot of different skills.
Philomena - There's more than the ones you're currently seeing. There's so much you can get good at in this game. There's even how fertile you are in the game.
Phil - Goodness!
Philomena - Yeah, but it always depends on the genes. You can have a long term problem where you have very good genes, but you grow infertile over time because you're not paying attention to it, or you're growing blind.
Phil - If I click the menu below skills I can go to my 'genes' menu.
Philomena - You actually have a set of genes for each slot. There is an ear slot, there is a horn slot, there's an eye slot, and a head slot, and so on. The gene that is on top is the dominant gene, and if the gene below is dark then it's the recessive gene. Each of those genes that you have influences the skill set you have.
Phil - Take me to somewhere where I've got to use these genes and I'll be challenged.
Philomena - Oh, you want to be challenged right ahead?
Phil - Yeah, I've got the hang of this, I'm ready for this.
Philomena - Since you're in story mode I don't think you will have much of a problem surviving on the first two islands or so. If you want to have a super hardcore experience, you can go into sandbox mode and start with the most difficult island.
Phil - Let's do it so that I can see where this game goes.
Philomena - Okay. Either killer islands - but those are very hard - or hard islands.
Phil - Let's do a hard island. Which do you recommend?
Philomena - What would I... do you want to get stung by lots of insects?
Phil - Yeah that sounds great, let's do that.
Philomena - Do you want to eaten by monkeys?
Phil - Sting me with insects.
Philomena - Sleepy reeds. Sleepy reeds is your selected island.
Phil - What have I got myself into? Okay, I've got this very big island with a lot of different hex areas that I can move to, and there's a lot of different types of terrain, and it looks like quite a dark swamp or jungle. And I've got two little animals, but they look really different! I didn't realise animals could look this different in the game. One's got a duck bill and is bright green, the other has got antlers and is brown and huge; and honestly it looks like if these two tried to mate, it would end really badly. Is that going to still work then, and will they mix their genes to create something new?
Philomena - It's fine. And your two animals: the one with the duck bill actually has a poison body. That is inspired by a poison frog. Predators that want to eat you will be very disgusted, because you are poisonous.
Phil - Now as I go through this world, can you just describe to me how you've dealt with not just the genes of each animal, but how the genes of animals in a group interact with each other? What sort of things are you modelling here?
Philomena - Basically the idea with the game was to model the five pillars of population genetics. There's a lot of natural selection that is basically trying to kill you in various occasions; you mostly try to avoid this by sexual selection. Sexual selection in nature is basically animals choosing who they're mating with. Often in many species it's females, so if you have ever seen a video of those little cute birds dancing around and the female looking at them, and thinking, "hmm, which one should I be picking", that is sexual selection,
Phil - And in the game how does that work?
Philomena - In the game that is you!
Phil - That's me? I'm sexual selection?
Philomena - You are sexual selection. You can basically decide who is interested in whom based on what criteria, since you have the broader overview of your species and where you want to take it.
Phil - So my female has a dominant gene for black eyes and a recessive gene for blue eyes. My male has a dominant gene for black eyes and a recessive gene for green eyes. If I mated them - which I actually have - could I control, of each parent's two genes, which one went down into the offspring? Or is it random like in real life?
Philomena - That is random.
Phil - Interesting. Have I got the baby yet?
Philomena - You have to end the day, then you get the baby.
Phil - Ok, let's end the day, let's see what the baby has...
Philomena - Black eyes.
Phil - You could have predicted that because that's a dominant...
Philomena - Black eyes... since both parents have it and it's dominant, chances were quite high.
Phil - We talked about two of the five pillars of population genetics, we talked about natural selection and sexual selection. What are the other three pillars?
Philomena - There's genetic flow, when one gene from a population comes into another population, so new blood into your existing population; and we have also seen genetic drift. Genetic drift is basically what happens within a population, especially if the population is small: you can see the frequency of genes changing. And especially if it's a little isolated population, this can have quite a big impact. And we have seen this also already in the game when we talked about the eye colour. If you have a little population and just one gene just randomly keeps popping up everywhere, then you can see the effect of genetic drift.
Phil - So over time we might get, among all our animals, a lot more black eye genes than we used to.
Philomena - Exactly, if by random chance the black eye gene keeps being passed down.
Phil - Cool. And the fifth one?
Philomena - The fifth one is mutation: when, based on random chance, your genes change. Usually this process is pretty random. In the game you can influence it a little bit: with each animal you can select a mutation that you would like to have, and then your offspring has a certain chance to actually show this mutation.
Phil - How close do you think all this is to real life in a group of animals?
Philomena - I think it's pretty abstract, but it still catches the basic principle of how it actually works. We also have a free educational version available and we have about 300 biology teachers who use it in class.
Phil - Most importantly, how can I win?
Philomena - You can never win.
Phil - I can never win?
Philomena - You can never win. In sandbox mode, that you're currently playing, you are just making your own challenges basically and trying to survive as long as you can. In the story mode there actually is a way to win. You started off with the little tiger animal, Adam, and you were kidnapped from your original island, so your goal would be to find a way back home to the original island. And then there's two possible endings to the game, because Adam had a very special immunity gene that only Adam has. If you get back there but you lost the special gene along the way because it wasn't passed down, then your original family doesn't recognise you anymore and you're just a stranger on this island. But if you manage to pass it down over all these generations, then they will recognise you and welcome you back into their family, which is the true ending of the game.
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