40 years of selfishness

14 August 2016
Presented by Kat Arney.

40 years ago Richard Dawkins' The Selfish Gene hit the shelves. We look back on how it changed the way many people think about genetics. Plus, linking nurture to nature, and a gigantic gene of the month.

In this episode

01:02 - Steve Jones - The Selfish Gene at 40

Richard Dawkins’ landmark book, The Selfish Gene, was first published in 1976. I caught up with geneticist Steve Jones for an overview.

Steve Jones - The Selfish Gene at 40
with Steve Jones, UCL

Kat - "The genes are the immortals, or rather, they are defined as genetic entities that come close to deserving the title. We, the individual survival machines in the world, can expect to live a few more decades. But the genes in the world have an expectation of life that must be measured not in decades but in thousands of millions of years. In a sexually reproducing species, the individual is too large and too temporary a genetic unit to qualify as a significant unit of natural selection. The group of individuals is an even larger unit. Genetically speaking, individuals and groups are like clouds in the sky or dust-clouds in the desert. They are temporary aggregations or federations. They are not stable through evolutionary time."  That's a quote from The Selfish gene, Richard Dawkins' landmark book that was first published in 1976. I caught up with fellow genetics author - and emeritus professor of genetics at UCL - Steve Jones, to find out how the book, and the ideas in it, were received when it first came out.

Steve - I have to say, rather in an embarrassed way, I didn't read it for many years after that. In fact, I think its initial impact was much less than its medium term impact. I should also say perhaps in my own defence that I didn't read the Origin of Species which I have become obsessed with until I was in my 30s. But yes, I read it. I think the most important thing about it was that it was written in 1976. And that was the prehistory of genetics. I mean, that was the Precambrian of genetics. We didn't know any genetics at all basically. We knew Mendel's Laws and we knew a bit about the mechanisms and we knew about DNA. But genetics has moved so fast forward since 1976 that you can't expect all Dawkins's claims to have stood up. I mean, no scientific theory could stand up in the face of such a torrent of new information which isn't to deny the fact that it's a very important book in the public perception of genetics.

Kat - From what I feel, it was one of the first public books really writing about Neo-Darwinism, trying to get Darwin's ideas about natural selection along with genetics and what we understood about evolution.

Steve - Yes, there were some semi-popular books before then. John Maynard Smith had written one. Speaking as an author and you yourself of course are an author, it's extremely hard to predict which books become best sellers and which aren't. publishers know that for well. I mean, more than half the books they publish make a loss, but they know that very occasionally, something will explode and this one did. I think it deserve to explode because it's a very engaging book. It's certainly if you look at the effect it's had on the public interest in biology, I think it had a sudden effect on that. I'm certainly not putting Dawkins up at the Darwin level. I don't think he would either. He's a reasonably modest man but I think he played a large part in persuading the public that genetics and evolution had a lot to do with each other. Now that fight had gone on throughout the 1920s but for quite a long time, there was this feeling that somehow genetics disproved Darwinism - that evolution happened with giant leaps which had big mutations so therefore, really have been beneath the public radar. What Richard Dawkins did was to bring it in to the public eye. I don't actually think and I think he himself would probably agree that all his ideas have stood up. And there's still a lot of controversy about them.

Kat - So, let's explore some of the ideas in the book and the book is called The Selfish Gene and there's a lot to unpack there about what do we mean by selfishness because this isn't a conscious gene going, "Ooh! I'm going to be selfish today." What did he actually mean by that?

Steve - Yes. Well, one said to him, "You could have called that book "The Effect of Kin Selection on Sex Ratios"."

Kat - Catchy!

Steve - And there are books which have got titles like that. I think he did talk about changing it at one time at the 30th anniversary 10 years ago. I think he said as far as I remember that he had preferred to call it the Immortal Gene.

Kat - Yeah, it's in the preface.

Steve - And if he'd called it that, he would've sold one tenth as many copies. So, I think as a popular science book as I often say, the first line in the United States Army's mule training manual - How to Train a Mule - is first, catch the animal's attention by striking it smartly between the eyes with a stout stick. And that's what he's doing with that title. He's striking the potential purchaser smartly between the eyes - The Selfish Gene - with a stout stick. So the purchaser will take it out of the shelf, open it up and then buy it. the problem is that what's happened really is it's sort of got into a circular boring argument about what you mean by 'selfish'. Bits of DNA aren't selfish. They don't drive sentient beings. I mean, sentient beings could be selfish, but the word isn't quite right. But I don't think that's crucial.

Kat - Let's explore what that actually means. So, what was the central idea that he proposed in the book?

Steve - Well, the central idea was Haldane's idea - you can dig it out in the ancient literature - that it would pay him to leap into the Thames to save two brothers or eight cousins. The point was that he would destroy his own genome by drowning in the Thames. But if he saved eight cousins, each of which shared one-eighth of his genome by definition then there would be no genetic loss. So, if he saved 9 cousins, or 10 cousins, or 20 cousins will actually pay him to drown. And Haldane being Haldane, just threw that off, but in fact, it makes an important point.

Kat - It's this idea that it's the genes that are what's being selected for. It's the genes that get passed on at the expense of the organism and I think the phrase that he uses, it's all about the replicator, about copying your genes rather than the vehicle - the flesh robot that they have a copy in.

Steve - Yeah, in the end, it comes down to theology okay. Christians have got this thing called the soul. Now, nobody knows what the soul is. But the soul somehow survives where it's the selfish soul. It survives where its agent - you and I, don't. When you try to track down by what you mean by the replicator, it's by no means clear in modern genetics context. One of the startling things about modern genetics is of course you're aware, is the discovery there are far fewer genes in the human genome in traditional sense than we ever imagined. While I was a student in Edinburgh which is a very big centre of genetics in those days which still is to a degree - in the '60s, we used to assume, I used to assume that to make anything as magnificent and handsome and sexy as myself would take a million genes, a million protein coding loci. It's an incredibly complicated machine. Well in the end, we only got 23,000 of them. You're left with the fact that 98.5 per cent of the genome is not coding replicators. What it is, we don't know. The other thing which again, I don't think the simplistic idea of the selfish replicator stands up well against is the discovery of the so-called missing heritability where you take something like human height where you know from the points of view of families - we're using family studies and adoptions and all these things - it's extremely clear that about 80 per cent of the variation in human height in any population is due to genetic variation. It's a highly heritable concept. But when people try to look for the genes behind that high heritability, it's not that they don't find it. They find too many. The last time I looked and I have looked for a while, there was about 150 or 200 different gene loci had been implicated in the inheritance of variation in human height within a population. But it only explained about 10 per cent of the total variation. So, it's quite conceivable that all genes affect all phenotypes. That's probably getting a bit too grand but it's not inconceivable that every gene affects everything and everything is affected by every gene. Now in that case, the idea that you can disentangle individual replicators as being selfish begins to look very murky.

Kat - I have seen some people trying to take Dawkins's ideas of the Selfish Gene and apply them to political and social ideas as well. Tell me a bit about how that's panned out.

Steve - Well, that hasn't panned out at all well, that's the problem. It's a very old problem. I go back to Darwin again. My favourite quote from Darwin which really summarizes a history of genetics from the beginning is that ignorance more frequently brings confidence than does knowledge. In other words, if you don't know something, it's tell me, is it to be 100 per cent confident on what you say and you can see that throughout the history of genetics. Now, Francis Galton, Charles Darwin's cousin who founded the Galton Lab at UCL where I work. He wrote a book - of course, you know - called Hereditary Genius. Galton was a very, very clever man. There's no question to that, interested in human qualities. His argument was that there was a terrible problem we face because people of low quality - people who went to King's College London let's say - were reproducing more than people of high quality went to University College London and we should do something about that. He wrote a quite bizarre letter to Nature which has been forgotten which is called Africa for the Chinese. He basically recommends that the Africans just go away and die and let the Chinese come in because the Chinese were biologically superior to Africans. Now, that of course, as we go through the nineteenth and into the twentieth century, that had a big effect. Plenty of people when I was a lad, would regard Africans as being subhuman. It had a terrible effect as of course we know in the eugenics movement which began in Britain with Galton and the Galton laboratory and was very strong at UCL. We look back into the 1930s. What did we know about human genetics? Zero. 0.601 per cent of what we know today. And yet, people were going out, sterilising people with complete confidence. The attempts to use biology of any kind to explain human society are all like that.

Kat - You're a writer of popular genetics books. I absolutely loved reading your books and found them incredibly informative. I'm now a writer of books - one book and I do a lot of public communication about genetics. It really feels like the Selfish Gene was the first book to pave the way for this kind of communication.

Steve - I'm not putting it down. I mean, I think it was. On a couple of occasions, I've had students come to me and say, "I came into genetics because of the Selfish Gene." I think that's true and that's a very important effect it's had. On two occasions, I've had a rather amusing experience of having students come up to me with a copy of the Selfish Gene and asking me to sign the book. What I've done on both of those occasions is to write, "I did not write this book - Steve Jones." As I was writing that sentence, it struck me. That's the saddest sentence I've ever written because it sold more than a million copies - I wish I had written the book! In the history of the perception of biology, it's an extremely important book. I'd be the first person to say that and to welcome that.

Kat - That's writer and geneticist Steve Jones, from UCL.

13:20 - Vardhman Rakyan - Nature meets nurture

Vardhman Rakyan has discovered that chemical tags on repetitive genes known as rDNA could be bridging the gap between nature and nurture.

Vardhman Rakyan - Nature meets nurture
with Vardhman Rakyan - QMUL

Kat - You're listening to the Naked Genetics podcast with me, Dr Kat Arney. Still to come, our Gene of the Month is truly titanic. But first, it's time to turn to the eternal struggle - the battle between nature and nurture. Over recent years, scientists have used huge genome-wide association studies, or GWAS, to find hundreds of genetic variations linked to a huge range of traits and diseases. But they're still missing something. And we know even less about how factors in the environment influence how our genes are turned on and off - something known as epigenetics. Now Vardhman Rakyan and his team from Queen Mary University of London have discovered that tiny chemical tags - called DNA methylation - on repetitive genes known as ribosomal or rDNA, could be passing information from one generation to the next, building a bridge between the effects of nature - our genes - and nurture, the environment. 

Vardhman - I suppose the core question is, what determines a person's phenotype, the way they look and the diseases they're susceptible to? In recent years, probably the biggest advance in terms of understanding phenotypes has been at the level of genetics.

Kat - That's the DNA that you've got?

Vardhman - Yes, that's exactly right. This has been made possible by these very large scale studies where people have looked across the entire genome and looked at a lot of genetic variants in lots and lots of people. They have indeed found for many diseases and phenotypes that there are genetic variants associated with diseases such as type 2 diabetes, type 1 diabetes, cancers and so on. I personally think that these genome-wide association studies as they're called GWASs have been very successful. Although one big surprise after these studies have been conducted over the last 7 or 8 years is that almost every case, we can still explain only a small proportion of the heritability in straightforward terms, it means how much of a person's specific phenotype of disease determined by genetic variation. There are precise definitions but operationally, that's fine.

Kat - So, for some diseases, we know that a certain proportion of it should be in the genes but when you start looking for it, you don't find that much.

Vardhman - In a manner of speaking, yes. Now, people are calling this the missing heritability. So, where is this missing heritability? People are now looking for rarer variants. So for example, there could be only one person out of a thousand who has a particular variant. So we need to do as people are doing that more sequencing, looking at more individuals. But there are suggestions that the missing heritability may lie elsewhere. It could be epigenetics or it could be in other parts of the genome that we simply have not looked at. There's a lot of the genome that we have not looked at such as the repetitive portion of the genome. So, a lot of repeat elements, retro elements, and ribosomal DNA - ribosomal DNA codes for the ribosome, the protein production machinery of the cell.

Kat - They're like the sort of the molecular chefs that make the stuff that makes our cells.

Vardhman - Yes. The surprising thing about rDNA is that there are many copies of it spread across different chromosomes. That's true in humans and true in all mammals. As an example, I could have just 40 copies of it, of rDNA and you could have 200 copies of the rDNA.

Kat - Does that mean that I'm loads better at making proteins than you are?

Vardhman - Surprisingly, not. A lot of these copies are silenced, are epigenetically silenced in fact. So, this has been known for a long time that the number of copies can vary amongst individuals. What is not that well-known though is each individual copy within a person or within a single genome can vary genetically. So, in the mice that we looked at, these are inbred mice that is, they've been bred together to try and eliminate genetic variation which can be a confounder in a variety of studies. So, this was a surprise that even within an inbred mouse which will have many copies of rDNA just like humans would - even with an inbred mouse, individual copies within a single mouse will be genetically different.

Kat - What was the idea for this study? What were you trying to look for?

Vardhman - What we were really interested in is how the maternal in utero environment influences the offspring's phenotype.

Kat - So basically like what your mum's tummy does to a baby.

Vardhman - Yeah, kind of like that.

Kat - Yeah, because a foetus is gestating in there, it's not in a completely sealed box. It's inside a female.

Vardhman - That's right. So it's exposed to the mum's environmental condition depending on whether the mum eats or doesn't eat, and other factors like smoking. So, what we were interested was in this process called developmental programming. In utero, when a foetus is exposed to various environmental factors, how does that affect the phenotype postnatally after the baby is born, as an adult, and so on? And there had been lots of suggestions and a lot of excellent work has been done by groups in the UK and overseas that have shown that in some cases, epigenetic marks in the offspring can be changed as a result of the mother's environment.

Kat - So, this is things happening to the mum that are somehow being written in in these marks in the baby's DNA.

Vardhman - Yeah. So, another way of putting it is these epigenetic changes represents a molecular memory of what the foetus was exposed to. So, that was the driver for our project.

Kat - So what did you do? What did you look at?

Vardhman - In our model, we looked at the effect of protein. We compared pregnant mums on a normal protein diet which is 20 per cent protein versus mothers on a slightly lower protein diet, 8 per cent protein. The offspring look healthy, there's no major effects. One big phenotype though is the offspring of low protein mums were approximately 25 per cent smaller.

Kat - They're little dinky mice!

Vardhman - They are small. So that's been shown also a number of times. There's one reason why we chose this model because it's been done a number of times and it's a very robust phenotype. So then we wanted to ask, can we see DNA methylation differences that associates with the smaller birth weight? When you take a sort of standard analytical procedures, you map it to the unique part of the genome. That's the easiest way to look at the data and we found nothing. So we then noticed that there was one part of the genome where we did see a very big methylation difference. This was in the part of the genome that is not a unique portion. It seem to be like a fragment of something else. And then when we'd look at this in more detail, we realised it was very similar to rDNA.

Kat - So, it's not the kind of protein coding genes. It's not the honest to God real genes if you want to call them that. It's these ribosomal DNA genes. What difference do you see between the mice that were fed high protein and the mice that were fed low protein?

Vardhman - The mice that were fed with low protein showed more methylation. Essentially, what that means is, with more methylation especially in the promoter region, the region that controls the expression of the gene, that turns gene expression down and this makes sense. You have this foetus developing inside a mum who is not getting enough protein. So the cells of the foetus are thinking, "We're not getting enough protein, so let's tune down protein production and we can do that in some ways by not making as many ribosomes. Hence, we methylate our ribosomal DNA" and that copes with the stressful conditions they're experiencing.

Kat - So this is almost a prediction that, "Okay, we're not getting much protein now. We might not have much protein in the future. Let's not try and do too much molecular cooking with all of this. Let's just wait and see."

Vardhman - Trying to carry out things as they would've been carried out might not be the best strategy here. Let's slow down protein production. We can have a smaller organism, but one that actually lives.

Kat - Because that's the goal really. It doesn't matter if you're a small baby, but as long as you're an alive baby, that works.

Vardhman - Indeed, yes. That's correct.

Kat - Not only are there these epigenetic differences depending on whether the mum gets more protein or not. But there also seem to be genetic differences, differences in the DNA sequence. What influence does that seem to have on the baby?

Vardhman - Okay, now that was a really big surprise. So, when we looked at these rDNA copies further, we realised they were genetically different. Now genetic differences within rDNA in the mouse have been shown before. But for us, we were looking at an inbred strain though. This was really surprising that this had not been shown because we would've assumed that with inbreeding, all these genetic differences would have been essentially bred out. So that's when we found these genetic differences. Essentially, we found two types of rDNA. One, which we can call the A variant because it has a specific nucleotide in the promoter A and another called the C variant because it has a C in that same position. Different copies will have C whereas other copies will have an A. So we compared the A variant to the C variant. To our surprise, most of the epigenetic changes that has increased methylation was occurring at the A variant. What I've told you so far is that within a single genome, there will be some A variants, some C variants. But the next thing we found was that the relative number of A variants to C variants varied from mouse to mouse, from brother to sister. If you were to look at in mice and in fact, even in humans, if you were to look at the genetic variation of the mum and the dad, you can only predict the genetic variation rDNA of the offspring with only a certain degree of probability. You cannot predict with a 100 per cent certainty. This was really surprising. And so then when we investigated further, we found that it was the mice which have more of this A variant rDNA copies that seem to attract more methylation and ended up being smaller. That was the sort of key finding and the key message of our paper.

Kat - So, this is a really incredible example of its nature - it's the DNA sequence - and it's nurture. It's something happening to the mum, a change in their diet, making this change in the babies. Has this kind of really strong link been found before?

Vardhman - Almost any phenotype is due to both genes and environment. In our opinion, this provides a very unique example and I think a very strong example of how genes interact with the environment to influence phenotype. So this is not by any stretch of the imagination a purely epigenetic effect, not at all. What we're saying is that the underlying genetics is absolutely key but that underlying genetics becomes important when exposed to a certain environment.

Kat - There is a lot of discussion about the rise in diseases, things like type 2 diabetes, rises in obesity, and trying to work out how do we link changes in diet, unhealthy diet in parents, in fathers and mothers to what we're seeing now in populations. Do you think that this is the link that we've been looking for?

Vardhman - I wouldn't say it's THE link, but I think it could be important for sure. We'll only really know after we've been able to design proper powerful assays for it. A lot of this, all science and technology, scientific discoveries go hand in hand. So in terms of what it means for humans, we've got a clear idea what we want to do. But the next few years at least, we want to develop our ability to be able to look at it and then I might have hopefully an answer. That's what we're aiming towards.

Kat - Vardhman Rakyan from Queen Mary University of London, and that work was published last month in the journal Science. And if you're interested in finding out more about how traits are passed on down the generations, check out my recent documentary for BBC Radio 4, called Down the Generations.
http://www.bbc.co.uk/programmes/b07krkgt

27:57 - Gene of the Month - Titin

Our gene of the month is Titin - one of the biggest genes in the genome.

Gene of the Month - Titin
with Kat Arney

And finally it's time for our gene of the month, and this time it's Titin. One of the biggest genes in the genome, it was first discovered in the late 1970s when the Titin protein was found in chicken breast muscle cells. Named after its enormous size - think of the Titanic - Titin encodes a large structural protein that's important for making muscles work properly. One of its key roles is in the heart, and around one in four people with a serious heart condition called dilated cardiomyopathy are known to have faults in their Titin gene. But many more people in the general population also carry faults in Titin, but don't seem to have heart problems. Researchers are now looking in more detail to find out exactly which faults in Titin are related to heart disease. Given that dilated cardiomyopathy can cause serious illness and death, knowing more about the 'bad' versions of Titin should help to identify families and individuals at risk, so they can be closely monitored for any signs of ticker trouble.

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