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Darwin Now pod 8: Genetic revolutions

Updated Tuesday, 24th November 2009

Genes provide a powerful record of our evolutionary past. Living things even share a genetic toolkit that can generate a breathtaking diversity of body forms. Can DNA also offer clues to what makes us uniquely human?

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Music: Variations on a Theme by Giuliani

Rissa de la Paz:

Hello and welcome to Darwin Now. When he published ‘On the Origin of Species,’ Darwin triggered a shake-up in our understanding of how living things are related and come to change over time. Little did he realise that 150 years later we’d be poring over a quite different type of document that has more than vindicated his theory. DNA has given us a molecular script that’s illuminating our evolutionary story in unexpected ways. Sean Carrol, Professor of Molecular Biology and Genetics at the University of Wisconsin.

Sean Carrol:

Not only does DNA contain the operating instructions for the building and workings of an individual creature, it contains a record of history. And in that record we have information about how that species is related to other species, how it’s different from other species, what changes have taken place that have allowed, for example a particular species to adapt to the habitat that it lives in. The average genome, meaning the collection of all the DNA information in an individual, has up to several hundred million to a few billion bits of information, and all of these bits can potentially be used to decipher some part of history.

Rissa de la Paz:

This ability to decipher history at the molecular level is thanks the new science of genomics, which compares the DNA of different species to probe the process of evolution. We now have the record of the genomes of about two thousand species. How can we begin to picture how much information that represents?

Sean Carrol:

If twenty years ago or so you took all the DNA information that scientists had deciphered across the world and you typed that out, it’s four letters, A, C, G and T, which are the letter-code of DNA. If you typed that out and put it into a book, it would fill the pages of about an average-sized novel. If you now typed out all the DNA information we have today, and typed that out, fill it in books and stack those books, those books would be more than two miles high. So we have this incredible treasure of DNA information that scientists are mining every day to peer deeply into how the evolutionary process works.

Rissa de la Paz:

Assembling the vast strings of genetic text into the unique sequence of an individual or a species and then deciphering what that sequence means is a triumph of technology, molecular biology and sheer human effort. Intriguing patterns have begun to emerge from this forest of genetic data.

It turns out, for instance, that certain genes have been preserved across many kingdoms of life across billions of years. These so-called ‘immortal genes’ are those involved in the machinery of cells that’s responsible for deciphering the DNA message. The genetic code has to be translated to form the family of molecules called proteins which include not only the building blocks of life but the molecules called enzymes which regulate its biochemistry.

Sean Carrol:

Now we know the genetic code is universal. And what we mean by that is that the same letters have the same meaning in all species in terms of decoding DNA eventually into protein. Now the machinery that does that decoding is very highly shared among all domains of life, so bacteria and plants and animals and fungi have certain genes that have had a function for such a long time, several billion years, and we can see this preservation in the code of those genes.

First it tells us that life has some very deep things in common, and that certainly fits Darwin’s inference that all life is descended from common ancestors. But it also tells us something profound about the process of natural selection. We know that every time DNA is copied mistakes get made, and those mistakes if unchecked would pile up and essentially the DNA code would disintegrate to gibberish. But that’s not what happens. What happens is that stretches of DNA codes, such as these genes that are shared among all these domains of life have been preserved for billions of years. That means that if a mutation happened that altered the performance of that gene in a negative way, that mutation would be purged from the population, it would be outcompeted by better forms of the gene. That’s what we mean by natural selection.

Rissa de la Paz:

Out of the roughly twenty thousand genes that we have, there are about a hundred such immortal genes that we share with other domains of life, including bacteria. The preservation of these immortal genes is evidence of the filtering power of natural selection to weed out and reject any changes that might be harmful to an organism’s survival.

But the DNA record has yielded other surprises: portions of DNA that have fallen into disuse and decay. These fossil genes represent a new type of record that sheds light on the evolutionary past.

Sean Carrol:

One of my favourite stories about fossil genes involves a set of fish species that live in the southern ocean, near the Antarctic. This is very cold water, about minus two degrees Celsius, and these fish have adapted to this extreme habitat in some pretty remarkable ways. And one feature that’s quite obvious about them is they have no red blood, so they’re the only animals with backbones, the only vertebrates on the planet without red blood. But if you look at their DNA and you look at a stretch of DNA in exactly the same place where their red-blooded fish cousins have genes that encode the proteins that carry oxygen in their bloodstream, one of those genes in missing in these so-called ice fish and the other gene is just a truncated remnant that’s just withering away.

And that tells us that the ancestors of these fish had these genes for carrying oxygen but their descendants don’t, there’s been a change in lifestyle. And this is something we can find again across all domains of life, sets of genes that are no longer being used, that are inactive but there’s enough DNA text remaining that we can tell that they used to function at some point in the ancestors of these creatures.

Rissa de la Paz:

So fossil genes offer clues to traits and functions that have been abandoned as species evolved new lifestyles. There are striking examples of such genes much closer to home.

Sean Carrol:

If you look in a mouse genome or you look in a dog genome, the largest class of genes, about five per cent of all their genes, are involved with detecting odours. Well, about half of all those genes in humans are fossil genes, they’re inactivated. So our repertoire of odour-detecting molecules is really decayed relative to our mammalian ancestors.

Now why might this be? We, for example, rely a lot on our sense of colour vision to find our way in the world, to spot food, to spot danger, to find our way home, to look each other. And it turns out that all old world primates have this sense of full colour vision that we have, and they all show this pattern of decayed repertoire of smell sensing genes. So again, a shift in lifestyle, shifting from a lifestyle sort of driven by the nose to a lifestyle driven by vision, is reflected in the genome as a bunch of genes in our case that are no longer working.

Rissa de la Paz:

We humans in fact have about 800 fossil genes and about 70 have fossilised just since our split from the common ancestor that we share with chimpanzees. That means there are about 70 genes still working in chimpanzees that are no longer working in us. What do fossil genes such as these tell us about evolution?

Sean Carrol:

There’s a process of both birth and death of genes, and it’s a quite dynamic process, and that as species are adapting, shifting lifestyles, some genes are no longer needed to equip those creatures for the best performance. And sort of the general rule of these fossil genes is use it or lose it; a gene that’s not contributing to the performance of a creature natural selection no longer is acting upon and the text of that gene will eventually decay.

Rissa de la Paz:

Another revelation from the DNA record – and something we could only have detected by using it – is how evolution can repeat itself in exquisite detail. Similar adaptations arise in very different species when they’re faced with similar challenges.

Sean Carrol:

One of the very common ways that animals blend with their surroundings is changes in their body colour. And there’s all sorts of examples of species we know that have dark and lighter forms. When we look at the genes responsible for making those colour difference, we can see the same gene altered in a same way in different species, living on different parts of the planet, living indifferent sorts of habitat. Species as different as fish and birds and reptiles and different species of mammals, the same changes taking place in the same gene.

And what that tells us is given similar conditions, in this case maybe a selective advantage to being darker, that evolution finds a similar solution, the modification of the same gene, and we have many, many cases of this. So we know, for example, that while old world primates invented full colour vision, Howler monkeys which live in the New World independently invented full colour vision by a similar means but at a different time, in a different place, in a different part of the world

Rissa de la Paz:

Even human evolution displays this theme of repetition. Take sickle cell anaemia, a blood condition that takes its name from the sickle-shaped appearance of the red blood cells in affected individuals. When a person inherits 2 copies of a gene with the sicke cell mutation, the oxygen-carrying molecule in the red blood cells is abnormal and a life-threatening anaemia results. Given this disadvantage, it’s astonishing to discover that not only has the sickle cell mutation arisen several times in our evolutionary history but that it persists in human populations. It turns out that individuals who inherit one copy of the sickle cell mutation and one copy of what we might call the normal gene have, in some circumstances, an unusual advantage.

Sean Carrol:

What was discovered in the 1950s is that having one copy of that mutation and one call it normal copy of the haemoglobin gene, gavesome protective benefit, particularly to young children, against malaria. So they had, for example, fewer parasites, less severe malaria when they were exposed to the organism. So this is a case of a trade-off and it turns out that if mutations in the globin genes will give some protective benefit to malaria, that outweighs the hazards, if you like, of that mutation being at high levels in a particular population.

Now, in places in the world where there is no malaria, we don’t see that mutation at all. So that mutation is prevented from becoming common, again by natural selection in areas where there’s no malaria, but it’s driven to very high frequency in areas that have a high incidence of malaria.

That mutation, the same change in our DNA code, has arisen at least five separate times in different parts of southern Europe, southern India and three different places in Africa, that have led to resistance to malaria in different human populations.

So we can trace with 100% accuracy the origin of different mutations, different adaptations within our species, within different species, to understand that evolution in fact does repeat itself given the same sorts of selective challenges.

Rissa de la Paz:

Nowhere is this demonstrated more powerfully than in the evolution of complex structures. Think of an organ as intricate as the human eye. How can something so complicated arise by a mechanism reliant on random change? The key here has been advances in the study of the evolution of development – evo devo, for short. Until relatively recently, biologists were simply spectators of the process: they could see various organs taking shape during the development of the embryo but didn’t know the details of what determined the number, size, shape or identity of particular body parts. Then, about 25 years ago, geneticists stumbled upon a remarkable set of genes that gave tantalising clues about the building of body parts.

Sean Carrol:

Body building genes are special. They play lots of roles in different parts of the body, and when they’re altered, when their function is compromised they often have very catastrophic effects. These genes were first identified in model animals such as the fruit fly, because mutations in them, say, would eliminate the eye altogether, or they’d put a body part in the wrong place, or they’d cause the formation of the wrong number of a particular set of body parts.

Those very same genes exist in us, and in most of the rest of the animal kingdom. So despite the great differences in appearance, there are a lot of common ingredients to building animal bodies. So you could say sort of the first lesson there is that looks are deceiving; we thought that different anatomies, different appearances would be brought about by different genes, but really very similar genes are involved in building body parts with similar functions. One of the genes that when mutated eliminates the formation of the fly eye, that same gene exists in us and when that’s mutated it can eliminate the formation of the human eye.

Rissa de la Paz:

The special role of body building genes is to command what other genes do. The proteins encoded by body building genes can turn on and off anything from dozens to hundreds of other genes. That’s why altering them can prove so catastrophic. What impact did the discovery of body building genes have on our understanding of evolution?

Sean Carrol:

It made us really rethink various issues in evolution because it had been assumed for a long time that the different sorts of eyes in the animal kingdom had evolved completely from scratch, so that a squid eye and a human eye and a bug eye, these were all independent solutions to the challenge of vision and they would have nothing in common, but as we’ve looked deeper into the genetics of building structures like the eye, we realise they have a remarkable of genetic ingredients in common. And what that tells us is that there’s a common set, we’ll call it a toolkit for building an eye that must go back in time very far to very early forms of animals, and that this set of genes has been building eyes for more than 500 million years.

Rissa de la Paz:

But if there’s a shared genetic toolkit, how do you get plants and animals displaying such a wonderful diversity of form?

Sean Carrol:

The building of an animal involves choreography of when genes are turned on and off, and where they’re turned on and off over time as the animal is developing. And small changes, sort of tweaking so that the gene might stay on in one place a little bit longer, or maybe it’s turned on in a new place in a particular species, that will result in different appearing products, different appearing animals.

So we understand there’s a very intimate connection between the making of an animal and the process of development, and the evolution of different forms of animals. And the body building genes are crucial to understanding this because it’s changes in the way these body building genes are used give us different anatomies, different forms of the animal kingdom.

Rissa de la Paz:

It’s a big jump from individual body parts to whole anatomies as distinct as snakes and birds, lobsters and butterflies, but by visualising how these genes influence development, we’re beginning to get a glimpse into the evolution of complex forms.

Sean Carrol:

Seeing is believing and seeing is understanding, so one of the powers now in evolutionary biology is that we can actually see at the DNA level the precise differences that explain differences in how animals are going to appear or function or how different organisms are going to function. And we can also peer into embryos and say okay, it’s at this moment that this animal starts to do something differently than something else that’s going to lead to that eventual obvious difference in the form of these creatures. So we have unprecedented clarity on the making of animals and the making of different forms of animals.

Rissa de la Paz:

So far so good. But can the DNA record offer fresh insights into how humans have evolved and what makes us different?

Sean Carrol:

One way to think about that is to compare humans with our closest living relative, the chimpanzee, where if you read across the DNA code of the two species there’s about 1% difference in individual genes, we’re 99% identical. In fact, if you decode those genes into proteins, 29% of our proteins are absolutely identical between chimpanzees and humans, there’s not a single replacement of any constituent in those proteins. So we’re biochemically very similar, but obviously anatomically and behaviourally we’re different.

Rissa de la Paz:

One obvious question is: where in the DNA are those meaningful differences between chimpanzees and humans? But perhaps it’s not quite as simple as that. We’re already beginning to realise that it’s the choreography of how genes are used that’s critical to the building of different bodies. And that choreography is determined largely by sequences in DNA that are separate from the so-called structural or coding genes that actually specify proteins. Some of the non-coding stretches of DNA are in fact genetic switches that determine the activity of the coding genes – whether they’re on or off. Building a human versus a chimpanzee must somehow involve differences in the choreography of these switches.

Sean Carrol:

For us to have larger brains, for our skull to be positioned on our spinal column the way it is, for our chest to have a little bit different dimensions, for the curvature of our spine to be different, for the digits of our hands to be different, that means that some difference decisions are being made in development of humans than are being made in the development of chimpanzees. And many of us believe that those differences, those key differences are residing in very subtle differences in the genetic switches, so the DNA sequence of non-coding DNA that are these places that determine the activity state of genes.

So right now the big challenge is to identify which genes are being used in meaningfully different ways between chimpanzees and humans, and to map in the DNA the functional differences where those are located in DNA. And there’s progress being made. It’s much harder to do this human/chimpanzee comparison because the sorts of experiments that we’re able to do on other models, like fruit flies or fish or mice, we can do those experiments in very large numbers and we can purposely do genetic crosses and we can move genes in and out of their genome to test our ideas, but we don’t have those methods available for humans and chimpanzees, so it’s a more difficult detective work to pinpointing the differences between ourselves and chimps, but we’re making progress.

Rissa de la Paz:

There is of course a relative much closer to us Homo sapiens, than even the chimpanzees.

Sean Carrol:

Neanderthals are very closely related to Homo Sapiens, they’re about 99.9% similar to us but, of course, they’re different in some particular ways. We’re about to have the DNA sequence of Neanderthals which will allow us to say well, how are we identical to Neanderthals, how are they different than us, and what might those differences signify, and then how are the two species, the two harmonies, Neanderthals and Sapiens, similar or different from chimpanzees. So we’re going to get a third comparison here, and you have to appreciate what an enormous technological achievement it is to sequence Neanderthal DNA because this ancient DNA in fossils is disintegrated to various degrees, it’s much like taking, you know, say the folio of Shakespeare and, you know, chopping it up into three and four word long bits and asking somebody to reassemble, you know, all of the plays. It’s very, very difficult, very technically challenging, but all those challenges are being surmounted.

So we’re going to know a lot more about human history, we’re going to know a lot more about the functional changes that make us human in the next ten years.

Rissa de la Paz:

So what of the future for the science of genomics? What new insights might we look forward to?

Sean Carrol:

Lots of functions that exist today are built upon some pre-existing functions which were built upon something else that existed where they were built upon something else, and we’re going to be able to trace back with lots of continuity how the more complex biochemical and anatomical systems of the body have been put together in evolutionary time. And I think that will sort of demystify part of the process of evolution for people because, you know, rather than having just a few points and sort of extrapolating what’s in between we’re going to, I think, have the power to reconstruct much of what’s in between in the assembly of a lot of the body’s biochemical and anatomical machinery.

Rissa de la Paz:

The journey from Darwin’s seminal text to DNA’s forensic molecular record has made been marked by unexpected twists and rich surprises. And if the story so far is anything to go by, we’re in for some thrilling future installments.

Music: Variations on a Theme by Giuliani

Rissa de la Paz:

This podcast was produced as a collaboration between the British Council and the Open University.

 

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