Blood of the Isles

by Bryan Sykes

  Without mutation, there simply is no evolution. Most of the time mutation, even when it occurs, has absolutely no effect. Very occasionally, though, mutations do drastically affect the working of whatever protein the gene is in charge of – and that is how devastating inherited diseases can begin their life. In my earlier career as a medical geneticist, working as I did with inherited bone diseases, I saw many patients whose bones would fracture at the slightest knock. They were badly deformed and often unable to walk – but often astonishingly cheerful and optimistic. Their disease, called osteogenesis imperfecta, a very serious form of brittle-bone disease, was caused by one of these random mutations in a bone collagen gene. But instead of making a harmless change to the DNA sequence, in these patients the mutation had hit a crucial DNA base in the collagen gene. The mutations in these patients, even though they change just a single DNA base, completely alter the structure of the collagen, turning it from an extremely strong protein into the biological equivalent of putty.

  Mutations can be good, bad or indifferent. Most are indifferent, like the mutations which produce the different blood groups. A few are bad, as in the brittle-bone patients. Vanishingly few are good, in the sense that they improve the way the protein works. On the whole the bad mutations are eliminated pretty swiftly as people with inherited diseases die or have fewer children. Good mutations can find themselves increasing from one generation to the next if they aid the survival of the people that carry them or help them have more children. Indifferent mutations, and they are in the majority, have no influence one way or the other on survival or success in breeding. They just get passed from one generation to the next, their fate entirely out of their hands. They risk elimination if they end up in someone who has no children or can do well if they find themselves in a large family. They might lead less dramatic lives than the mutations that bring success or devastation. But it is these, the silent passengers of evolution, that are its most articulate chroniclers. This is precisely because they cause no ripples, they are unseen by natural selection and are neither promoted nor destroyed by its attentions. But nowadays, thanks to the breakthroughs of the last twenty years, we can see them in the read-out from the DNA analyser. And we can use them to trace our ancestry.

  While Arthur Mourant did what he could with the very limited number of blood groups, there is almost no limit to the amount of different DNA sequences that we are now able to detect. It is this massive increase in our ability to distinguish one person’s DNA from another which has made all the difference in our ability to trace our ancestry and discover our genetic origins. But with all this choice, which were going to be the best genes to concentrate on, and why?

  During my work on ancient bones I wanted to give myself the best chance of recovering DNA so I chose to focus on a rather unusual piece of DNA. Most of our DNA is contained within the cell nucleus, attached to tiny threadlike structures called chromosomes. This is where the collagen genes, the haemoglobin genes and the blood-group genes reside. For all of them, as for most of our ‘nuclear’ genes, we have only two copies in each cell, one from each of our parents. However, outside the cell nucleus, though still inside the cell membrane, there is a different source of DNA altogether. In the liquid cytoplasm surrounding the nucleus are tiny particles called mitochondria. These particles control many of the steps in aerobic metabolism and they have an interesting evolutionary history, having once been free-living bacteria. From our point of view at the time, where this DNA had come from and what it did was unimportant. What counted was that there was far more of it in the average cell, maybe a thousand times more, than the DNA of any of the nuclear genes. If only a few cells survived in the ancient bones, targeting mitochondrial DNA would maximize our chances. It turned out to be the right decision, and we found mitochondrial DNA in the first batch of bones we tried. It is still extremely hard to recover nuclear genes from ancient specimens, while getting out the mitochondrial DNA is now almost routine.

  As well as its abundance in each cell, mitochondrial DNA (or mDNA for short) has two other outstanding properties to recommend it as a window into the human past. Firstly, it mutates about twenty times faster than regular nuclear DNA. The error-checking mechanisms in mDNA are much less vigilant than they are in the nucleus. Our species has been around for about 150,000 years and, although this seems to us like a very long time, the nuclear DNA mutation rate is so low that the vast majority of it is completely unchanged since that time. In a typical stretch of nuclear DNA 1,000 bases long, nineteen out of twenty people will have exactly the same sequence. Within the same sized stretch of mDNA, almost everyone is different.

  The second excellent feature of mDNA is its very unusual inheritance pattern. As we have seen, most of the nuclear genes are inherited equally from both parents. You have received one copy of each nuclear gene from your mother’s egg and one from your father’s fertilizing sperm. But you got all of your mDNA only from your mother, and for one very simple reason. Compared to sperm, eggs are huge cells, bulging with cytoplasm, which is crammed with a quarter of a million mitochondria. Sperm do have a few mitochondria, about a hundred, in what is called the mid-piece, which connects the sperm head, containing all the nuclear DNA, to the tail. The thrashing tail needs the aerobic energy output of the mitochondria in the mid-piece to fuel its progress towards the egg.

  But once the successful sperm penetrates the egg to deliver its precious load of nuclear DNA, its mitochondria are not only vastly outnumbered but are deliberately destroyed. This is why, although the fertilized egg contains nuclear DNA from both father and mother, all the mitochondria, and so all the mitochondrial DNA, is from the mother.

  The process is repeated generation after generation after generation. Nuclear DNA comes from the father and mother, mDNA only from the mother. Consider your own mDNA for a moment. It is powering your aerobic metabolism in every cell – from the cells in your retina which collect the focused image from the page, to the muscles in your arm that turn the pages, to the cells that are burning fuel to keep you warm. All these functions are controlled by your mDNA which, because of its unusual inheritance, you have got only from your mother. Who got it from her mother. Who got it from her mother and so on. At any time in the past, be it 100, 1,000, even 10,000 years ago, there was only one woman alive at the time from whom you have inherited your mDNA. Even though I have known this for years it still amazes me to think about it.

  The combination of plenty of genetic variation with its matrilineal inheritance makes mDNA the perfect guide to the human past. But it needs to be complemented, because it can tell only one side of the story. Mitochondrial DNA can only tell the history of women. Very fortunately, there is a piece of DNA which can do the same for men. This companion guide to our genetic history could not be more different. This is the piece of DNA that is entirely male. It is the Y-chromosome.

  Inside the nucleus of every human cell are a total of forty-six chromosomes. Forty-four out of the forty-six carry on them the great majority of the 10,000 genes that build and run our bodies. They include the blood-group, collagen and haemoglobin genes we have already met and many, many more. They direct almost everything, from aspects of our physical appearance like eye and hair colour, to our immune systems, to our innate psychological and emotional make-up. In everybody, male and female, these forty-four chromosomes come in pairs and are inherited from both parents, twenty-two from one, twenty-two from the other.

  The other two chromosomes, called X and Y, are different in that they are not always inherited from both parents. And not everybody has both of them. Females have two X-chromosomes and men have one X-chromosome and one Y-chromosome. In the official notation of genetics, women are XX and men are XY. However, despite what I have come to appreciate that most people believe, the X-chromosome has nothing directly to do with sex. Women are not women because they possess two X chromosomes – the truth is far more interesting. Women are female because they don’t have a Y-chromosome. How can that be?

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p; Looked at under the microscope, the X and Y chromosomes look quite different. Both are the same shape, like tiny threads, but the X-chromosome is about five times as long. The differences between X and Y don’t stop there. Thanks to the output from the Human Genome Project we now have the DNA sequence for both chromosomes. The larger X-chromosome is very like the other forty-four chromosomes. It carries about 1,000 genes which control a range of different cellular activities. The Y-chromosome, on the other hand, is a genetic wreck with only twenty-seven genes that appear to be working properly. The rest of the chromosome is made up of long stretches of so-called ‘junk’ DNA. This is DNA that, unlike genes that do things, has no known function. It is just there. The evolutionary implications for this tremendous difference between X- and Y-chromosomes are fascinating, but not especially relevant here. What does matter is that just one of the twenty-seven active genes on the Y-chromosome, the sex gene, is what makes males.

  For the first six weeks of life, there is no visible difference between male and female embryos. At about that time, the sex gene on the Y-chromosome switches on. This sends a signal to a whole series of other genes situated on other chromosomes, which, between them, actively divert embryonic development away from female and towards male. Embryos that don’t have a Y-chromosome just carry on along the normal female development pathway and are born girls. The X-chromosome has nothing to do with it. Men truly are genetically modified women.

  This mechanism for deciding sex which humans have inherited from their distant mammalian ancestors creates the second of our guides to our genetic origins. Men carry both an X- and a Y-chromosome in all of their cells – except mature sperm. Sperm occur in two different genetic forms, indistinguishable under the microscope and in their swimming capabilities. Stem cells in the male testis are dividing furiously to keep up the supply of sperm and like the other cells in the body have the XY combination of sex chromosomes. At the final division, the cell divides one last time but the resulting sperm only get one of the sex chromosomes, not both. Half the sperm receive an X-chromosome from this division while the other half get a Y-chromosome. The sex of the child entirely depends on which sort of sperm wins the race to the egg. If it’s got an X-chromosome then the egg, which already has one X-chromosome, becomes XX after fertilization, develops as a female embryo and is born a girl. If, on the other hand, the winning sperm contains a Y-chromosome, the fertilized egg becomes XY and develops into a boy. The simple conclusion is this: Y-chromosomes get passed down the male line from father to son.

  Looking backwards, if you are a man, you got your Y-chromosome from your father, who got it from his father. Who got it from his father. Sounds familiar? It is the mirror image of the inheritance pattern for mitochondrial DNA. The Y-chromosome is the perfect complement to mDNA, telling the history of men. But does it have enough genetic variability to be practically useful? It took a very long time to find any mutations at all on the Y-chromosome. For those scientists involved, and thankfully I wasn’t one of them, it was a frustrating few years. In one of the first studies looking for diversity among human Y-chromosomes, 14,000 bases were sequenced from twelve men from widely scattered geographical localities. Only a single mutation was discovered. Another lab sequenced the same 700-base segment from the Y-chromosomes of thirty-eight different men and didn’t find a single mutation in any of them. At long last, and helped by an ingenious technique for finding the elusive mutations, the Y-chromosome began to show its genetic jewels. Slowly, slowly, mutations that had changed one DNA base to another were teased out of the otherwise barren desert of uniformity.

  With these two pieces of DNA we have the perfect companions for our exploration of the genetic past. One follows the female line, the other tracks the male genealogy. What could be better? They had been my guides in Polynesia and in Europe and I knew them well. Among their many qualities is that they both group people into clans. When my colleagues and I had been trying to make sense of the mDNA results from Europe in the early 1990s, we noticed that the 800 or so samples from volunteers from all over Europe fell into seven quite distinct groups based on their mDNA sequences.

  Unlike the chromosomes in the cell nucleus, which are straightforward linear strings of DNA, mitochondrial DNA is formed into a circle, which is a hangover from when the mitochondria themselves were free-living bacteria. The human mitochondrial DNA circle is exactly 16,589 DNA bases in length, but fortunately it is unnecessary to read the entire sequence. Most of the mitochondrial DNA circle is taken up with genes that code for the enzymes involved in aerobic metabolism, which is the prime function of mitochondria in the cell. Because these enzymes have a very particular structure, decided by their amino-acid sequence, mutations in the genes which alter the amino-acid sequence almost always diminish or destroy the enzyme activity. The individuals who are unfortunate enough to experience these mutations in their mDNA usually die. Aerobic metabolism is such a vital part of life that we cannot tolerate even the slightest malfunction. The genetic result is that because these individuals rarely live long enough to have any children, the mutations are not passed on to future generations. If all mDNA mutations behaved like this, we would never find any genetic differences between individuals and it would be quite useless as a guide to the past because everybody’s mDNA would be the same. However, fortunately for our purposes, not all mDNA does code for these vital metabolic enzymes.

  Approximately 1,000 of the 16,589 DNA bases in the mDNA circle have a different function altogether, one that does not depend on the precise sequence. This stretch of DNA is called the ‘control region’ because it controls the way mDNA copies itself during cell division. Fortunately for us, part of this control region comprises a stretch of 400 bases whose precise sequence is unimportant. It is really just a piece of genetic padding. It must be there and it must be 400 bases long for the control region to work properly, but it doesn’t seem to matter what these 400 bases actually are. This is the complete opposite to the parts of mDNA that code for the metabolic enzymes, which, as we have seen, need to have a very particular sequence. The vital consequence for us of this tolerance in the DNA sequence of the control region is that when a mutation happens it doesn’t affect the performance of the mitochondria at all. Instead of killing the individual who carries it, the control-region mutations just carry on unnoticed through the generations, and we can find them.

  During our work in Europe it was the mDNA sequences that we found in the control region that showed us that there were seven principal groups. Within each group, everybody shared a particular set of control-region mutations. The notation that we used to describe these mutations was as simple as we could make it. We chose one particular sequence as our ‘reference sequence’. If we use the metaphor of DNA as a word, then the reference sequence is its standard spelling. The sequence we chose as the standard was the one we most frequently encountered in Europe. If a particular mDNA sequence differed from the reference at the 126th base of the 400 in the control region, then it was denoted simply as 126. If there was another mutation at the 294th position, then the notation became 126, 294. We found a lot of people who shared this particular combination of mutations and they formed one of our seven groups. In other groups there were different sets of ‘signature’ mutations. However, within the groups like the one defined by mutations at 126 and 294, there were plenty of other mutations as well. While about a third of people within the group had just the bare minimum of 126, 294, the rest had one, two, three or even more additional mutations.

  By looking for the signature mutations it was fairly easy to place any individual DNA into one of the seven groups. Occasionally we would find individuals where one of the signature mutations had changed back to the original reference, but on the whole it was quite straightforward. But what did these groups actually signify? It had to mean that everyone within the same group must be related to one another through their matrilineal ancestors, which was the line we were following with mDNA. If two people in the same group had been
able to follow their maternal ancestry back in time through their mothers and their mother’s mothers and so on, at some point they would converge. There would have been a woman living in the past who was the common ancestor of both of them. It then struck me, after what now feels like an embarrassingly long time, that if this worked for two people in the same clan it must, by an inevitable logic, also work for the entire clan. If one were to trace back all the maternal lines of everybody within each clan, they would end up with just one woman. There was no alternative. Amazing as it sounds, this has to be true.

  I realized at once that these clan mothers, as I called them, were not some kind of theoretical ancestors, but real living, breathing women. No, not just women, they were mothers as well. Mothers who had survived and whose children, or at least whose daughters, had survived and who in turn had survived and had daughters and so on, right down to the present day. Though men have mDNA, they do not pass it on to their children, but they do inherit it from their mothers. Originally to emphasize to myself that these clan mothers were real individuals, I gave them names, each of which began with the letter by which the seven different groups were by then known among scientists. So the clan mother of Group H became Helena, T became Tara, J became Jasmine, X became Xenia, V became Velda, K became Katrine and U became Ursula. Over 95 per cent of native Europeans are in one of the seven maternal clans, and so it followed that these seven women were the maternal ancestors of almost all Europeans. As soon as I had given them names, they came alive and I had to know more about them. I became quite desperate to build up a picture of their lives. I wanted to know all there was to know about these seven women, the women who soon came to be known as the Seven Daughters of Eve.

  The first thing I wanted to know was how long ago these seven women had lived. Were we talking about hundreds, or thousands, or tens of thousands of years ago? The answer came by looking at the extra mutations within the clan. Taking the clan defined by the signature mutations at 126 and 294, which is the clan of Tara and the one to which I belong, everyone within the clan shares these two mutations, for the simple reason that Tara herself had these mutations and everyone in the clan is one of her direct matrilineal descendants. These two mutations have come down through the generations unchanged from the clan mother herself. But how many generations? How long ago did Tara live? That is where the additional mutations come in. Although roughly a third of people in Tara’s clan have only these two mutations, the rest have additional changes. I have one extra mutation, at position 292, which makes my mDNA sequence 126, 292, 294. Other members of the clan have experienced more mutations. All these additional mutations must have occurred since Tara’s time. Fortunately we know the mutation rate for the mDNA control region. It is approximately one change every 20,000 years. Since mutations happen completely randomly, not every line of descent from Tara will experience the same number of mutations. Some may be spared altogether and retain just the signature mutations at 126 and 294. Some maternal lines, like mine, will have been hit once since Tara’s time, others more than once, some not at all. By working out the average number of additional mutations within the clan, we can then estimate how old the clan is, or, to put it another way, how long ago Tara herself lived. For her clan, the average number of additional mutations within the clan is almost exactly 0.85. With a mutation rate of 1 change per 20,000 years, the conclusion is that Tara lived 17,000 years ago.