[MUSIC] Hello, welcome back. The way we sequenced the first genomes took years and enormous amounts of money. We used Sanger technology. That meant that we broke the DNA up, the genome up, into little bits and then we sequenced it each bit individually. Using Sanger technology to sequence 3 billion nucleotides in the human genome was audacious, was enormously brave. If you're gonna use Sanger technology, you need thousands of machines. This is what a sequencing center looked like back in 2001. Needed warehouses of Sanger sequencing machines working twenty-four hours a day, seven days a week for several years to get a genome done. But not anymore. We've had a revolution in technology. With the new machines we have now, you don't have to separate the fragments and sequence each one individually. Next generation sequences do sequencing in parallel, which means that thousands, or even millions, of DNA fragments are sequenced simultaneously providing a much faster, and less expensive, way of sequencing. So some of the sequencers that have come out in the last year, they can each sequence two genomes in a day. You may have heard of Moore's Law, computer power's increasing at an exponential rate, computers doubling speed every eighteen months? Well, DNA sequences are doubling much faster? In fact, there's said to be an exponential growth in the rate of exponential growth. That means that the cost of sequencing DNA has plummeted from about $100,000 for a million letters of DNA code in 2001, to around 10 cents today. By 2012, a machine small enough to sit on this table could do in a day what 10 years before it had taken warehouses full of machines to do. So with our new technologies we've been able to sequence thousands of human genomes which, of course, enables us to compare and contrast them. And one thing is actually clear from these comparisons, we have a lot of genomic variations. The commonest of these are called Single Nucleotide Polymorphisms, called SNP's for short. And that's where one base substitutes for another. On average, I'm gonna vary from you in about one nucleotide every thousand bases. So, we look at this sticker here. After a particular loci, as we say in genetics, you may have an A, your friend may have a T, someone sitting next to you may have a G. Then about 1,000 base pairs on average downstream from that, that's an average pickup, maybe more, maybe less, I may have an A, you may have a G, your friend may have a C. So, based on these snips, unrelated humans share 99.9% of their DNA sequences. So that makes us seem very closely related. And, indeed, we are very closely related. But remember, that's an average of one snip every thousand base pairs. You have 3 billion base pairs from your mum. You've got three billion base pairs from your dad. So that's six billion base pairs in your genome. That means you could differ from the person sitting next to you by several million nucleotides. That's unlikely, because when you compare lots and lots of people you find that a lot of these SNPs are common. They're found in lots of people. So, a particular SNP may be found in 10%, 20%, or 70% of people. Looking at populations, these common SNPs control common variation amongst people in their height, or their weight, or skin color, or other features. What makes individuals unique is not the uniqueness at a particular SNP, but a unique combination of many possible SNPs and where these SNPs occur. So, because most of the genome is not coding for protein, most of these SNPs do not have an effect on the coding of a protein. They don't effect the protein directly. Some of them affect the expression of a protein, because they occur in regulatory regions, and some of them probably actually have no effect at all, because the might for example be in a retrotransposon. We are not, therefore, just interested in total number of differences, but whether these differences happen in DNA sequences that control important functions. Over the last 10,000 years, we've evolved a lot of adaptations to an agricultural and urban life in different climates, and many of these adaptations just involved one or two genes. These changes are going to make up a minute portion of your genome, but they're still profoundly alter to your biology. We're going to be looking at examples of that throughout the course. In the meantime, I can use dogs to illuminate this point about how a few genes can have a big impact. Dogs were domesticated from wolves only about 15,000 years ago, and now they are the most variable animal in the world. But it turns out that only a few mutations in key genes controlling size distinguish much of the difference between a great dane and a chihuahua. It's not how many mutations you have, it's where they happen that counts. So a single small mutation that happened in someone just 8,000 years ago is today responsible for 300 million people having blue eyes. Scientists believe this blue eye allele got so common so quickly because it was subject in sexual selection. It's how people find mates. Well, as well as SNPs, we also have INDELs. INDELs is an abbreviation of insertions and deletions. That's where you have extra DNA sequence, or a missing DNA sequence, compared to other people. These stretches of DNA, they can be as little as one base pair, or could be a million base pairs long. You may have a genome several million base pairs smaller or larger than mine, and what's really weird is that these large INDELs can cause you to have extra genes, or to be missing genes compared to me. We call this copy number variation of genes, and we hadn't expected it at all. In consequence, we're never gonna be able to say that there are a specific number of genes in the human genome. You may have 20,345 genes, whereas I may have more or less. And these can be important genes, genes that affect our individuality, such as our height, our metabolism, personality, and so on. Scientists are still trying to work out what impact copy number variance have on our biology and evolution. But, the very least, the discovery of copy number variations make the phrase a normal genome very dubious. If I have a human genome sequence, I can look at its basic structure. I can use computer algorithms and the educated eye to count the number of genes. But I can't say what it is about that genome that makes it human. Most power that comes from the informational view of life derives from comparisons. I need to compare our genome with non-humans to see what we have and what we lack that makes us human. Now, if I have a chimp genome I can line it up against the human genome, and then I will see that they are 98.5% the same. So I'm gonna be most interested in the 1.5% that is different cuz that's what will make a chimp a chimp and a human a human. So let's have a look at our nearest and dearest. Here's the family tree of us, apes, the family Hominoidea. You can see that not only are we an ape, we are an African ape. We are more closely related to them than we are to the Asian ape, the orangutan. Moreover, the chimp is not only our closest relation, we are the chimp's closest relation. We are more closely related to chimps than gorillas are. So why do we look so different? Why do we look so different than chimps? Well, let's have a look at this adult chimp here. I do indeed look very different from her, but what about that little baby chimp? Not quite so different. We humans look a lot more like a baby chimp than we look like an adult. Our evolution can be seen as infantilism. We are sexually mature baby chimps. This is also called Paedomorphism. Paedo meaning child, and morphism meaning body. This is the skull of an adult chimp and I'm to compare with that of a modern human. The foramen magnum, which is the hole were the spinal cord goes, in the adult chimp is at an angle. Why is that? That's because the adult chimp is quadrupedal. It walks on all fours. Look at the prognathous snout of this chimp. Pognathous means the jaw juts out, like this. It's got really big jaws with great big teeth. And, this is the sagittal crest, up here for those huge jaw muscles to attach to. Now this is the skull of a baby chimp. What does this skull look like? Does it look more like a human skull, or an adult chimp skull? Well, it looks a lot more like our skull, right? And in the baby chimp, just like us, the foramen magnum, where the spinal cord goes, is downwardly orientated. That's an adaption to actually hanging onto the mother's fur. That's why the baby has a much more erect posture. We've attained that feature in order to be bipedal. The baby chimp has got teeth like ours, small, little teeth. It's got small jaws. It's got a flat face. And most importantly, a domed skull. Which is good because you can put a big brain in a big, domed skull. With a volume of about 1,350 cubic centimeters, our brains are about three times as big as those of a chimp's. In particular, the human brain has got this great big expanded cortex, the folded outermost layer that is home to our most sophisticated mental processes. Another point about our paedomorphism is that we have an elongated childhood. Now to explain why this matters, lets think about young animals. They are full of the joy of life. They are spontaneous. They act as if they're free. Likewise, many humans stay playful and curious all their lives. Like baby animals, they like to try new things, which probably made us a uniquely creative ape. Adult chimps, they're crotchety, stuck in their ways. Which is not what it takes to be creative and innovative. So, what are the genetic differences responsible for these phenotypic and behavioral differences between us and the chimps? In comparing the chimp and human genomes, we're looking at how the same ancestral DNA has changed from a common ancestor, and is passed down through the chimp and human lineages. So try lining the generations up in your head. Generation after generation of your ancestors. And on the other hand, take a chimp and line up generations of its ancestors stretching back. How far did you have to go? How many generations have to pass before the two lineages meet, before you get to that last common ancestor of us and the chimps? To estimate when the human chimp split occurred, geneticists used the molecular clock method. As two species diverge, their DNA becomes different, due to the accumulation of mutants. The amount of genetic difference between us and the chimp, will therefore be proportional to the length of time since we diverged from a common ancestor. So the first thing you need to do is to estimate the mutation rate. The best way of estimating mutation rates is to compare genomes of children with their parents. And that's like watching the molecular clock in real time. In 2012, Augustine Hall and colleagues harnessed a genetic study of seventy-eight children and their parents to count the number of new mutations in each child's genome. They found that every child has on average thirty-six new mutations. To convert this into an estimate of when our ancestors split from chimps, we need to know how long a generation is. Chimpanzee mothers range in age from twelve to forty-four years at the birth of their offspring, but the average age of reproduction is about twenty-five, which is very similar to humans. Knowing how many random genetic differences there are between humans and chimps, and knowing that these accumulate at the rate of about thirty-six every twenty-five years, it was estimated that we split from chimps at least 7 million years ago. That figure has become the consensus after several other mutation rate measurements. There's another 2012 study, analyze DNA for more than 85,000 Icelanders, focusing on short stretches of DNA called micro-satellites. And that study estimated the timing of the split at 7.5 million years ago. So a split about seven million years ago, points a finger at Sahelanthropus as a potential last common ancestor. It lived about seven million years ago, in Africa. And this anatomy kind of makes sense for a common ancestor. This is oura reconstruction of our one and only Sahelanthropus skull. It suggests that the owner is the oldest known member of the human family. Sahelanthropus has many primitive, ape like features. It's got a small brain case. And it's got others, such as the very large brow ridges, and the small canine teeth which are characteristic of later hominids. However, if it is a common ancestor of us and the chimps, it's interesting that, like many apes at the time, it had a downwardly orientated foramen magnum at the base of the skull where the spine would have inserted. This suggests a more upright posture and locomotion than chimps. Although, whether Sahelanthropus walked on two legs is hotly debated. But that supports some scientists, who have interpreted the chimp genome and skeleton, and suggested that the chimp is secondarily quadripedal. They mean by that that they were originally more bipedal and only quite recently came back on all fours as a knuckle walker. [SOUND]
