[MUSIC] Welcome back. So let me line up genomes. We're looking at what has changed and what has been preserved in the chimp and human genomes, since they diverged from a common ancestor, perhaps our friend sell in a purpose here, 7 million years ago. Take any stretch of human DNA. And the stretch of chimp DNA that corresponds to it. They'll represent the same piece of ancestral DNA passed down in two separate lineages, over the course of 7 million years. Now if we take sequence and the civilian intended to be gibberish up here, from a chimp and a human, and you put it through a computer, you're gonna find hidden messages. This is hidden. This is hidden. Computers are good at finding this kind of thing, stuff that's better preserved than it should've been just by chance and stuff that is different. Before the ability of computers to extract useful information from genomes, bioinformatics. Of course, even big data, computers are crucial. They enable us to ask questions to get answers in ways we never had before. Applying bioinformatics to the human and chimp sequence, we find about 98.5% of it is conserved. At least 1.5% that's interesting, but it identifies a set of mutations that accumulated in the DNA of the chimp lineage, and some of these would have made a chimp a chimp, and another set of mutations that accumulated in our lineage, making us humans. So how do we differ from chimps? Well, about one in a hundred base pairs is different as compared to an average of one in a thousand between you and me, and given that the genome is 3 billion base pairs long, that means there may be 30 million human specific letters of code that are not shared by the chimp. In addition, there are about 5 million INDELs, which remember means assertions and deletions in the genome. And they're mostly in regions that don't encode proteins. And that means that not many of those 5 million INDELs will contain genes. So there's not gonna be many copy number variations in us and chimps. Now bare in mind that there are copy number variations between us. So I may have more or less genes than you. But if we look at those genes where modern humans all seem to have the same number, then about 30 genes are replicated in us since we split from chimps. That's not many, so we have a very similar number of genes as a chimp. Interestingly, a lot of the extra genes we've got are involved in plane development. The best study of these is a gene called SRGAP2. Genes have names like that. Don't worry about it. Anyway, this gene duplicated 3 to 4 million years ago, when we first began using tools. And again 2.5 million years ago, when our genus homo separated from the Australopithecines who had brain sizes not much larger than that of modern eggs. So what that means is we now have three copies of the gene, whereas chimps only have one. Studies of mice have shown that having these extra copies of SRGAP2 would have changed our ancestors neurons, so they developed complicated shapes that made them capable of exchanging information with a larger number of neighboring cells. So SRGAP2 teaches us that evolution wasn't just about giving us bigger brains, it also changed the way our brain cells interacted. You know, something else interesting about these duplications is that they would've changed brain development immediately and dramatically. So human ancestors with two, three, or even more copies of the gene could've coexisted at one point, which is kind of fun to think about. What drew is still out on the impact of most of the other indels, which is not surprising, as we're still trying to work out the impact of the indels on copy number variance in human variability. So scientists comparing humans and chimps, they've mostly focused on those SNP's. It's estimated that out of the 30 million SNP differences with the chimpans, 10,000 were changes to protein coding genes. That altered our bodies, and therefore was subject to selection. And on top of that there's gonna be mutations to regulatory regions of our DNA that turn genes on and off. So that the questions are, which of those particular DNA changes actually made us human, and how do we identify the sequences that make us human? Well to find out which of these spelling differences in DNA sequences are most important, Katherine Pollard at the University of California in San Francisco, has developed powerful computer software that's scanning the genomes of human chimps and other vertebrates. She's looking for hot spots along the genome where DNA's changed especially rapidly in the lineage that led to humans. Pollard and her team reasoned that DNA sequences that had undergone the most modification, since the human chimps split where the sequences that most likely shaped humankind. So when chimp and monkey and mouse and cats and chicken and fish have exactly the same letter at a certain place for hundreds of millions of years, it suggests that evolution wouldn't let it change, because it was needed for an important role in these animals. So the Pollard lab has thus far identified 202 cases, where there's a sudden burst of change in a DNA region in the human lineage. And they call these recently changed regions Human Accelerated Regions, or HARs, H-A-R-s HARs. And what's really interesting, which a lot of the sequences that are really different between us and chimps don't encode proteins. So that means proteins don't have it all their own way in evolution, but then we could have guessed that, right? It comes back to the fact that a lot of the 98% junk matters. It contains regulatory sequences that tell other genes when to turn on and off. There is a whole lot of DNA having purposes that scientists are only just beginning to understand. The majority of halves seem involved in gene regulation, because they are sitting in front of genes or at least near them. So for these halves, Pollard and the researchers figured out what gene is next to. And then they ask, where and when is that gene switched on and off during every logical development? And then is this expression pattern different in the human than in a mouse or that of a chimp? If it is, then the novel pattern may prove to be relevant to an understanding of how humans are distinctive creatures. Well, HAR1 tops the list of the most divergent sequences between us and chimps. And this is an exciting finding because it seems directly linked to us and our braininess. So, look at this table, it shows the HAR1 sequence in us, in chimps and in the chickens. This region of the genome as you can see has changed very little from most of vertebrate evolution. Because the chimp and the chicken sequences here differ by just two letters. While the fact that HAR1 has been essentially frozen in time for 300 million years, since the chimp and chicken have a lot of common ancestor, indicates that it does something very important. However, the human HAR1 has undergone 18 substitutions. That it underwent abrupt revision in humans suggest that the function was significantly modified in our lineage. Now the real exciting thing about HAR1 is it's in an genetic region that is turned on early in neurons, that play a key role in developing the neocortex. The vencourt outermost brain layer. When things go wrong in these neurons, you get a cerebral cortex alaxpholdic. A very sad condition called lissencephaly. There's no one know what HAR1 does in those neurons. It's just active in the right time and place to be instrumental in the formation of a healthy cortex. Thus potentially HAR1 would have ordered ancestral human brain function. We don't really know much about how the human cortex develops, but the H-A-R-1, the HAR1 provides a new lead in the target for experimentation. So aside from braininess, what other feature is often used to distinguish humans from our fellow apes? We're the apes with the big planes and we've got the opposable thumbs. So would you like to hazard a guess, what you think H-A-R-2 does? HAR2 does? It turns out, the second most divergence sequence between us and chimp is a regulatory region, an enhancer that drives gene activity in the wrist and the thumb during fetal development. But that's particularly interesting, it's the ancestral version. In other primates doesn't do this. The human HAR2, R2, perhaps their thought contributes to human specific hand coordination and the dexterity to manufacture complex tools. Now please note, that doesn't make chimp hands inferior. Chimps don't want a thumb. Chimps swing through the trees. All you need is a little hook for that. A thumb would get in the way of a chimp and its lifestyle of choice. Now there are several other preliminary stories relevant to the brain. HAR152, for example, is near the gene encoding a protein called neurogenin 2 that's expressed in a region of the hippocampus. We'll talk about the hippocampus in later lectures. The hippocampus has a central role in learning and memory. Pollard's group believed that, once all of the experiments have been done, it's gonna turn out that more than half of the halves of the homogenate genes that do things in our brains. Thus even though arms make up a minute portion of the genome, changes in these regions could profoundly alter the human brain, influencing the activity of whole networks of genes. Now look at this model. You have a master regulatory sequence, the pops and codes of regulatory protein which switches on a battery of other genes. Some of these in turn switch on other genes, together a cascade of changes. Just resulting from one sequence changing. Perhaps that's this down stream gene here produces an enzyme that makes a hormone. You take the gene, that particular downstream gene, and produce slightly more or less hormone, and I'll be a little different than the other kids on the block. But if I mutate a master regulator downstream here, upstream here, beg your pardon, I could affect hundreds of genes. It'll have a radical impact. It's possible I won't even get to be born, and if I am born, I'll certainly be different, and natural and sexual selection will see if it works. It may be, then, that the way to evolve a human from a chimp human ancestor without adding much genetic innovation, is to change science where changes make an important difference in an organism's functioning. By changing regulatory sequences that tell genes when and where to turn on and off, you can redeploy the existing squad of genes in new and interesting ways. And the results can be dramatic, like changing a sports manager could have a much greater impact on a team's performance than just switching out individual players. [NOISE]
