[MUSIC] Welcome back. As I mentioned at the start of last week's lectures, all throughout human history people have pondered the meaning of life and being human in order to find the essence of who we are. Geneticists have also been trying to figure this out because an understanding of who we are can't be achieved without pursuing our biology. For a whole lot of reasons this question is going to be a lot more complicated for a human being, then for say a fish asking why it likes to eat worms. The complications are likely to be at their most extreme in considering the biology of some of the stuff that interests us most. The biology of poor health and the normal behaviors. We're usually asking whose fault is it that something bad has occurred. With a mass murderer, do you blame a damaged, a non functioning frontal cortex? Do you blame bad genes? Gene for aggression? An abusive family? If your kid is failing at school is he learning disabled? Is he lazy? And is he lazy because of poor upbringing, or because he has genes? Not for being learning disabled, but being a slacker. While in the next couple of lectures, we shall look at what contemporary science teaches us about how genes enable or constrain us and how their functioning is regulated by environment. We're gonna start with the simplest case, traits controlled by single genes, just as Mendel the father of genetics did with his pea plants. Mendel's plants were always one thing or another. They were either tall, or they were short. Their flowers were purple, or they were white. The peas were yellow, or they were green. We call this discontinuous variation. If we had a single gene controlling eye color, and it came in two forms, or alleles. Alleles, as we say in genetics. Then I might have a choice of brown or blue eyes. That would be one thing or another. So we'd say it's discontinuous. If I have two or three genes controlling eye color, I might have a step wise progression from blue to green to brown. But if I have multiple genes controlling eye color, as we do, each making a small contribution to shade, I could go from various shades of blue, to various shades of green, to various shades of brown. And we would call this appearance of blending continuous variation. And most of the important differences between us are controlled by multiple genes so you get that effect of continuous variation. So there are hundreds of genes controlling our height, which means that most of us aren't very tall or very short, we're something in between. Several thousand so-called monogenic or Mendelian human diseases caused by a mutation in a single gene. Cystic fibrosis is a well-known example and cystic fibrosis, like most of these other diseases are recessive, which means that you need two copies of the damaged gene to cause disease. Well quite often having a single copy of the gene has benefits, at least in some environments, or in combination with some other alleles, which may explain why they've been retained in populations. So famously, a single copy of the allele for sickle cell anemia protects you against malaria. Now, monogenic illnesses make up a fraction of genetic diseases. It has to be true, because all disease has a genetic component. The fact that the virus has a big impact on you means that your genetically determined immune system is poorly able to cope. Where someone else, or a chimpanzee, might have no trouble. If a virus causes only a mild disease then that means your immune system is up to the job of dealing with it. Even something like breaking a leg has a genetic component. How well you repair the break will depend on genetics as well as environmental factors. We've all heard or know of people who spent 80 interesting years smoking and drinking, and are still well and hearty. There was a fellow in England called Buster Martin. He was England's oldest worker. He smoked heavily, he drunk several pints of beer a day, and he died when he was about 97. Of course scientists are very interested in the genomes of guys like Buster, cause he must have had some genetic protection from his vices. If we could identify what these are, maybe we could devise medicines, that would do the same for us less fortunate folk. Well, the story of personal genetics highlights the successes and limitations of the modern revolution in personalized medicine. Companies like 23andMe are offering directly to you, the consumer, the use of sequencing technology to pick up millions of gene variants. Most of these companies use microwaves or DNA chips, they're the same thing. These little instruments that you can hold in your hand. They hold millions of microscopic spots of DNA and each spot is complimentary to a specific region of your genome. You can look at that little matchstick there for a size comparison. What DNA microarrays, like these, can be used for SNP variance in your genome, so you can compare your genome profile with that of other people. That technology became really cheap in the 21st century and indispensable. But technologies in evolutionary science and there is an extraordinary turnover in technologies. Microwaves, which were critical a few years back, are now being displaced by personal genomes. So in this course I'm not going to be focusing too much on the technologies, by technologists views, as they are here today and gone tomorrow. Instead let's ask whether using technologies that interrogate the genome actually help us to understand disease of the genetic roots of our behavior. Human genetics has become like a giant Excel spreadsheet, where all the genetic variants listed on the top and all the traits are listed down the side, and we try to find links. Perhaps I'm looking at asthma and cancer, heart disease, and I'm finding what SNPs and INDELs are found in people with each of these conditions. I might also be looking at other kinds of traits, such as height and obesity, intelligence and various character traits or beliefs like religious beliefs. Now these kind of studies are known as genome-wide association studies, or GWAS, and they can involve tens of thousands of people. [INAUDIBLE] they're going to also be looking for genetic variance in the non-coding DNA. Remember from last week we called that junk DNA? We noted, we emphasized, that in reality that so-called jump includes a lot of crucial regulatory DNA, and most of what goes on with genes is regulational gene activity and that's controlled at the environment. In terms of disease, GWAS studies have implicated over 1,000 genes with involvement in over 100 common diseases. The early discoveries found genes with major effects in serious diseases like macular degeneration, which is the commonest cause of blindness. High risk of this disease can now be predicted with reasonable accuracy from DNA testing. It turned out that a lot of common conditions, such as asthma and diabetes, were controlled not by one or two genes, but by tens of genes or even hundreds or thousands of genes. It was also found a different set of genes might be responsible for asthma or obesity in different people. Now, obviously, unlike mono-genetic diseases, gene tests involving one or two genes are likely to be pretty useless for predicting a disease caused by the interactions of hundreds of genes. But on the good side, the very good side, many of the gene discoveries for common diseases turned out to be interesting in terms of understanding their biology. So GWAS studies have identified mechanisms by which diseases start and the biological pathways that are disrupted. Now with that kind of knowledge, we can figure out treatments. So in some diseases, such as inflammatory bowel disease, entirely new completely unexpected pathways have been discovered. In other diseases new insights into existing pathways have been given. So the autoimmune problems that lead to type one diabetes have been cracked wide open. Let's have another look at obesity as an example. Now GY studies have addressed basic questions as to why some people are thin and others fat, and why being fat makes some people ill. It turns out that genetics plays a much bigger role in obesity than previously thought, because it covers not just molecular biology of how the body processes food, but also behavioral traits such as propensity to exercise and your appetite. A lot of genes are involved in all of those traits but some may be more important than others. A study that came out in July 2013 showed that the high risk version, high risk allele of the FTO gene, associated with obesity, makes fatty foods more tempting, more delicious, and orders levels of a hormone called ghrelin, which makes people hungry. So our intrinsic biology, our genetics, tells us how much we want to move and eat and we're less in direct control of body weight than we like to think. Obesity, of course, is an example of the problems that arrive in us living in a world as radically different from the one in which we evolved. For subsistence hunters, it's a good strategy to eat all you can when you're lucky enough to come across a rich energy source like sugar or fat. Now maybe [INAUDIBLE] alleles of FTO designed by selection to find these foods so pleasant. However, for those of us fortunate enough to be surrounded by an almost limitless supply of cake and deep fried burgers, decidedly unhealthy to continuously gorge ourselves, we're fighting those innate genetic tendencies that are not healthy for us. The inability to find individual genes that are always associated with some medical conditions, various other traits have led to a big shift in attitude. And for many geneticists to change their focus to people who seem protected from common diseases. I just mentioned Buster Martin and of course there's lots of other people who've lived decades. 70, 80, 90, or more interesting years of drinking and smoking and they still seem whole and hearty. There's increasing evidence that the big reason we don't find those single genes for diseases, or that diseases may be caused by different genes in different people, is because some of us may also have protective sets of genes, and these override genes associated with disease of aging. So geneticists are sequencing the DNA of centenarians, or people they all the wellderly. These are people over the age of 80 who have no chronic diseases. And these studies are coming up trumps. So far they've identified five or six biochemical pathways that are most often revved up or inhibited in the wellderly. A lot of the gene variants in the long-lived people effected insulin IGF-1 pathway. Now IGF-1 plays an important role in childhood growth, but it's also been implicated as an accelerant to cancers and as a powerful regulator of metabolism. One hope here is that these studies may someday lead to drugs that help us reach a ripe and healthy old age. Well, let's hope they do. They also hope that you might now be able to see that the views of the popular media are simplistic. The media claims specific genes for all sorts of things, including for why do we behave as we do. If you type into Google, scientists find gene fault, I'll leave the last bit blank, you're going to get hundreds of thousands of hits. It's noticeable that time and time again, scientists find the gene for depression or hair loss or cancer. It's sometimes said that the most dangerous word in genetics is for. And in some ways for is also the most dangerous word in society. It's used stupidly, very simplistically. The idea that everything has a simple cause. Well genetics isn't that. In 2009 a murderer in Italy got a reduced sentence because he had alleles associated with criminality. Some United States courts have gone the other way and accepted genetic factors as evidence for the prosecution. Leading to higher sentences on the basis that people with particular alleles cannot be cured. They're going to remain a risk to society for longer. A study published in science in 2012 asked judges to impose a prison term on a hypothetical convict. When the judges were initially told that the offender was a psychopath they tempted to consider it an aggravating factor in sentencing. When they had additional expert testimony, the biological factors could explain the guilty man's behavior, and so that information is mitigating and handed down a shorter sentence. Do you think this could be a dangerous road to go down? After all, most violent crime is linked with the SRY gene, the gene on the Y chromosome that determines maleness. Would get off because they were a bloke and do you think that having the Y chromosome should lead to a harsher sentence? After the wait we're going to talk about a very famous psychologist who is [INAUDIBLE] will predict in a psychopath. But he's not a violent man, he credits this to his upbringing. So in other words his childhood environment protected him Yay!
