[MUSIC] Welcome to today's talk. Today I'm gonna discuss comparative and developmented genomics and how we can use the fact that we're quite similar genetically to many other organisms to our benefit when studying human genetics. It's difficult to study the function of genes in humans, since currently the easiest way to study the function of a gene is to see what happens when there's a mutation and that gene no longer functions properly. So, to study human diseases, we need to examine people afflicted by a disease, naturally. Well, that presents problem if we want to study the 22,500 genes in humans. We'd have to look at the entire population, and wait for a person to have a disease, and then try to figure out which of the 22,500 genes is broken. And then examine the symptoms that way. Well, that's a lot of work and a lot of waiting. But what we found is we can create mice, called knock-out mice, where we intentionally remove a gene, or knock-out a specific gene's function. This allows us to control specifically which genes we want to remove and we can observe the resulting phenotype or symptoms. A Nobel Prize was awarded to the scientist who developed this technique of studying gene function in knockout mice. What we see is when you knock out a mouse's function for a specific gene, it often affects many aspects of the phenotype. Remember that term, pleiotropy? We can't just do this in humans because it's not ethical to remove the function of a gene just to see what it does. So we study mice when trying to examine human diseases, that leads us to another interesting field of genetics called comparative genomics. Genomics is the study of whole genomes. Insects and other model organisms like mice can provide insight into humans through the power of comparison. By comparing the genomes of different organisms, we line up the sequences and look for similarities or differences in corresponding regions. And what we see is that we're really all genetic relatives. One interesting example of these relations can be seen by examining an enzyme class called kinases. When we compare these kinases in humans to Drosophila, or fly gametes, we see some kinase proteins are only found in humans. Well it's quite interesting, as we see that many more kinases are shared with flies, more so than are human specific. And what that demonstrates is a level of homology with similarity between humans and the seemingly unrelated organism, the fly. Flies can give us a lot of insight about the human genome and the human condition. We can look at Drosophila and see that there are hundreds of disease associated genes that have already been identified. And a lot of these disease causing genes might have been identified in Drosophila, also cause similar diseases in humans. Some examples are cancer, and the tin man gene I discussed earlier. And diseases like Parkinson's and Huntington's can be studied using flies as a model system. So insects are great for studying human diseases in its progression, because theyre inexpensive, easy to rear, quick to grow, they have relatively small genomes and minimal ethical implications. That means we can use flies to develop and test drugs which could possibly treat or cure human diseases. We can make fly genes nonfunctional and absorb the phenotype, like what we saw with knock out mice. One way we can do that is to remove or disrupt the genes' functions by using a technique called RNAi or RNA interference. Flies have less than 15,000 genes compared to our 22,500 genes, and their genome is very well annotated. There's a lot of data and analyses that are available about flies. They're also significantly similar to humans, and we've examined or reported a lot of conserved biochemical pathways in flies that are also seen in humans. There are Drosophila homologs for 60% of the genes involved in human cancers. One example is p53, the tumor suppressor gene, which is implicated in a host of human cancers. Beyond cancer, we can use model organisms to research where and when developmental genes are expressed and how these genes influence one another. This study is called developmental genetics. And what we see is that mRNA proteins effect development based on their concentration and location within cells. And in early embryonic development, the body, the major axises, the number and orientation of segments of the body are determined, as well as the identity of each segment by proteins in mRNA. Theres polarity, a dorsal back region, a ventral front region. There's a head anterior region and a posterior hind region, and a cascade of genes regulates and establishes this polarity or identity of the body parts. And in humans, we call these homeotic genes. This tells your body where the head should be, where the arms should be, where the legs develop and what structures are on the face for example. These genes, again, are the major regulators in development that allow you to form properly. In mammals, they're called hox genes. Interesting, we even have hox genes that are no longer functional, and sometimes we see the expression of such hox genes and we call that an atavism. That's the reappearance of an ancestral condition. The same gene could be fully functional in another organism but isn't functional in us. For example, the gene for tail formation, that's broken in us. However, every once in a while, human babies bone with vestigial tail and in this baby there was a mutation that occurred that allowed the broken hox gene to be expressed again. That's fascinating, because it shows us we had many genes that are broken or no longer expressed just hanging out in our genome. And we can use comparative genomics to determine which ancestor we inherited these broken genes from. The similarity among genes in different species shows our genetic homology. And because of this we see structural homologies and developmental homologies. And all of the similarity is because life has a common ancestor. That's where our DNA ultimately came from. A great example of this is with the gene that controls eye formation. The eyeless gene of flies controls eye development. In mice and humans, the gene that controls eye development is similar to the fly's gene. In humans it's called the Pax6 gene, and knocking out the Pax6 homolog in mice creates an eyeless mouse. The human homologue of Pax6 has been con-sorbed and this gene is really similar in sequence to the fly eyeless gene. All of these genes are the master controllers for eye development. So, what we're talking about here are three different species, flies, humans, and mice, but one set of homologous genes with very similar DNA sequences that are nearly identical in function. These genes are so similar in the the three different species that the mouse homolog for Pax6 can actually trigger development of an eye in a fly. Another question you may be asking yourself is, why do we call the gene for eye development flies, eyeless? Well, we can most easily observe what a gene does when it's broken. So often times we'll name a gene after phenotype that's observed when there's a mutation. So if you take a look at the human chromosome and examine the gene names, you'd think that most of our genes actually cause diseases. That's not the case, though. It's just the easiest way to observe a specific genes function, is when it breaks. So that's how a lot of genes got there name, based on when they're broken. Fortunately, if your watching this video, the genes you need to survive aren't broken. Besides just examining structural genes, such as the ones that are required to form eyes, we can better understand human behavior from fly behavior. We can do this because of that genetic homology that we were talking about. Let's look at alcohol, for instance. After alcohol exposure, flies become hyperactive then uncoordinated and well, they pass out. The behavior of drunken flies is virtually identical to that of humans, which means that drugs that treat alcoholism in flies may also be successful in treating alcoholism in humans. To quote Ulrike Heberlein, a Drosophila geneticist, I'm still amazed that there are so many similarities between the behavior of these little flies and the behavior of humans when exposed to drugs. There are also mutant flies that are deprived of sleep, much in the same way a lot of humans are. And these flies need sleep, they want sleep, but they can't stay asleep. They're great models for studying insomnia and drugs to treat insomnia. There's also mutation in flies called fruitless, and the fruitless gene among other genes, can trigger and effect sexual orientation. So by altering serotonin levels in these flies we see that it causes male-male preference. And this male-male preference due to this mutation is actually seen in other animals as well. Also remember a while back we discussed aggression. Well, this can be studied and possibly treated using flies as well. Some genes and proteins that have been researched include dopamine, androgens like testosterone, and and monoamine oxidase A, to name a few. So, scientists have studied large human families with aggressive and violent tendencies, and what they found is it's mostly seen in men and there's a behavioral pattern of many violent offenses. One of the potential reasons for this could be the genetic mutation mapped to the X chromosome. An allele of the monoamine oxidase-A gene that we already talked about called the warrior allele. So men have one copy of the X chromosome, where this gene is located, whereas women have two copies. So it's possible and very likely that women have a dominant version, and most women have the dominant version associated with normal behavior, that might be masking the warrior of the old version of this gene. So like we discussed earlier, the gene that codes for monoamine oxidase type A will affect the breakdown of the neuro transmitter serotonin. And the warrior version of this gene causes an monoamine oxidase type A deficiency, which when coupled with a abusive childhoods, tends to lead to aggressive behavior in adulthood. We can study those flys with this mutation and absorb their behavior to better understand the underlying cause of aggression. But more importantly, how to treat it. So you may be wondering, an aggressive fruit fly? Well, it sounds strange but it's not, flies can be aggressive. They demonstrate wing threats, they can box and fence using their legs, so they'll push and punch each other. So, model organisms like mice and flies are a great way to study human diseases, behavior, and treatments. Of course, you may never think of flies the same way again, knowing they get drunk and rowdy just like humans. [SOUND]
