 So, it is with great pleasure that we can welcome Dr. Eric Spana for our first NHGRI DNA Day lecture. All right. Well, thank you so much for having me. Like, this is kind of crazy. Like, last year, at this time for DNA Day, it was a group of eight undergrads in their genome research education society, and today at NIH. So, but they had free t-shirts. Just saying, free t-shirts. So where this came from, actually, was I teach a genetics and developmental biology class, and we were going through one day, the basic tenets of some genetics things, and doing Drosophila eye color, because fruit flies rule, and their eyes were just doing this. They were like, oh, oh, oh, and their eyes were rolling up in the back of their head, and they're just, they've got this bored expression, and for some reason we went off on a little tangent that I usually do, into Harry Potter, and their eyes perked up and we just started working through lots of good things, and they, one of them in particular was really enthusiastic and was good enough to write all the stuff down, and we'll see her at the end, and so it became kind of a nice little thing. So, here we go, Harry Potter and the Genetics of Wizarding, so we're going to have a little audience participation thing, so when I point at you, you're going to have all the answers, right? Good, good, good, good, all right, so we need to do some basic ground rules, we have to set some definitions, because, all right, magic, we're going to find magic is breaking the rules of physics by thinking about it. Now, if you've seen or read any Harry Potter, there's a thing where you can just decide to be an animal, and if you want to decide to be a rat for 12 years, you can be a rat for 12 years, despite the changes in mass and brain morphology. So, witches and wizards can use magic, we'll use witches and wizards interchangeably, we're going to use wizarding as the name of the gene, just because it would be weird for Harry Potter to have a witching gene. Muggles and squibs cannot, so if you haven't seen this, this requires some definitions. Muggles are humans who can't use magic like me and presumably you. Muggles are individuals who can't use magic but are born of magical parents, so there's some genetics going on. Okay, lastly, this is fantasy, I am not completely insane, it's fun to think about, and I think about it way too much, and you're going to know that I think about this way too much in a few minutes, but this fantasy, all right, so we have to go some rules and evidence because there are no peer-reviewed journals in this field, so we have to use the evidence given to us, and that involves these seven books, as well as molecular biology to sell and a few others. I do have the new edition, I'm not still using the fourth, I have six. So we've got Harry Potter one through seven, those seven books turned into eight movies which irritatingly changed formats halfway through. There's a couple of little books that JK Rowling wrote to raise the money called Quidditch Through the Ages, and another one called Fantastic Beasts and Where to Find Them, which is a pamphlet about this big, which is going to be turned into a movie trilogy starting this fall. So I'll have new source material soon. Finally there's a website called Pottermore where the true Harry Potter nerds spend way too much time, okay? So those are our source of it, and there's one more that actually counts, and that of course is JK Rowling's Twitter account. It's her universe, it's her rules, if she says it, it goes. So I am a professor at Duke, I'd ever said I was a good one. This is all easily examined at this wiki where I get most of my information. So don't be me, do your own research, don't take them off of Wikipedia. What we don't use is unacceptable evidence, which include blogs, quotes here say you're terrible, terrible fan fiction, quotes from actors. They're cute and all, but I don't believe them. So here's our evidence. We may have to do a little background. So let's do some biology review, get everybody up to speed. We're going to start off with this little wizard kid. This is Harry Potter, just FYI. All right, so if we take this little wizard kid and we look up on his hairline, we can see that his body is made up of different tissues. And so here's a hair and here's some blood vessels that oxygenate that. There's some muscles, there's an epidermis. There's some cells called melanocytes that give color to the hair. And if we blow up this region of epidermis, we can see even more definition of individual cells, where they have different morphologies. And these little melanocyte cells help give pigment to the skin. And so people are made of tissues, tissues are made of cells. Cells, that little green circle in the center there, is a nucleus. And in that nucleus is all of your DNA, roughly. So all of your DNA or your genome is inside that nucleus. And our genomes are broken up into things called chromosomes, of which we've got 23 different ones. And each of them comes as a set of two. They come paired because you get one of them from mom at conception and one of them from dad at conception. So the left one's come from mom, the right one's come from dad, all the way down the row. And if you are a female, you have two X chromosomes. If you are male, you have an X and a Y. And this entire set is in each one of those cells in every cell in this tissue, in every cell of this wizard. Okay, what are those chromosomes made of? They're just stretches of DNA and they comprise of genes. Watching your Twitter feed today, that was the first question. And I was gonna give mine answer, but I decided to take Metro instead. So I like to think of a gene as just a stretch of DNA that does a job. Most of the time, that job is to make a protein. So this gene has some regions that are gonna help it convert this DNA into another molecule called RNA, which is a similar molecule and equivalent to changing font in Microsoft Word. So we're gonna go from DNA to RNA. And then that RNA is gonna get translated into a completely different language of amino acids to make a protein. So the protein is gonna go off and do a job. What do you think? Are we all there? Good, good, good. Okay, so we have to, let's wrap this up for an example. All right, so this is all about your mutation and MC1R causes red hair. Here's our favorite red-haired family. These are the Weasleys and they all have red hair. So let's take a look at how their red hair works. In the melanocyte cells in the hair, they have two copies of the MC1R gene. And that MC1R gene, they got, whoop, there we go, got one from mom, one from dad. Some proteins bind to these enhancer regions on those genes, makes the RNA, makes the MC1R protein in those melanocyte cells. MC1R binds another protein called MSH. It goes through a neat little signal transduction program, and it makes something called U-melanin, which is a pigment. And U-melanin fills the cell. So U-melanin is a brown pigment, and that's the phenotype. So the phenotype is the trait we can see in the organism. In this case, the genotype is that we have two good copies or plus copies of the MC1R gene. So it's homozygous for the MC1R gene. Now, if we break one, we can generate a mutation in MC1R from one of your parents. That mutation affects the RNA, it makes this little mutant protein. That little mutant protein can't bind MSH, but this one can. And MSH can still cause that program to make U-melanin, makes all the U-melanin you need. And you get brown pigment is the phenotype. So even though you only have one good copy, you still get the same brown pigment. But if you miss both, if they're both broken, you can't bind MSH. And instead of making melanin, you make something called pheomelanin, which is actually reddish. You make lots of pheomelanin, and now your phenotype is a red pigment if you've got both copies lost. Okay, how does this look in action? No, wait, so that gives us some other definitions. We can define things as possessive or dominant, based on how they work. We have two copies of every gene, and if we have two copies, there's only three different choices of how they look. Either we have two good ones, we have one of each, or we have two bad ones. That's really the only options. And if we can see the trait down here with the two mutant copies, that's called a recessive mutation. If we can see the trait in this one, that's called a dominant mutation. So, let's, a few examples of Harry Potter. Here's our recessive example, Weasley Hare. So, Molly and Arthur had a boatload of kids, Bill, Charlie, Percy, Fred, George, Ron, and Ginny, right? Ginny grows up to marry this sketchy Potter kid. They, much older than this, have children. And they have dark-haired James, and they have dark-haired Albus, and they have red-haired Lily. Now, Ginny has red hair. She's got two mutant copies of MC1R. She has to donate one to the children. Harry has dark hair, he has to have at least one good copy. So therefore, James and Albus have to have gotten a good copy of it from dad, and a red-haired copy from mom. Lily, on the other hand, had to get a red hair from mom and a red hair from dad. So that implies Harry was actually heterozygous for hair color, and he was, because his mom had red hair and his dad had dark hair. So, outstanding casting, that actually worked. Okay, there's our recessive example for hair color that works out pretty well. Dominant example, Franger's hair. Turns out that having curly hair is actually a dominant trait in humans. And so, if you look at her super curly, frizzy hair, which actually looks like a bad perm here, it does, doesn't it? Yeah, you look at her parents and you can see how super curly their hair is. But you can't. So something else has to be going on. What I'm going to propose here is that dad actually has super curly hair. Because that's what I look like with short hair. I have super curly hair. In fact, according to 23andMe, I am heterozygous for Triker Hyala. So, either he has it and you can't see it, or she's got a really good flat iron. So, we've got better dominant examples in humans, though. We have to jump out of Harry Potter for a minute. Do we know who this guy is? Do you know his name? Hout Ruegen. Hout Ruegen is the six-fingered man in The Princess Bride. He is the six-fingered man. Six fingers is polydactyly. If anybody watched TV last night, Tyrion. Tyrion Laster's statue is a trait called a contraplasia. Both of these are dominant human traits that are much easier to see than hair curl. This is actually caused by a mutation in an FGF receptor. And this is misexpression of a gene called sonic hedgehog, both well-characterized. Okay, so we should do some wizarding things. It's in the title. All right, some wizarding things. Let's test it. So, I work in fruit fly genetics. My terminology when discussing humans is horrible. Because I make fruit flies together. And really, I shouldn't talk about meeting humans together. But I do anyway. So, we're going to mate a witch to a muggle and test the progeny. So, if we have a witch, marry some muggle. And if there's Mrs. Finnegan, Mr. Finnegan, they can have a shamus. Shamus is a little wizard, one of Harry's buddies. If that witch is a full-blood witch and has two copies of the wizarding gene and the muggle doesn't have any, then shamus is heterozygous for wizarding. You can see the trait with one copy, therefore it's a dominant trait. Piece of cake, right? That's not bad. But if we erase it and do it again, we can take a homozygous recessive witch, where she needed both copies lost to show the trait. A heterozygous muggle who has one copy of this recessive gene lost, just like Harry is, can't see his red hair, and you get a recessive shamus. So, there's the indication that it's a recessive trait. So, our evidence there is terrible. We need better evidence. So, this is the real problem in the population. You never know who is going to have it. So, what I'm going to do is jump out of the population. So, we're going to mate a wizard to someone who cannot have the gene. And there's, the way you describe who can't have the gene is by describing who can. And who can have the gene are humans, like Neville. House elves, that's a Dobian creature, right? Goblins, Gripbook, and Vila. Okay, she's only a quarter of Vila, but y'all knew that. So, those are organisms and things that can actually break the rules of physics by thinking about it in this world. So, we can't marry a wizard to one of those and get a result. There's a few others, but that's close enough. So, someone who can't have the gene would say be like a giant. No magic used in the giant population. Who made a giant to a wizard, and their names were perhaps Frid Wolfa and Mr. Hagrid. They would have a son named Rubius, who was actually a student at Hogwarts and can use magic. Giants don't have any wizarding gene, has to donate a plus. Full blood wizard has to donate a wizarding gene, therefore, dominant trait. You'll have to forgive my N of one, but I don't write the stories. So, we've got a dominant trait. Furthermore, we can take Frid Wolfa and Hagrid and Rubius Hagrid, and notice that Frid Wolfa is a female giant. She has two X chromosomes. She has to donate an X to Hagrid. Papa Hagrid is a male. He has an X and a Y. Rubius is a male, so he can get dad's Y. Therefore, it's not on the X chromosome. Theoretically, it could be on the Y. Can it be on the Y? No, it can't be on the Y, because witches exist. Well, not really exist, but you get the point. Also, we just did this like three slides ago, if you're paying attention. So, now we've got the wizarding gene is not on the X chromosome. The chromosomes that are not X chromosomes are called autosomes. So, that means wizarding is now an autosomal dominant mutation. All right, quiz time. These six wizards fall cleanly into two categories, pure bloods and half bloods. Which ones are on the right? So, these are half blood wizards. I just showed you Seamus was heterozygous for wizarding. Snape has a book named after him called The Half-Blood Prince. And he was the bad guy the whole time. So, half blood wizards have to be wizarding over wild type, wizarding over plus. Whereas, these good lineage full blood wizards have two copies of the wizarding gene. Are these ones better at breaking the rules of physics by thinking about it than these ones? No. And we know that because JKK rolling drills it into our head over and over and over. And those pure bloods and half bloods have the same phenotype. And that's actually called complete dominance in genetics. Where there is no additive effect by having that second mutation. This is really rare and dominant. He has autosomal dominant traits. Much more severe. Hair curl, way tighter curls. Echondroplasia is no longer a statue but lethality. So, way more, way more, way more rare to have this word complete dominance. Okay. So, now we've got a nice autosomal dominant, complete dominant mutation. Where did she come from? All right. There she is. She's got one copy of the wizarding gene. Her parents have zero. They can't hide a wizarding gene like they can hide curly hair. So, if she's got this and they're both this, where does this come from? As a matter of fact, it's called, what's that? That's okay. In reality, the answer is usually not the dad. In this situation, we are not going to invoke not the dad. We're going to invoke everybody who they say they are. But it's true. So, but the answer is likely, if you believe parentage, a de novo mutation. So, from this nice little example from St. Jude's to a male and a female with no family history of cancer ends up with a mutation usually in his sperm. And that mutation, when inherited at the one cell stage, can cause that defect and an affected offspring. If this were the Granger family, it would look like this. No family history of magic use, a mutation in his germ line, and suddenly his kid uses magic by thinking about it. This is actually a little common, a little not uncommon, depending how you think about it. This happens at a frequency about 77 per generation. So, there's 77 changes in your genome that aren't in your parents. But only one of those is usually in a gene because most of the empty space takes the bullets. So, we can generate new mutations by de novo mutation. So, we know how to get new wizards. How often does it happen? So, if this were a clinical study, you would have this information from hospital records and pediatricians for little kids. Wizards don't do that. So, we have to go with what we've got, which is they go to school. Granger went to his birth in 79. Justin Finch Fletchly. Does anybody remember him? Really? I like you, people. 1980 and Colin Creavey, 1981. Most people go, oh. So, those are the three muggle-born wizards that went to Hogwarts in those Harry Potter years. So, now, if we can just figure out who goes to Hogwarts, that would be okay. So, who goes to Hogwarts? Little English kids? Yeah, little English wizards. Little Scottish wizards? Yes. Little Welsh wizards? Yes, but there aren't any. But one of the founders of Hogwarts was Welsh. So, I guess so. Little Republic of Ireland kids. Little Northern Ireland kids. So, Finigan's described as Irish, but then, so is everybody from the island. I'm going to go with not the Republic of Ireland kids, because that Quidditch team wasn't actually referred to as alumni, ever. And also, if it's just the UK, then politics is easier. So, that means all of the UK goes to Hogwarts. All right, so, there's the number of births in the UK over those years. And we get to about 740,000. So, for every 734,000 births in 1979, there was one wizard born. So, is one in 750ish thousand, is that common? Actually, it's kind of super rare. So, if wizarding is one in 750, a chondroplasia, that's here in Lancaster, is about one in 30,000. So, you're 20 times more likely to be born with dwarfism than wizarding. Huntington's, which is a neural degeneration disease, one in 200,000. Prageria, which is a premature aging disease, one in 4 million. So, this actually falls into the super rare class of human mutations. To put these in, well, put these in numbers I can understand, this is about four numbers in the powerball, which is one in 650,000. In the United States, in 2012, there would have been five muggle-born wizards born, but 133 of the chondroplasia, one Prageria, and you'd have only made 10 grand on the powerball. That's not even the big powerball prize. That's a little prize. So, generating new wizards, super uncommon. How do you get rid of it? So, now we have to get rid of it. There's a few ways we can do it. One is the, well, of course kind of mechanism, and the other one is, oh, that requires some hand-waving on my part. So, we've got a witch, marries a muggle, and generates a half-blood wizard. Piece of cake. Not going to change there. We have a half-blood witch, marries a muggle, and if she donates the wizarding gene, you've got another half-blood. But if she donates the plus, now you've got a squib because it's the non-magical progeny of a magical parent. This squib has a likelihood of having magic in his lineage of one in 750,000. Because there's no more gene there. But what about this guy? So, we've got a full-blood witch, a full-blood wizard, and a progeny who can't use magic. Now, there's a few ways we can go about explaining Filch. One of which is this. What if mom and dad really aren't the full-bloods they say they are, and they are really half-bloods, and they get what I would refer to as the disappointing segregation events, where they end up getting the two pluses. So, mom and dad are nice witches, wizards, but now they have a kid who has a one in 750,000 chance of being a wizard. And that, that's too sad. But we also have to be able to explain this. Because even if we invoke de novo mutation to knock out one of those wizarding genes, the other one should still do the job. It's dominant. So, we have to come up with a mechanism where we can knock out both of them in one shot. And this is where I've clearly thought way too much about this. This is the second site wizarding suppressor. So, if you like genetics, a suppressor is a mutation that makes your phenotype less severe. And in this case, it's going to reduce its severity to zero. So, in this case, we have some brain cells, and there's going to be a gene, and it's going to make some sort of little squiggly wizarding protein. And it's going to go to a bunch of question marks that are going to allow you to break the rules of physics. So, if we've got this, we can invoke one more gene. If we have it de novo mutation that happens in what we're going to call the squib gene. And now that squib gene comes down here, it gets translated and makes some squib proteins. And what those proteins are are DNA binding proteins. And instead of turning on things, they turn things off, like the wizarding gene in these whatever cell type is appropriate. All right, so now we've got squib gene binding that promoter, no transcription, no translation, no magic use as the phenotype, though you are homozygous for having two good copies of wizarding. One with squib gene can turn off both. If we look at this in sort of pedigree style, we can have muggles that look like this, half blood witches and wizards, and full blood witches and wizards. Except that we're not talking about one gene now, we're talking about two. And so, our muggles now have a wizarding gene on the left and a squib gene on the right. And our wizards have a wizarding gene on the left and a squib gene on the right. And if they have a squib, if they're mutant for squib, now that's inactivating their wizarding gene. All right, here's what it looks like. So this is actually a nice example of genetic epistasis, which is the phenotype of one gene depending on the genotype of another. So our phenotype of wizarding is dependent on the genotype of squib. So squib is epistatic to wizarding, if you really want to get genetic about it. So here we have Mrs. Witch, Mary's Mr. Wizard, and he has an event and they have a little squib son. And because wizards are horrible, horrible people, they take their little squib son and they kick him right out of society and make him marry some muggle girl and he grows up to be an accountant or something terrible. So he's a full blood wizard that he's carrying this squib gene. He's carrying one copy of that squib gene. She has no copies. He has to donate a copy of wizarding. That's all he has to donate for the next generation. But he's now, instead of 150,000, he has a one in two chance of donating squib. And if he donates the plus, he ends up having a witch for a daughter. This is Molly Weasley's second cousin and his daughter, Mafalda. Now, here's where it gets bad and then worse. This event is only supported by interviews with JK Rowling. So she wrote Mafalda to be in Goblet of Fire as Hermione's foil and then removed her. And this story used to be on her website, but then she threw away her website to make Pottermore and Mafalda never made it to Pottermore. So it breaks the rules of our evidence at the beginning unless we can fix it. So if we can get... I am not beneath cheating. So if we can get her... That fits too, by the way. So if we can get Mafalda to Pottermore, that'll give us evidence for a good dominant suppressor squib gene. So here's our second site wizarding suppressor. So a little review, dominant autosomal. Exhibits complete dominance. Has a de novo mutation rate. This is really rare. And it's suppressed by a squib mutation. Some of these actually sound a little familiar. It's actually kind of similar to a known condition called lactase persistence, which you would know as lactose tolerance. Autosomal dominant. You have one copy of lactase persistence. You maintain the lactase gene through adulthood and you can drink milk. If you don't, milk is the devil. It's completely dominant. One copy, you're fine. Two copies, you're also fine. And you can identify a de novo mutation rate by its frequency in populations because it's spread through populations. So the little red spots are high frequency of a population of lactase persistence. Like, we can't get this in wizarding because as soon as you make a new wizarding mutation, you're crossed out of the genetic pool and put into the little segregating population. So, back to... All right, no, future directions. It's a science talk. I have to end with future directions, right? A little phylogenetics because humans are weird. Only a small population can use magic, whereas all the other magic creatures, all the population can. So is that magic as recent into the population or is that squib as kicking over the population? Other genetic traits, Harry Potter fans are always like, well, what about blah, blah, blah, blah, blah? And I'm like, I have to pay attention now. Examples of epigenetic inheritance. They actually look like there's a few, which is kind of fun. And finally, the most important one, of course, is secure ministry of magic funding for my research, which I'm pretty sure is in Bethesda. Is that... Yeah. All right, so some acknowledgments. So Emily Rothen was an undergraduate in my class and then did an independent study on fruit flies in my lab, not on Harry Potter. And worked through a ton of this stuff, was really awesome. In biology, I work around at Drosophila Lab and we have this history of working in a big room, a fly room, and we have a fly room at Duke. And sometimes you're talking about wind signaling and sometimes you're talking about wizards. And so it was actually Amy Bejavik's great idea for the healthy, was the squid suppressor should work. Mine was way more complicated. And Muhammad Noor's helped with some other stuff. And of course, I'm that old and I have that kid. And so you run all the Harry Potter lore through the expert in the house to make sure everything works. So with that, I will take any questions you have. If you have any questions. All right, I think the pedigree stuff works great. And how the genes work. So the beginning part for the dominant recessive, like that I think works really well. 6 through 12, maybe not K. K's a little hard. K's like coloring is fun. Well, it was when I was in K. I actually, K might now be sequencing. So I think the pedigree stuff is fun because it gives you the things happen and you donate traits to your offspring. The other stuff gets a little harder. But I like that I think is that's when you're reaching. That's the 12 part. Right, because even you can bring those in, but you can bring them in with hair color. Because there is epistasis in different hair colors. And especially if you move from humans to Labradors. Is that right? So Labrador retrievers have multiple hair color things and you can do genetic epistasis with. So I'll go with that. All right, so here's the one I'm working on, thinking about now is a colleague and I are contemplating for fall. What's in Captain America's super soldier serum? And I'm going to go with CRISPR, myostatin. Myostatin is the big, right? That's like, and then you need a cell penetrating peptide to get your CRISPR through the organism. So what do you think? Does that sound like kind of, it's like, yeah, you can. And then you kind of go, wait, wait, we could actually do that. I could do that in flies, couldn't I? Of course, a model system in flies would be great too for magic. I have a screen worked out. I'm pretty sure all you have to do is immunize them and then look for things that shouldn't happen. Right, you're like, let's search the vials for bananas. We didn't put bananas to anything. Yeah, so the problem with those are you're not allowed to use, is it copyrighted names or, and so, there's no Pokemon names. There's no Superman or Batman. So you would need something slightly off. And there is a hairy, but it's spelled different. So now I'm going to think about that. I know there's good genetics and breeding. That's ecology. I haven't actually done that, but like, back when I was playing some, a little too much Pokemon. You could do some pretty good transmission genetics. Right, it was literally working out four generation crosses to generate the traits you wanted. And the best part is you're finding out how to do this from eight year olds. Like, it was super impressive. One of the places I actually got the, oh, I could actually give a talk about this was, so I go to this sort of nerd convention called DragonCon in Atlanta. And a professor from, I'm not going to remember his name, I think he's at the University of British Columbia, gave a talk on the science of X-Men. And it was Wolverine superpower isn't strength, it's, or the skeletal thing. It's actually scar-free healing, which he explained with extra epidermal stem cells, because fatal surgery does not have, doesn't have scars because they have so much. And then Mystique was changing colors by thinking about it, that octopus do that. And so there was that example and I think, I can't remember if it was like, the idea that Cyclops was generating like this eye beam of thing, which was the crazy idea of running rodopsins backwards. Right, instead of absorbing photons to create energy, it was actually using energy to create photons. I don't think that would work, but it sounds awesome. So I'm trying to stay away from X-Men. Because that's his thing, maybe some inhumans. I watch a little too much TV. But yeah, I've got some Marvel ideas that I'm kind of kicking around, but they have to go. The other one is, I did a little talk on the evolution of Fantastic Beasts. So what's kind of clever and interesting about the Harry Potter universe is that it's happening in real time, essentially in our shadow, so that anything you find in there has to be also explained by our science. And so you have to be able to explain how that dragon can breathe fire, because it's not a magical creation. It was derived from evolution like everything else, and how they end up with different traits. And that was kind of fun, but we're going to wait until the movie comes out to add to the source material. Wait for the play to come out, because then I get the next generation. So I can do traits going through three generations, which was essentially completely useless in Star Wars. Like, I was so excited for that to come out to go, oh, look, we've got a whole extra Skywalker lineage, and we're going to get another... Bizarrely, I did a Star Wars talk, and it was ecology. It was the ecology of Tatooine. Because there's this desert planet with these big, giant, furry mammals. The world of those things eating. So I had to come up with a solution for what those giant things could eat to generate that biomass. The short answer was tan-colored insects, because if it works for blue whales, it could work for bamboos. Hi. So it came from probably like the third day of class, in the genetics class I teach, three, four years ago, where they were super bored. And we got on a tangent and got on a roll, and had fun, and it progressed. And then we would come back to it and go, but what about that? And so it just got over and longer and longer. Bizarre. Sorry, what? Actually, the hair? The hair is to make that one joke. It's making me crazy. Like, I am so close to just going, shaving it all off and switching the pictures. This is what I look like with curly hair. Because once they produce a squib, they kick them out of society. And it probably depends on the return to society of how that squib was generated. If it was generated via the disappointing segregation event, they're never coming back. If it was generated like Mifalda, that kid was going to end up at Hogwarts. And I mean, probably ostracized, which I think was part of the issue of her not being in the story. But yeah, there's no good ability to see what the frequency of squibs are, because the only way you can identify the squib phenotype is in the context of a wizard. So it really could be that it is rampant through a human population, and that the presence of wizards is actually the loss of squib. Yeah, so the epigenetic stuff, not necessarily inheritance, because I can't think of any inheritance yet, but regulation of like Neville. Neville didn't express, wasn't a very good wizard doing his little, they were worried about he was going to be a squib, and that just screams epigenetic regulation. Due to traumatic, yeah. And I think there's a few other examples of that. I haven't gone through it to see if there's any other, Dumbledore's sister. Yeah. So that was the other one. So Dumbledore's sister and Voldemort's mother. I think Voldemort's mother was another example. But this is the stuff where you have to have like, really studied your Harry Potter. Okay, so you've got your mediocre wizards, and you've got your really awesome wizards, right? Here's my explanation for that. We'll see if you buy it. I come from a basketball school. If you know this, it's Duke's a basketball place. And the way I like to think about it is, genetics makes you 6'8". But it doesn't make you good at basketball. So genetics makes you able to use magic. But it doesn't make you good at it. And I think some of the better examples are actually the Weasley family, where they've all inherited the same things. But Ginny's blowing things up in fourth grade. And Ron's not. Ron's kind of a loser. I know there's a, I can't, Ron apologists are everywhere. But I think that was it, right? And Hermione super practiced at it. And so it got really good. And so I want to go with the skill, not necessarily genetic. A little bit, right? Could we just make it a multi-locust complex trait? Can I get some, can I get some run some 23 minute data on? You could, but there would have to be a way to grade, to quantify quality of wizarding. Like, I need their alscores, right? I need to contact the director of study, undergraduate studies at Hogwarts, and have them send me their files. Like the Weasley twins, who are actually pretty good, but pretty terrible at school. Oh, so molecular, where do you generate a molecular mechanism for breaking the rules of physics by thinking about it? Next? So, so it's funny, because like, you know, I said, I'm talking to the neurobiologist, has the office next to me. I'm like, so what part of the brain would that be? And she's just shaking her head going, what's the matter with you? Right? You deal your thinking with your final cortex, is that right? Right, so it would have to be there. I would go with not developmental, right? So it's not a, you make a new structure, and then it exists through time, because the epigenetic regulation says you can switch it on or off. So it's got to be there. And what's even more mind-blowing is, somehow you have to keep that brain structure when you're a rat for 10 years. Because you can still do things when you're a rat or a dog or, is there other ones? McGonagall was a cat for at least one scene. No, that's why there's giant question marks, because no, no, no, wouldn't that be nice? Like the number of times I sent tweets is a little inappropriate going, please solve this for me. But if anybody, if anybody has her on your speed dial, you know, I'd be, I'd be grateful. We're not viewing that dimension of existence. Yeah, see now I'm sitting there going, I'm gonna wait for Dr. Strange to come out. That might be in there. It's fun to think about that, isn't it? Like just to take the idea of like, because in science we're all sort of like problem solvers. And we're so used to going with the, this is my problem for today, that when you look at the silly problem, you're like, I better keep up with the answer for that. Like, and it's just sort of, it's the fun way to use your head on your commute, right? I drive, so, right? Like, bio statin, that'll do it, yeah. So, all right, do we have more? Oh, am I just like skipping the bad data? For the wizarding gene dominance, no, because there's really not that good of, there's not that much mating out to non wizards, right? So it's like the population size is really low. And for the suppressor, I mean, that's almost the bad evidence, right? That Mifalda, right? Because she's not real. But no, I can't think of any good, because there's hardly any multiple lineage of individuals, right? But the thing I thought was, and when I showed the Weasley pedigree at conferences, usually they get something like, kind of response, because it's kind of surprising that it works out so well, right? And then you go, wow, we never think about that stuff. But she lives in Scotland. And the, what is it, 20% of the Scottish population is red hair? So, I think it's just, they know it like the back of their hand, because everybody knows it like the back of their hand. Now, whether she actually got the casting people to do that, I mean, I think she had hands in like what everyone was picked, so that it would make sure. But yeah, you know, I don't have Petunia, right? Which was Lily's sister, did not have red hair, did she? And that's like, I need to go expand that pedigree just for fun. And especially when the play comes out. So, we'll see what the next generations look like when they grow up. I'm not thinking of any just now, but like, and I probably would actually admit it, because the good thing about it is, it's a really small sample size, like the seven books, right? And so, there's hardly any conflicting data, which is the problem with other fantasy worlds. Like, this is just small enough where it's interesting and they haven't screwed itself up yet. Whereas, if you try to go to comics, I mean, it's an inconsistent nightmare. Or, I think Star Wars is, oh, Star Trek is horrible. The continuity of Star Trek is awful. But Star Wars is actually a little, was apparently pretty good, because there was one guy. You ever heard that story? There was one guy who was like so good at lore that Lucasfilm hired him. And he had taken everything out of his head and put it into a giant database, so that Lucasfilm could know all the stuff that they said. Good, great job. So, if I could get that for this. Yeah, so, if you ever had any questions, you can tweet me there. I will be a good guy and reply. What's that? Not like other. Not like other. I'll be a good guy and reply until you become annoying, and then I'll stop. What do you think? Are we done? Yeah. Are we good? You should go. Y'all should get back to work. So, y'all have to go back to work now. Sorry. I don't.