New Rules For Heredity (Non-Mendelian Inheritance of Epigenetics)

Intro

0:00And not everything is about genetics, meaning not everything is about the hardware of the DNA. It's also about the sort of software which is the epigenetics part of it. They've done a thorough analysis of the genome and found that up to 7% of the DNA obeys these kinds of different weird rules. 7% that's 1 in 14. So one in 14 genes, that's not a joke. Hello internet. This is your captain speaking Lester Nar. And breaking news, the Candyman is home. Ooh. Ow. Ooh. What is that? Someone called a dentist. Is that a cavity? We are [music] back here in

0:41studio by popular demand after months with just me and my back with our resident PhD Krishna Chowdery. Welcome [music] back, good sir. How are you? >> How's it going, man? Um, I have barely had any sleep over the past two months, but uh, you've been doing a great job

Krishna returns from paternity leave

1:00with all all of your content and now we are back in the studio. It's been it's been crazy. It's it's been really crazy. And I remember like the baby came, you know, for for for our viewers, the baby came two weeks early and the day that it happened, we were supposed to record two additional episodes in preparation for my paternity break. and I texted you from the hospital like, "Hey, it's today. Abort mission mission. We're going to we're going to just roll with it." But I'm glad to be back. Um, seems I've missed quite a bit. Quite a bit has happened in the world. Um, the most important thing that happened is probably Lewis Hamilton won his first

1:40[laughter] race with Ferrari. Finally, the promise of Lewis Hamilton has paid off for Ferrari. So, I'm wearing my Ferrari gear for that. >> We are very grateful to have uh Krishna back here in the promised land at FFP Nation. Um, and in honor of you entering

Today’s topic: non-Mendelian epigenetic inheritance

2:02fatherhood, uh, today's deep dive is going to be about non-Mandelian epigenetic inheritance. And so, we're going to learn about the science from the ground up today because this is from

Questions of inheritance and fatherhood

2:15First Principles.

2:31So, I was recently blessed with my first child and questions of inheritance are very forward in my mind, right? um questions that every person of color asks like how dark is the baby going to be, you know, among other things like what color is are his eyes going to be? Is he going to be an athlete? But, you know, that's one of the big ones. Um if anyone's out there who's brown, they know they know what I'm talking about. And so, for most of the traits that are out there, you can use rules that were established 160 years ago by this guy called Gregor Mandel. And these traits follow Mandelian laws of inheritance. This is the stuff that you learn in like

3:11AP Bio. If you ever took AP bio in high school, the rules are pretty simple and we're going to go over them. There's like these dominant genes, recessive genes, some and by and large those rules work,

DNA hardware vs. epigenetic software

3:24but as with all things in biology, there are always exceptions. And genetics is something that has a bunch of exceptions because you're, you know, down to the molecular level and there's always weird stuff happening. And not everything is about genetics. Meaning not everything is about the hardware of the DNA. It's also about the sort of software which is the epigenetics part of things. This is a very dynamic package. This is how the DNA is wrapped around inside the cell. How much the DNA has access to protein making machinery, things like that. And those things can change much more quickly than the actual genetic sequence

4:06itself. And we're only just starting to get into studying that higher level of genetic machinery, right? And it turns out that that those traits can also be inherited. Like this software package on top of the hardware is something that is also passed down. And we're just starting to understand that. There's exceptions for how it gets passed down. Most of the time, again, it follows Mandelian rules, but sometimes it doesn't. And that's what this story is about. There's a new paper out of John's Hopkins University and Texas A&M that is documenting a new type of non-Mandelian inheritance of epigenetics in mammals. And it's showing that this genetics is

4:47far stranger and far more dynamic and far more interesting than I think Mendel could ever have imagined 160 years ago. And so, like, why why is this a big deal, right? Obviously, anything related to genetics is a big deal because genetics is like the blueprint of life is the blueprint for who we are. But it touches on everything from like why identical twins can have different disease outcomes, right? Identical twins have the same exact DNA DNA, but sometimes one twin is going to have one disease and the other twin is going to be just fine. That's because the software package on top is different, right? Um diseases can skip generations.

Why epigenetics matters for disease and inheritance

5:26That's something that happens to do with epigenetics. And sometimes the same gene variant can be benign in one person. If you do the genetic sequencing of two individuals, they'll have the same gene variant, but one individual will get the disease and the other one won't. Again, that has to do with the software on top. So, this paper marks like a major shift in how we think about epigenetic inheritance, especially in mammals. And it shows that this is not actually an exception. That's the big part. Okay?

The 7% finding and the quiet revolution in heredity

5:55They've done a thorough analysis of the genome and found that up to 7% of the DNA obeys these kinds of different weird rules. 7% that's one in 14. So one in 14 genes that's not a joke. >> That's that's pretty statistically significant as we like to say. >> Yes. Exactly. Like that's something that you do have to worry about if we want to like get a really comprehensive idea of how genetics affects outcomes and all that stuff. So, we're living through kind of a quiet revolution in the understanding of heredity. And in this episode, what I want to do is go through how it all started 200 years ago. We're going to start with Mandel. Then I'm going to take you through some of the

6:36history of the field and then why this particular paper is happening now and not 10 years ago or 20 years ago. There's some key technological advancements that have happened in recent years that is enabling this kind of analysis and it's very very cool. There's an interesting there's a a mutual friend that we have that had been doing work around some of this epigenetic stuff uh you know through

Generational trauma, epigenetics, and why now

6:58grant funding through the NHS and it it what is I think this is very timely because there's been a lot of chatter in social media around you know this idea of generational trauma >> as sort of a a non-scientific term and this the idea that there is uh an impact on outcomes that are related to these concepts of like generational trauma and we're I think this is going to start to brush up against some of these social conversations that have been happening. Uh and I'm I'm super curious to understand you know particularly your point about why now are we able to start to get a better idea of what's going on on the epigenetic layer. >> Yes, that that part is really really cool. the techn the biotechnology there

7:40is really really cool and what you're alluding to is the fact that you know trauma is something that is not going to affect the genetic layer but it is going to affect the epigenetic layer because the epigenetic layer is the one that is dynamic and changes throughout the life of an organism. We mo by and large have the DNA that we were born with. Okay, unless you know if you look at tumors, there's a lot of mutations there and tumor cells have very different DNA compared to um normal benign cells, right? But epigenetically, the reason why this cell is a skin cell and this cell is an eye cell and the the cells inside my brain are neurons, that

8:20has to do with epigenetics, right? because the cell is making a choice what part of the gene to read out from and what part to to ignore. That's the software level that I'm talking about. So, it's it's extremely important for us to understand, right? So, we're going to start as always on this podcast, guys. I'm uh I might be a little rusty. It's been 2 months of no, as I said, barely any sleep. So, just bear with me if I'm a little slow. But, we're going to start as always with the history. Okay? We're going to go back. The story of genetics probably begins in the um 160 years ago improbably in a monastery. Okay. Gregor

Gregor Mendel and the birth of genetics

9:01Johan Mendel >> Johan, >> he was an Augustinian monk who spent eight years crossbreeding pea plants. And the the green circle, you see the guy in the green circle in the back row, that's Mendel along with all of his other um monks. >> Yes. in in his monastery. He was crossbreeding pea plants for like eight years. He tracked 29,000 plants across multiple generations. >> That's huge. >> It's huge. This was this was his hobby and he took it very seriously. He's the first guy to really do largecale statistical analysis of gardening effectively. Okay. >> He he was the first green thumb.

9:41>> Yeah. Yeah. Yeah. Yeah. He he before Zack Galifan Atkins had [laughter] the Netflix show um about gardening which by the way um a good friend of ours Trevor is the editor on that show. So go check it out on Netflix. It's a really good show actually. >> Um so you can see his garden today actually the Mendle's garden. You can see it in Berno which is currently in the Czech Republic or I think now it's called Cetchia if if I'm watching the World Cup correctly. >> I've heard it. Czecha. >> Czecha. Yeah. So, but it used to be called the Czech Republic. That's what I'm comfortable with. But Czecha, Cheschia, one of those. You can actually go see the the garden and see the the beds where he was planting the pea

10:22plants, which I think is really cool. One day when FFP Pod goes on a field trip, that is definitely a place we're going to visit. It's the birthplace. That garden is the birthplace of genetics, right? I think that's so cool. Um, so why peas? First of all, okay,

Why Mendel chose pea plants

10:36this is something that we talk about a lot on this podcast and is a staple for the biomedical research community, which is model organisms, right? You have to choose the organism that you want to that you want to study as a system and you have to make that choice very deliberately for very specific reasons. Mendel is one of the first guys to do this. He chose peas because the bar one, the garden pee is actually pretty easy to grow. >> Mhm. You don't have to worry about it too much. Y it's has easily observable contrasting traits. These are the traits that he was studying. For example, is the P round or wrinkled? That's a binary. You can look at the thing and

11:17there's no middle ground. It's either round or it's wrinkled, right? Um when you cut up the P, is it yellow or green inside? >> The flower, is it white or is it purple? Like these are all binary things that there's no you know when you when you're trying to do statistical analysis by hand, right? You don't you don't have like computer vision nonsense, right? And you you just got a notebook. You're you're you're just making tally marks. So you need really easily identifiable traits that are in binary. The pea plant has seven of these, which is really nice. Okay. Okay. So the the idea of what you're saying is you want to have the fewest amount of variables to sort of control for uh one from at least in this time period from a management it's

11:58like a management challenge. >> Uh but two there there's less to deal with in terms of judging outcomes. >> Yes. Exactly. There's no like um subjectivity >> in what the offspring of this and this was. Right. You can just be like, "Okay, I I bred round and wrinkled and I got this many wrinkled, this many round, and I can just make the tally marks, right?" Um, the other big thing about pea plants is they self-fertilize. So, that means that Mendel can really easily control crosses by you can manually just transfer pollen. You can like take like a Q-tip or I I I think he used a paintbrush at the time. He would take the pollen from one paintbrush and and put it in the stigma of the other one to

12:39like crossbreed manually. And I think we've got a we've got a photo of that in the next photo, photo five. Um,

Controlled breeding and true-breeding lines

12:45>> this is this is how he did it. He would cut the the stamon, which is the male part. >> Um, or am I No, no, the pollen is the male part. So, he would cut the pollen part and then he would use a brush to take the the sperm effectively and put it in the female part of the of the flower. >> So, this was it was a controlled breeding. Yes. Because the also again the the surface the surface area of how you would do so was was very discreet. >> Yeah, exactly. It's super easy to control, right? And the first thing he does is he develops true breeding lines. What that means is he's going to self-pollinate a bunch of pea plants, which pea plants are totally chill with. They don't care about like, oh, lack of

13:25genetic diversity, all that. They're actually, that's one of the reasons why it's a good thing to use pea plants. And you keep self-pollinating until all of the offspring are something called true breeding. Meaning they always produce the same offspring identical to the parent. It's like you're making clones y over and over. So now what you do is you you're starting out with a clean slate. Yes. Right. There's there's no genetic variability in this plant >> and its um gametes and its sperm and the the egg. Right. It's like if you if I were to take the sperm and the egg of this and combine it, I would just get the same thing again. Mhm. >> So it's like uh a feedback cycle and completely clean, right? For example, offspring of purple flower time purple

14:06flower always going to give me purple flower at this point. That's why it's called true breeding. Okay. >> That so the idea is we we have everyone is effectively genetically >> the same. >> Yeah. And there's no nonsense in the in the like from one generation to the next. I'm not getting weird like effects. It's it's not just that this uh line of the generation is the same. It's that subsequent and prior to some number of generations forward and back are consistently coming in as the same. So you're also removing the idea that oh this one was but the next one might not be. >> Yeah. Yeah. Exactly. So now when I do crosses in I take the parent generation the P and I do a cross let's say from a

14:46purple and a white I'm going to get some weird effects. Right. But I know that's not from the purple doing its own thing or the white doing its own thing. I know it's because of the interaction of these two. Does that make sense? That's why you got to start with that true breeding. >> This is a good This is a really important point which is we're we're creating the canvas from which we're going to test in a way that removes any prior muddying of the waters. >> Yes. >> Uh so that we can look downstream and say we had a clean foundation with which we're building from. >> Exactly. Yeah. And now I can isolate the effect to an interaction between two individuals that have different genetics. >> That makes sense. >> Okay, here's what he observed. Okay, so

Mendel’s purple and white flower experiment

15:27he takes the parent generation. Let's let's let's just talk about the flower color right now. There's seven other traits that he could look at, but they all actually obeyed these rules, but it's nice to talk about flower color cuz looks good on TV. Okay, so I'm going to take a true breeding purple and a true breeding white plant. I'm going to breed those two. the first generation. That's the F1, the first filial generation is is how how he put it. That one has all purple. Immediately you notice something weird. You're not getting a mix. >> Mhm. >> Right. You're not getting um like lighter purple >> like pink. >> It's not a blend. >> It's not a blend. >> It's not a mix of half and half. >> It's not even half and half. It's fully

16:07all purple. >> Okay. First thing that's kind of weird. >> Okay. It's almost as if the the first generation is also true breeding, >> right? So you're like, "Hey, so is the first is the white just like doing nothing, >> right? >> Is everything coming from one? >> Is everything just coming from one? What's going on?" That's when you take do the second cross. So you do a second filial F2 generation where you take two of the first generation ones and you cross them. And now you get something weird. You get the white back, but the ratio of purple to white is always, and I mean always 3 to one >> in his notebooks. >> Okay, >> he's got 29,000 plants that he's doing

16:48this with and it's almost always 3:1. Like statistically, that's the ratio that he's getting. Okay, >> I think I see it. This is very weird. It's very So, and with no context and no foundation. >> Yeah. Now, it's like trivial, >> right? But it's it's why did we we had two different the first generation all only similar to one of the two parents but the second generation that was bred from that F1 generation where everything was the same as one parent is a 3:1 ratio of one parent to another. >> Yeah. >> Almost all of the time. >> Almost all of the time. Okay. So let's try to figure out what how this would happen. Okay.

Dominant and recessive traits

17:26>> Mendle doesn't know. >> Right. >> Okay. Mendle doesn't know anything about genes. He doesn't know anything about chromosomes. He just knows plants are doing this. Okay. So he takes a purely sort of empirical approach which is I'm just going to describe the mathematics as I see it. Okay. I'm going to make up some rules that are just math rules. Okay. About what happens. First thing he figures out and what we've already seen is the principle of dominance. There's two traits. One of them is going to dominate over the other. Yeah. Okay. In this case that we saw it was the um purple the purple trait which now we call an alil. >> Um there's two different types of alals the purple and the white. And the purple al is going to dominate over the um

18:09white alil which we'll call recessive. So there's dominant and recessive. That's the first thing you establish. Second is something that he establishes called the law of segregation. This is the segregation of traits. Okay. What he says is there's actually two copies of an alil that every individual has. And if I have a true breeding plant, um

The law of segregation

18:31let's say let's say the the the the trait that we're looking for is the color of the flower. And we're going to denote the type of alil by a capital A if it's dominant and a lowercase A if it's recessive. Okay. Now, if I have something that's true breeding, that means that I have two copies of the same dominant alil. Capital A, capital A, that's the one on the left up. And then the white true breeding is going to be lowercase A, lowerase A for recessive recessive. Okay? Now, when I cross them, there's going to be four different ways to choose the A and the A, right? I can choose the first capital A and either of

19:11the two lower cases or the second capital A and all. That's four total. But every single time I'm going to get a capital A and a lowercase A. So that first generation is going to have at least one dominant >> copy capital A all the time. Every single one is going to have a capital A and a lower case A. And because the capital A is present, >> the dominant is present. I'm going to get the dominant phenotype >> and the thing is going to be purple. But now let's take the first generation that capital A lowercase A, which we're going to call hetererozygous because there's heterero there's two different copies, >> right? One of each, one, >> one of each. Yeah. Compared to homozygous, which is what we had in the parent generation, that true breeding is now what we call homozygous. So if we

19:53take two hetererozygous parents >> and we cross them now, combinotaurically, >> I'm going to get three offspring that have at least a capital A. There's actually going to be one that's kind of like the true breeding parent. >> Yes. >> In the beginning, the capital A, capital A right? >> That's the one we have in this top left. >> Yeah. in in the in the square. Those are called punit squares. Now, but um the top left, that's capital A, capital A. That's going to be purple. The two on the off diagonal, that's going to have a capital A and a lowerase A. But because there's at least one, I'm still going to get purple. And only one out of the four is going to have homozygous recessive lowerase A,

20:34lowerase A, and that's what's going to be white. >> This is this is interesting. And and I think a key point here is we had the pure the the pure breed generation at first. Two dominants from one the purple, two recessives from the white. The first generation because you always are going to have that dominant from the purple from the one side. You're always ever going to get this dominant recessive combo. >> Yeah. >> And so the reason why that first gen first gen >> always has dominant. And so that's why there you you don't ever see the white, >> right? because it's always being basically overrun by the recessive white is being overrun by the the the dominant. >> The thing that the where you get the diversity of color

21:14begins to arise

Why the 3:1 ratio appears

21:17when you have two dominant recessive as the parents. >> Yeah. The hetererozygous pair. >> The hetererozygous pair. And that's finally when you start to see from the original P1 >> Mhm. >> the recessive begin to appear, but also from the the the ma the math we you brought up earlier, it makes sense that only one it's always going to be 3 to one because of the way that it's uh this dynamic pair from each. >> Yes, exactly. It's always going to be 3 to1. So this is an empirical rule that he comes up with. It makes sense. And the the the other nice thing about this kind of mathematics is it explains something else which is the law of independent assortment.

Independent assortment

21:53um what he did and this is something that we're seeing actually in fruit flies because um the particular visual that I found was for fruit flies but he also did this for pea plants as well. Okay, [snorts] what you can do is you can take two true breeding um you can you can take a true breeding parent generation with different traits in a pea plant. You could say it's always purple and it's always tall. And I'm going to cross that with always white, always short. Okay? So now I have homozygous for two traits in my parents. I'm going to get some

22:35offspring that are again always purple, always tall because the tall part is going to work the same way as the purple part. And so everyone's going to be the same. But now I do a cross between those guys. Now, if you just do the mathematics, there's going to be 16 different choices instead of four because you're doing four by four across. And the mathematics is going to be such that I'm going to get a ratio of 9 to 3 to 3:1. Okay? Nine being I'm going to get the dominant parts of both. Three being I'm going to get the dominant of one, the recessive of the other. The other three being I'm going to get the do dominant of the second one, recessive of the first one, and only one out of 16. I'm going to

23:17recover that first generation of like recessive recessive. Okay. >> Mhm. It's it's bas it scales as you as you get to more traits here. The the the ratio of distribution effectively scales exactly accordingly. >> Yeah. And in this particular one, we're looking at fruit flies where um we're seeing eye color and body color. Okay. And eye color red is dominant and body color brown is dominant. >> Black for both is recessive. And so we're seeing 9 to 3 to 3:1. And you can go through the the punit square there and figure out how each of the alals was matched. And you can convince yourself that this is the case. >> That makes total sense.

23:57>> Okay. This is called the independent assortment law. meaning that the two different traits independently

Mendel is ignored, then rediscovered

24:06do combinatorics. They're not like related to one another. It's not like the eye color >> goes with body color is like correlated in some way. So that that was his thing. Okay. So these are Mendele's laws. >> He presented these findings in 1865 published in 1866 experiments on plant hybrids. Um the response complete silence. Paper is ignored. It's cited a handful of times over the next 35 years. He died in 1884. Um unknown as a scientist. >> Terrible. >> Um and his discoveries were buried in some obscure journal. >> Terrible. >> Okay. 35 years later, we've got three botonists who start doing the same thing. Okay. Hugo Deere in the

24:49Netherlands, Carl Corin in Germany, and Eric von Sherark in Austria. and they independently figure all of this out and then as they're deep diving into the literature because the first thing you do is has someone else done it you know in the modern day there's a joke in academia there's always like a jiang at all that's done it [laughter] that's done it before so back then they're doing the same thing they're trying to find like has someone else done it and all three of them actually find Mendel's old paper in the literature and they

From mathematical rules to biological mechanisms

25:18realize so these are the three and they rediscover Mendel's work in 1900 and they're like well somebody beat us to the punch And this this is now colloquially known as the rediscovery of Mendel and it launched modern genetics because now they're like okay so there is some kind of level of understanding that we can figure out right >> now the next >> focus is always how do we go from empirical math rules to some kind of mechanistic understanding right what is actually happening right >> in the organism that is doing this >> right so we we can predict but we don't know how it works >> yeah exactly okay So, first first question, natural question. Where are the alals?

25:58>> Yeah. >> Right. You're saying there's these two types of alals. Well, and it seems like there's like actual stuff, >> right? That's like moving like and like there's like physically two thingies that like get independently that come out and then they recombine and stuff like that. But if if that's the case, there should be something I can find inside organisms that is an alil, right? So Walter Sutton, he's a graduate student at Columbia University at the time and he proposes in 1902 1903 that these men these alals are located on chromosomes. Okay, he was actually working on grasshoppers at the time and

Chromosomes and the physical basis of heredity

26:36in grasshoppers he could stain the chromosomes and what he figured was that there's these thread-like structures called chromosomes and they come in pairs. So that's interesting. That that's interesting >> cuz the alals come in pairs and they separate during cell division. And if you if you look at the gametes which are the sperm and the egg, they each get half and half. >> So he's like coincidence? I think not. >> Where there's smoke, there's fire. >> Yes. He's like he's like this could be the physical basis for Mandelian law of heredity. Um people are still doubting

Thomas Hunt Morgan and fruit flies

27:09it because it's it's coincidence. Okay. you could be missing something that also goes half and half. >> Just because it has similar behavior >> Yeah. >> does not mean it's it's not a causal link. >> Yeah. It's not a causal link. There's there's a there's a correlation, but in order to establish causation, you got to dig deeper, right? And this is where a guy Thomas Hunt Morgan comes in. also at Columbia University early 1900s Columbia was doing amazing with um just like early biology like even before DNA before you know molecular biology just like this kind of this kind of early rudimentary work so Thomas Hunt Morgan at Columbia University he starts using the Drosophila

27:50fruitfly he's the one who actually establishes the fruitfly as the model organism nowadays the fruitfly is used in neuroscience research development genetics all sorts of things he's the first guy to be like, let's do let's let's go to town with the fruitfly. >> So So Mandel was the pea plant and then Morgan now moved us into a more complex biological organism that is a better model organism. >> Yeah, that's an animal so it can like learn and stuff like like it sleeps so you can do like there's so many more things you can do with a drosophila, right? And Morgan's team discovers that there's some traits that are sex linked like red eye color. Here's what I mean by that. So,

28:30um, what he does is he finds, um, a female with red eyes and then a male with white eyes. And when they have offspring, all of the kids have red eyes. So, you could just be like, "Oh, red eye is like this like uh, you know, um, homozygous type dominant trait or whatever. Now, let's take the female again that has red eyes. So, in this case, you're going to this is going to be a hetererozygous female, right? because the male had a white eye. So, this female is going to have um one redeye al and one white al. And now I'm going to cross that with a redeyed male. Okay. >> Mhm.

29:10>> So, the male and and we we've done a true breeding with the male to make sure that the the male is fully red. When we cross it, most of the offspring,

Sex-linked inheritance

29:22in fact, every single one of the female offsprings has red eyes, but the males are half and half. They're not even doing >> three to one, >> right? >> Now, they're doing half and half, >> right? >> And he identifies that the redey alil is actually on the sex chromosome. And the way sex chromosomes work is we only get one if we're male, right? The white chromosome isn't really a chromosome if I'm completely honest, right? We have X and Y. The Y, like if you look at the two side by side, the X chromosome is this big and has a bunch of extremely important genes. The Y chromosome has absolutely like nothing, [laughter] right? It's like it's it's in really tiny. And it's in fact, it's so tiny

30:03that there's it's like the way the chromosome is like tied up. Um there's a there's a little centromeir that like holds the two strands together. And that the Y chromosome is so tiny that there's very little room for genetic recombination. >> And so that's why like the Y chromosome like your Y chromosome is identical to your dad's Y chromosome to his dad's to his dad's for like 10 generations because it's so small that physically you can't like mix things. Anyways, so the the point is >> he identified a a particular chromosome with that trait, right? >> And the reason why males are coming up

30:4350/50 is because they only get one X chromosome from the mom, right? So either you're going to get the red one or you're going to get the the white one, >> right? >> And that's it. >> The females on the other hand, they're getting one from the mom and one from the dad. And the dad is guaranteed to be red. So even if I get the white one from the mom, the dad is guaranteed to be red. So all of the female offspring are going to have red eye color. >> That's fascinating. Yeah. Yeah. And so we've added another layer here. Yes. >> To because before we were saying the traits uh were not correlated uh you know color, size. >> Yeah. >> But now with sex chromosomes >> now it's like if they're on that sex chromosome then the math is a bit different. And actually the correlated part is the second thing that Thomas

31:24Hunt Morgan did which is he showed that some of the traits

Linked genes and the first major crack in Mendel

31:29happen to be inherited together. Okay. So, you know, before I was I was showing you about how um body color and eye color under Drosophila, they were independently assorted. Yes. But there's some that >> if I have red and some other trait, those are going to go together. Okay. Why would they go together? Well, now it's obvious because if they're on the chromosome, if they're on the same chromosome, then they're coming in a package, right? And so if if if they're coming in a package, you're going to have this correlation and that violates Mendle's law of independent um assortment. >> If I order something from Amazon, >> we thought it was going to come in two separate packages which could have two different delivery dates, but it

32:10actually came in a big box with two little boxes in it and they were shipped at the same time. Yeah. Very bad crude analogy but >> no, but that's exact that's exactly what's happening, right? And this this is actually the first major empirical crack um to Mendele's laws. Okay. This is the first time where it's like no Mendle was actually wrong, but also he did it's fine. Like he had no idea what you know um >> he did it in a cave with a box of scraps. >> Yeah. Exactly. Yeah. Yeah. Yeah. So it's it's fine. Morgan actually won the Nobel Prize in Physiology. He's one of the first um Americans to win the Nobel Prize in Physiology and Medicine. And side note about um Thomas Morgan, he's quite a character. So he's the nephew of Confederate General John Hunt Morgan who who got his butt kicked somewhere in the

32:52north. And then um the greatgrandson of Francis Scott Key who is the um author of the Star Spangled Banner. >> No way. >> Yes. This guy's quite interesting. So he established something called the fly room in Colombia that became kind of this legendary place where scientists from all over the world would come and hang out and learn about how to take care of fruit flies, how to make sure that you know the crossing is the same because for Mendel it's like pretty easy. You just cut the thing, you take a paintbrush. Here you got to like make the flies mate and stuff, right? So it's a bit more of a process but there's a lot more room to to work with

33:32scientifically. It became it became this legendary place um established the

Why fruit flies became a foundational model organism

33:37fruitfly as a model organism and you know the lineage of that is seen in every single university that does serious biomedical research. They have a a fly lab somewhere doing something. >> Isn't it incredible something that people when they're in their house are trying to look for ways to make these things go away? Not specifically the fruitfly, but you just saw >> fly. I mean, yeah, fruit flies are a big, you know, they're big and and it is a cornerstone of us getting a greater understanding not only of our our own lives as humans, but the lives of all animals on the planet. It's just >> it's still going and it's right, it's still happening. >> It's still happening. There's still so much we can learn from the flute fruit fly. It's pretty insane. Um, another

Caltech, Morgan, and the genetics lineage

34:19cool thing about Thomas Hunt Morgan is he went on to found the department of biology at Caltech. When Caltech started in the 1920s, Caltech was this insane place because like they so they hired like the all stars like they just poached all of the big w cuz they just got a bunch of money um I believe from the um the Rockefeller Foundation either them or Carnegie they're whoever whatever they're dead but like if they were alive they'd be pissed that I was mixing them up but one of them gave a lot of money and they just so George Hail who was kind of the founder at the time he he took this Pasadena Community College type thing and was like, "All right, we're just going to hire the

35:00biggest names." It's kind of like when you start like a new team or something, you just like hire the best coach. If you if you got the money, right, you hire the best coach, you hire like Erling Holland or whatever. >> The the perfect analogy for this in in soccer and football is PSG a couple of years ago. >> Oh, really? >> You know, the French [clears throat] league has been viewed for a while as being sort of a farmers league. They got Neymar, they got Messi, uh uh they got Mbappe, Donnarum, a bunch of other players. They just got like literally all the best players in the world. >> Yeah. At the same time. >> At the same time. Yeah. And >> that's what Caltech did. >> That's what they did >> in in the 1920s. They got Milicanin for physics. They got >> um Thomas Huntton Morgan for biology. It was just an insane place to like start out like that.

35:41>> I will I will note it's sometime it doesn't always work because it did not work for PSG. They had that they couldn't win the Champions League and then and then Messi and Mbappé left and uh Neymar left and then they won the Champions League. >> Oh, that's hilarious. >> So, it it can work. >> It can work. Yeah, >> it worked in Caltech's case. >> Yes. Yes. [laughter] Certainly. Because they just they they became like a top institution immediately, which usually it takes years of work to do that, right? Um and his students have won the Nobel Prize too like uh John Howard Northrup he's a Berkeley professor 1946 chemistry Nobel for isolation and crystallization of enzymes and Herman Miller won the 1946 Nobel Prize in medicine for X-rays to make

36:23so big lineage from Thomas >> legacy >> anyways after Morgan then you have the modern synthesis of genetics so this is we've covered this in a previous episode um with James Watson and his discovery

DNA, Watson, Crick, and Rosalind Franklin

36:36of DNA A but um Avery Mclody and McCarti they showed in 1944 that genes are from DNA and then Watson and Crick together crucially with um evidence from Rosalyn Franklin discovered the helical structure of DNA and how the the sequence of base pairs is really how genes work. We had a huge deep dive on this particularly uh the work of Rosalyn Franklin which in part was not included in a lot of the accolades that came afterwards has since been rectified at least slightly at least slightly >> at least slightly in the modern era. Um it's a great deep dive if you haven't watched it already because that also has a great uh the science is great but the

37:16palace intrigue and how the university ecosystem worked and was being established not only in the UK but in the US at the time was was really really fascinating. Um >> yeah and just just how many shenanigans >> so much so much >> so much shenanigans. Um, so now we've

How DNA stores genetic information

37:34got kind of a more complete picture of how genes work and how Mendle's laws come from genes. So I just want to go over all of that. Okay, so first we know now from, you know, all of the work is DNA stores the data of these alals and genes. And what an alle really is is one version of the ATGC sequence. Okay, the different alil will be a different version of that ATGC sequence, right? and the two alals are different in only a few base pairs because that's going to code for a different protein and that protein is going to make the different trait. >> For folks who might not know, when you say ATCG sequence, can you clarify? >> Yeah. Yeah. Yeah. Yeah. Good point. Um the ATCGs are the nucleotides that make

38:14up DNA. So DNA is a molecule that's kind of a twisted ladder and the rungs of the ladder come in four different types A, T, G, and C. The sequence of those letters in that ladder tell you what kind of protein to make. >> Okay? >> So, it's like they're rungs on the ladder. They can be in different order. And so, you can do different things based on the order that they're in. And each chromosome comes in with a different rungs on the latter order from each of the parents in this context. >> Yes. Exactly. And when we say that there are two alals, what we really mean is there's two distinct sequences of ATGC's, right, that will code for the protein. And though and that DNA is stored in the chromosome. So when we see the chromosome like the two strands,

38:55each strand is a giant molecule, a single molecule of DNA that if you were to unravel would be like this big literally like that fits inside every single one of our cells. But it's like it's like several inches long. >> That's so >> right a single molecule of just ATGC strung together, right? And it's wrapped around a bunch of stuff to create the chromosomes. So that's what a chromosome is. All right, now we know what a chromosome is. Now each chromosome as we said has two chromatids. Those are the two different sequences of DNA and each alil is located on the different chromatids. So now when we look at the laws of independent assortment and things like that and how to create gameamtes well during meiosis the two chromatids they replicate and then they

39:37physically separate into different cells. So the sperm cells all get half one chromatid each. And that's now making sense right with the whole punet squares and all that stuff. How's that working? Well, when the egg and the sperm come together, you get half and half to create a hole. Right. Right. So, so now that that's making sense. Now, the independent assortment works. The whole correlated genes also works because if you're on the same chromatid, then you're going to get the same package. And then finally, how does the dominant and um recessive work, right? Well, a lot of times the dominant version just codes for the protein that works and the recessive version codes for the protein that doesn't work. So if you get two dominance, you just get

40:18maybe a little bit more of the protein. There can be some gene regulation stuff to like downplay one of the chromatids so that I don't like have too much of the same protein. There's actually stuff that goes on there which is very interesting. But if I have like the hetererozygous meaning one functional type and one dysfunctional type, I still have working copy. So I can create that gene. But if I have two dysfunctional types, then I've got no way to create the gene. Eye color is a very good example of this. the um OCA2 alil combinations. So um there's a there's a gene for mel melanosome melanosome

Eye color and dominant vs. recessive alleles

40:54that's the protein that gives brown eye color. Okay. And if you've got two versions of that protein then you're going to create melanosome and you're going to have brown eyes. >> If you've got single version of the protein body can still create melanosome. But if you've got no functional melanosome then it's kind of like the naked retina. Mhm. >> Or not retina, iris is the color that you're going to see. It's a bit more complicated obviously because you have like green and hazel and so there's different versions of even melanosome and there's other little things that go in. But by and large, this is how dominant versus recessive works >> and this is why people have to wear sunglasses if they have light colored eyes because they don't have that melanosome that provides that

41:35>> additional protection for the eyes as as one one example. >> Exactly. So, and so far what we've been covering is effectively it's still been Mandelian. Even like Thomas Hunt Morgan talking about the packages coming together, it's still Mandelian in some sense, right? I mean, you're you're kind of proving his point that they come in these packages. It's just that some of them are correlated. There are now a a growing there is now a growing body of work that there are a lot of exceptions. >> And so, that's what we're going to get to next. But before we do that, we've got some housekeeping. >> Some housekeeping here. So, we are super excited everybody to have our resident PhD Christian Achowdery back in the studio. We I'm so excited for our

Housekeeping, studio updates, and support

42:16upcoming episodes. We are working through a studio redesign. You might notice that our dock behind us is in a different location. We have some neon signs coming in shortly and we are adding the FFP bookshelf that will be behind us and we are going to have a collection of some of our favorite books. We would love to get some suggestions for what you think should go into the FFP library. So, over the next couple of episodes, you'll start to see things begin to take place and a little bit of changing of scenery. If you enjoy the show, if you are happy to see us back doing these deep dives, not only on

42:56the frontier of science research, but the context with how we got there. You can always support the show by sharing clips or your favorite episodes with your friends, family, and colleagues. You can watch the show. We always encourage you to watch the show on YouTube and Spotify. The full video podcast is available there. You can listen wherever you get your podcast. And for clips, we're across our socials, Tik Tok, Instagram X. Some of the best key moments from the show. Easy to send that DM to slide into the DMs. Getting more eyes on the show is super helpful for us. If you can support the show directly, we have a donation portal on the website ffpod.com/donate.

43:39And if you haven't been to the website, you can watch full episodes. We have chaptering. We link out to all of our research papers that we cover connected to each episode. And I will note there have been some of you that have been asking for an RSS feed for the website. We are working on that as well. So, keep an eye out for that over the next couple of weeks. So, be sure to comment what books you want to see on the bookshelf. I hope we didn't order uh neon signs that are too big. They're going to be quite large, >> so hopefully it works out here. But, we

Paramutation and maize

44:12are super grateful for all of you in FFP Nation and the audience who have been super supportive of the show. We are super excited to get back on the hopper here. We have some great great episodes lined up. But before we get to those great episodes, we need to finish up because I'm very curious about how we now talk about epigenetics as it relates to this background we've just talked about on Mandelian genetics. >> Right. So what we've talked about so far is just the genetic part of things and even then we've only talked about Mendele's rules and from our understanding now it's been 160 years of study. It is a gross oversimplification of what is actually happening. Now, the

44:53goal here is to predict from genetic input what the offspring's genotype is going to be, what the offspring's genetic m makeup is going to be, and then how the offspring is going to look on the outside, right? By by look, I mean like what are the traits that it has, okay? Even if it's on the inside, right? But that that's what we call a phenotype compared to the genotype, which is just the actual genetic makeup. Now, as people worked on this over many many years, anomalies started piling up. Okay, there are several several. We are going to focus on um just one. Okay, the anomaly is called paramutation. It starts with maze. It was first documented in the 1950s by geneticist

45:35Alexander Brink when he was studying the red one locus in mae location of the red one gene in maze. Maize is just corn, but biologists always say maze for some reason. Okay. Um, maybe someone can tell me why in the comments, but I've never seen someone just say corn, [laughter] but then I look at the photos and it's just corn. Okay, anyways, so the the the red one location in this organism controls for the anthocyanin pigment. Okay, and that's the pigment that is responsible for the dark coloring of corn kernels. You've seen like those like exotic corn that like it's like purple. That's what this is. Okay, >> so that's the trait that we're going to look at. And in Zim, we have this dish

46:16called sodza, which is cornmeal. And you can have sort of, you know, different color styles. You usually don't use when you have that uh red pigment style, you'll usually just cook it straight. You won't make that into cornmeal. It'll usually be either yellow or white. But that's it's an we call it maze back home. Yeah. Um which is interesting. >> Yeah. But like but these are Americans that are working on it. So that's what I just want to know what what's going on. Okay. [laughter] Like even like um um Dorothy um no it's um Barbara Mcccleintoch with the jumping jeans. She discovered those in maze. It's maze. >> Maze. >> Okay, whatever. Anyways, so let's let's talk about this red one location. Okay, the anthocyanin pigment pathway. Here is

46:56what he observed. Okay, what I'm going to do is do kind of the same thing that um Mendle used to do, which is I'm going to get two true breeding plants. one that has the purple pigment thingy and then one that doesn't. I'm going to cross those.

When the expected dominant trait disappears

47:11Weirdly, I get all recessive. >> Mhm. >> Even though the purple is the pigment, >> right? Like, so that should be dominant >> because that's the working pigment according to like what I told you about what is dominant and recessive. It's not just arbitrary. It's just like one is the protein is actually working. The other one the protein is not working. here. If I have a true breeding purple and a true breeding green, I'm actually getting no working pigment. I'm getting all green. It's like the opposite of the F1 generation, right? This isn't even getting to F2. This is like in the F1 generation. It's as if Mendele did purple cross white and got all white. >> That's okay. That's fasc which which would not make sense given that the >> given that it was all purple

47:51>> is all had the dominance across. It should have the dominance in all four of the >> offspring. Yeah. Okay. So again, what the hell? >> What's going on there? >> What's going on there? So, so now next thing to do is now I mean, usually what you do is you take that and then you crossbreed with itself. So you do a self-fertilization, but now things are weird. So now let's let's cross it with a true breeding purple again, right? Because let's say something weird happened and I got like recessive recessive here. Um, and then the purple. Or maybe I got like one bit of purple, but like it's not showing up in the in the F2 generation. I should get some purple.

The purple gene gets silenced

48:28>> I cross it, I get all green, no purple. It's almost as if the green, whatever it is, has like completely nixed the advantage of the purple gene. >> And silenced it. This is called a paramutation. Okay. >> Fascinating. And it's also it's it's as if there's the new the newly altered silent al that that's there, right? Because I know I have the purple >> al. But that purple al has somehow been silenced. And now that purple al you would assume if it if it made it with another purple al. But this purple al has turned to the dark side somehow and and started mixing all of its other compatriots with the

49:09purple al. >> We call it the Anakin al. >> Yeah. Yeah. Yeah. Yeah. Something like that, right? It's like you've got like a weird corrupted computer file that now goes and infects every other computer. >> And so what this brings up is that there's not this 100% all of the time sort of viewpoint. >> That's the first thing. Yeah. >> Because this should be dominant. >> Yeah. First of all, it's not dominant. But okay, fine. But now it's it's making everything else recessive somehow. It has an ability, >> right? Crossgeneration downstream. It's not just a oneoff outlier. >> Exactly. Yeah. This is very strange. Okay. This was the 1950s. It was a very big deal when when when when it was discovered. Okay. And so now to now we've got a better understanding of what's going on. So in order to

49:50understand this, we've got to understand two things. Okay. First thing is gene regulation. That is the um that is some of the software on top of the genetics. Okay. So we've got two types of gene regulation pathways. You've got enhancers and promoters. We've talked about this a lot on the podcast, right? When you've got a gene, the gene is a recipe for creating a protein. Right? But there is an on button that is telling the machinery to come make the protein and then there is a volume control button that is saying how much protein to make. That is the promoter and the enhancer respectively. The promoter is the on button, the enhancer is the volume control. >> I loved that episode where we talked

50:30about this. >> Yeah, we we we we've talked about this a lot, right? And frequently what happens is the promoter is right next to the gene because like basically what happens is you've got the gene on this part. This is the part that has the recipe. The promoter is right next to it. So, what it's going to do is take something called RNA polymerase, which is the thing that makes it into RNA that then goes into making proteins. The promoter is going to be like, yo, RNA polymerase, come over here, attach to me, and then go this way, and it's going to be like D and goes that way. The enhancer can be way far apart from where the from where the gene is. And the the genetic code can literally fold such that the enhancer gets close to the promoter. the enhancer recruits the RNA polymerase to come and it it's it's very essential for

51:13creating that two-step sort of regulation. >> Yes. >> Right. So this is genetic regulation. That's the first thing we got to understand. Second thing we got to understand is epigenetics. Okay. Epigenetics is the software and the modifying of the structure of DNA and chromatin. Chromatin is the thread that the DNA is right. Um there's two levels

DNA methylation explained

51:34to doing this that are by and large these are the two level levels of epigenetics. The first one is something called methylation effectively as I told you DNA is made up of four distinct nucleotides ATG and C. Now the C the cytosine can sometimes be modified by attaching a methyl group. A methyl group is I think just CH3. You just take a CH3 part of a molecule and you attach it to the to the cytosine. When you do that, if you've got a bunch of cytosine in a segment of DNA that has these methyl groups, the RNA polymerase can't really get to it because you've altered the the look and

52:15the RNA polymerase comes in and it's like, I don't know what I'm looking at. I'm going to go somewhere else. >> I'm I'm going to go somewhere else. >> Right? So, so this is one way to silence parts of the dean, parts of the genetic sequence by just like adding a little chemical tag. And th those are the little tiny um like red pins that you're seeing. Okay? And they only attach crucially to the C the cytosine. Okay? So the A's, T's, and G's are always left alone. Okay? The the part of what we're

Chromatin, histones, and gene packaging

52:41we're sort of speaking to here is there's in the practice of your body generating the proteins that your genetics sort of has the instructions for. >> That's a whole functional process. >> Yeah. >> In and of itself. And much like all functional processes and it there there are opportunities for it to break down in multiple different places. >> Yeah. And that's where you begin to get the impacts on outcomes because you might have the instructions, but when you go to the factory to build it, the power goes off, the the doors are locked,

53:22>> you you offshore it to China, whatever. >> Yeah. [laughter] Exactly. Yeah. Exactly. Exactly. And so, so that's the first part, the methylation. Okay. The second step is in order to actually create the chromatin, which is the stuff that makes chromosomes. It's like a thicker sort of wool compared to stringy. The DNA is like a string and then the chromatin is like wool. You have to like sort of bunch up a bunch of string together to create the thicker part, right? And in order to do that, what if you if you bring that photo back, you wrap it around these nucleosomes which are made up of histones. Okay? So they're like little proteins that you wrap it around and then those sort of get packaged together. Right? Now if you wrap it

54:02around that part of DNA that's wrapped around the the nucleosome the RNA polymerase can't get to. Right? So this is another level of silencing certain parts of the DNA. If you don't ever want this part of DNA >> to to be expressed in a cell like let's say you're an eye cell. I don't want the proteins that neurons want. package it up and you know put it in a warehouse, put it in your garage effectively, right? Only read the part that tells me how to be an eye. >> And this is where how it's able to control for if all cells all have the same instruction list, how it only focuses on a certain portion, a certain portion of it in order to >> build out the complex different parts of

54:44us where it's not just reading everything and >> not really having >> you don't we don't have like a bunch of mini like Krishna, right? It's like no there's like skin Krishna, hair Krishna and all that all that other kind of stuff. So that is epigenetics. Okay, these two sort of layers that's that's effectively what we want to focus on. Um how do we how does this explain the maze

RNA interference as a mobile silencer

55:06paramutation that we observed? Well, it's a combination of the genetic regulation with the epigenetic um silencing. Okay. Right. >> Right. Here's what's happening. There's something called RNA interference. What that is is tiny little bits of RNA that act like mobile silencers. A part of the DNA makes this RNA interference thingy. It's a little piece of RNA that goes and like attaches to DNA elsewhere. And because this thing is small enough, it can just move around the nucleus. Okay? And what it does is

55:49recruit DNA methylation machinery to come in and put those methyl groups in the C's. Okay. So now what's going to happen? What's going to happen is I've got my purple um I've got my purple trait and I've got the green trait. They both actually have the gene for purple. What's different is that the green one has a mechanism to create this small tiny thingy of RNA to go and silence that purple gene. Right? >> Okay. Right. >> The purple one doesn't have that. >> But now when I cross it, >> I'm going to get one one of the chromatins is going to have that thing

56:30that makes the little tiny RNA, the RNA interference. But that RNA interference is going to go do it for both. >> Right. Right. because it's not it's not um it is not limited by it is free is able to free flow through the nucleus and do what it did previously to get the green. >> Yeah. >> And so regardless of the fact that both have this dominant purple uh this sort of secondary >> Yeah. >> functional process is free to move despite the genetic code and instruction. >> Exactly. Yeah. And because now the RNA interference is on both the chromatins. Now when I take that and and I subsequently breed it with another true breeding purple again all the offspring are >> that makes sense, right? >> Because the RNA interference is kind of

57:11like this little mini molecular virus type thing, right? >> Just because you have the instructions doesn't mean your body is going to execute on them. >> Yeah. Yeah. You if you've got an agent that's just like like erasing it, >> right? or like you know putting like a paper on top of the instructions or whatever. >> That's a really interesting note. It it that again going back to this idea that there is there is sort of a a few layers between the instruction and the completed production of the protein. >> Yeah.

Why this is non-Mendelian epigenetic inheritance

57:40>> And there are mechanisms that can go and silence component parts >> uh in that production process. >> Yeah. >> And in the case we just brought up >> that was happening even though there was a purple dominant on the green. That's what was happening. And so when if you just looked purely at the genetic >> at the genetic thing, you'd be like, "This should be the green should also be purple. It's got the purple gene on it." >> And now this epigenetic layer around the silencing on the C. >> Uh uh. >> Yeah. Getting methylated. >> Getting methylated is what is causing the different phenotypic outcome. >> Yes. Very good. Exactly. And this is non-Mandelian because it's doing all

58:21this weird shenanigans and it's the epigenetics that's doing it. [clears throat] Okay, so this is the this is already an example of non-Mandelian epigenetic inheritance. >> But for the longest time, this has been ubiquitously reported in plants, insects like Drosophila because we're so good at Drosophila genome that like it's like easy to find. Okay, but proving their prevalence in higher order mammals was next to impossible. And we're going to get into why. That's where the technological revolution comes in that enables this paper. Okay. And just a side note, in 2006 there was a paper that showed that mice can have RNA mediated non-Mandelian inheritance, but there was a lot of dismissal of the

59:01findings because um they were like, "Oh, this is just something that happens in strange transgenic mice because the mouse model that was used here was transgenic." And I think it's totally fair. I just want to This is the funding issue thing. >> Oh, this is the funding issue thing. Yeah. >> We don't We don't have to get into it. We don't have to get into it. >> The trans mice. Yes. Trans >> Genic mice, right? Please do not cut our funding. >> We're not We're not making mice trans. But in any case, it was an interesting little finding. I mean, it got published in Nature, so it was a big deal. But again, it's in transgenic mice. It's easier to do analysis in transgenic mice because you've got a very nice blueprint of what the genetics is. it's not a

59:42naturally like sort of super diverse genetic population, right? So, you know exactly what to look for. Um, but perhaps it's not so general, right? And if it's an RNA mediated thing, maybe it's just special and it's not as general as like DNA methylation. This RNA mediated mechanism was not through DNA methylation. It was through something else. There's a bunch of other stuff that can happen. Right. >> So, the point was they were looking this mice population is not necessarily representative of the natural world in a way that we can extrapolate the results. >> Exactly. Yeah. And it's like at the end of the day I want to see like is this something I can apply to humans. Right. >> Um so still some scientists suspected

Why mammals were hard to prove

1:00:17that param mutation is probably happening in mammals. I mean it's happening in plants so ubiquitously. It should pro there there shouldn't be there's no like um first principles reason why it shouldn't be happening in mammals, right? But you need to you need to actually get get the evidence. And for for a long time the it was largely at the level of theory. Now why is that the case? Why is it so hard to prove? So it has to do with measuring DNA methylation. >> Okay. >> Okay. How does one if I get a strand of DNA? It's actually very easy to sequence DNA. Okay. There's ever since the days of the 1960s and 70s. I mean we've sequenced the entire human genome. Now

1:00:58we've se sequenced tens of thousands of human genomes. I think it's up to the even might be millions now. So, you know, sequencing DNA is not a big deal because it's distinct A T GC, right? There's ways that I can make the A like combine with um a T that has a little fl like, you know, a little GFP tag that like lights up a certain color. So then like every time it's red, I know it's an A. Every time it's a G, I know it's it's green, it's a G, right? And like there's so many cool sequencing technologies, but those sequencing technologies aren't good with methylation. Okay, one way to do it that a lot of people use is

1:01:39bulfide sequencing. Okay, here's how you do it. You take your you take your DNA.

Bisulfite sequencing and methylation detection

1:01:46Okay, you take your DNA. Now, your DNA is going to have AT um ATGC's all over. Some of the C's, some of the cytoines is going to have that methyl group. Okay. >> Those little red pointies. >> Yeah, those little red pointies here. Here as well. They're little like red tags on the C's, right? There's some C's that are that are like blue. And then there's other C's you can tell that are not. And those are like normal cytosines that aren't methylated, right? What you're going to do is you're going to treat it with a detergent effectively, okay? A chemical treatment that is going to convert unmethylated cytoines into uricils. Use U is the letter that is used in RNA. Okay? So, it's going to leave the the cytoines with the methyl

1:02:27alone, but it's going to change the season to use. Okay? And then I just sequence like normal, >> right? >> Like like I used to, >> right? >> Okay. Right. >> Because I'm good at sequencing. I'm not good at the the like finding where the methyl is. But this is one way, right? Because I've just I've taken all the ones that don't have the methyl groups. I've turned them into another letter. And then now I just sequence like normal. And I'm like, "Oh, this is a U. The DNA shouldn't have a U. That's probably where the the the C was, right? Or I can like I can I can sequence the original gene and then I can sequence the gene after um treating it with this detergent and wherever the difference is, that's where the C's are. Wherever the C remains, that's where the methyl groups are.

1:03:08>> Right. And then now we know where the methylated cytosine is. >> Yeah. Because any cytosine that survived had to have had a methyl group on it. >> That makes sense. which now gives us a different map [clears throat] >> to to analyze that's not just in indistinguishable C's >> methylated versus non-methylated. >> Now you can imagine treating a molecule like DNA with chemical is not a good idea. Okay? And of course not because what ends up happening is something

The problem with short reads

1:03:35called catastrophic DNA degradation. Here's how sequencing works. Okay? You've got a giant thing of DNA. When I treat it with detergent, it's going to break up into short parts. Okay. And I'm going to get a bunch of different short parts. And now I have a combinatoric puzzle to stitch together all of these short parts into a big part. Right. >> Yes. >> The problem is these short reads are about 150 base pairs long max. It's not a lot. Okay. Because a lot of times nothing happens. Okay. And so if I've got repetitive sequences of DNA, I could just fool myself into thinking, oh, this is all part of the same sequence rather than this is the first repeat, this is

1:04:15the second repeat. It's kind of like, have you seen that like crazy puzzle of the Beatle White album, >> right? Where it's just it's a the Beatles white album and it just says the Beatles with a white and like it's incredibly difficult because everything is white. So imagine here like if I've got repeated sections of DNA, I don't know whether this thing came from this part or this part or this part, right? >> 100%. And some puzzle pieces go together when they're not supposed to be next to each other. >> Yeah. Yeah. Yeah. Because the because just, you know, >> just kind of the >> Yeah. It's like it's like this side of the puzzle piece goes together, but when you put it together with the rest, the other three parts don't make any sense. Yeah. Like it's it's a really incredibly hard puzzle. Right. So that's one reason why you don't want that. The next is loss of alic phasing. Right. If I want

1:04:58to study non-Mandelian inheritance, what I really like to know is which parent

Allelic phasing: which parent did it come from?

1:05:02the epigenetic mark came from. That's that's why the the maze thing was was such a big deal, right? Because I could tell like what was happening, right? >> But in order to do that, what that requires is each of these short reads to have a mutation from the par from one parent and not from the other. Right? It's like it's like, oh, this part is a T. I know that the mom had the T here and not the dad had a C here. So I know that this part comes from the mom. But if I have short enough reads that are 150, the probability of getting one of these single nucleotide permutations in my short read is very low. >> Mhm. >> Right. >> Because the shorter the thing is, the probability of something going wrong is >> right >> is not that high. >> So the methylation could be different

1:05:44between two identical, but I don't know which one came from the mom, which one came from the dad. >> That's actually a really good point. And that's that's fundamentally >> Yeah. And fundamentally, the whole point of what you're trying to do is you need to be able to make that that connection. >> Yeah. I I'd like to know which paternal chromosome it came from from the entire whole. >> It's like you have two white puzzles. One is the Beatles white album and one is whatever the White Stripes white album >> and it's like the white piece >> and now you're taking the white piece from what? >> Yeah. It's like they're all white and but is this the white album? Like and so now you're So >> that's exactly right. That's that's a good good analogy. Exactly. Okay. So that's been the problem. I don't know how to do it. It's like we've been relying on the sequencing technology that gives us the sequence of DNA, but

1:06:27it's not designed for methylation reads, >> right? Which which is key for us to be able to identify, >> you know, where we're going to see these mutations that cause the dominant to get suppressed. >> Yeah. Yeah. And all of this weird shenanigan >> all the weird stuff we just all the weird stuff >> it kind of deres at least in part from from this >> from understanding where which chromosome is the parent right [clears throat] which chromatid came from which parent okay so now we get to why it's happening now the Oxford nanopore revolution okay this is an

The Oxford Nanopore revolution

1:07:00insanely cool technology >> here's how it works okay it's it goes to biohysical detection what you do is you take your native DNA strand and you pass it through a nanopore. It's a little hole in a membrane kind of like ion channels like the the the pro the there's a membrane that separates in and out and then you've got a you've got a little hole that's made out of protein that one strand of DNA goes through there. There's a thing above it that unzips the DNA so that one strand goes this way, one strand goes through. Okay? And what you're going to do is measure the current across the membrane. Okay? the the the current that's going through

1:07:41from from this side to this side. Now, A, T, G, and C are different molecules. They're they have different sizes. They have different little residues. One, they have different shapes. And so, every time the four goes through, there's going to be a tiny different current for each of the four. >> Isn't that sick? >> I'm so We're so smart, dude. Isn't that so sick? >> That's very clever. The visual analogy I sort of think about is like if you unzip the zipper of your jacket, it's like the unzipping of the DNA. And each of these are then going into something that's going to read >> each segment of four, which is basically just going to have a different fingerprint.

1:08:21>> Exactly. Like imagine imagine your zipper. Let's go with that analogy. I like that. Imagine your zipper, but each of those tiny little zip thingies is a different um composition of plastic. Okay? And so when I go through this like little hole, it's going to sound different, right? The the red plastic is going to sound different from the white plastic. And so if I've got a little sound recorder that just records the right, I can I can then have a computer program >> decode what type of plastic was the four zipper parts. And that's what's happening here. And so on the right hand side, you see the current versus the time. >> Yeah. Yeah. Yeah. >> Completely different signatures. And then you've got like, you know, it's probably not even machine learning. This

1:09:03is a very simple like computational task to do. >> This is really good. >> Okay. Now, this was originally um this was originally invented for just genome sequencing cuz A, T's, G's, and C's, right? But now a C with a methyl group is going to sound even more different. >> Bingo. >> You see? >> Bingo. Yeah. Makes total sense. >> So, there's just going to be a fifth signature >> signature >> that I have to look for. >> Yep. That it makes to I mean, it makes total sense. It makes total sense.

Ultra-long reads and methylated cytosines

1:09:31>> Why is this advantageous? One, you can do ultra long reads. You're not treating the thing with detergent, >> right? You just you just you just you just stick this thing through and you can get hundreds of thousands of base pairs. We're going from 150 to now several orders of magnitude of like how long you can make the read, right? So, it's like the it's like, you know, when when sometimes you you you like go to the Airbnb and like you open the puzzle box and half of it's done. >> They're like, "Do [laughter] >> Right." cuz then because then you can post it on Instagram like two hours later I did it [laughter] >> that that's it's a really interesting note though that through this biohysical detection method which again was used

1:10:11for sequencing the point is because we understood the methylation process in and of itself you could then extrapolate that the C in this biohysical detection is going to just have again that slightly different fingerprint and that's all Yeah, that's all you need to look for now. And and again, just this narrow now we can and again now being able to sequence longer. >> Yeah, it's huge. >> Gets back to this uh chromatid. >> Uh >> yeah, because now you've got a longer sequence. There's in a 100,000 base pairs, you're going to be able to identify which one came from the mom and which one came from the dad. >> 100%. >> Wow. >> Isn't that sick? >> And and and the thing is this Oxford nanopore evolution was not necessarily

1:10:53for u methylation uh detection. It's just someone was like, "Wait a minute. Yeah, this is the the physics works out here, right? Um, it's called Oxford Nanopore detection because it was a technology licensed by Oxford Nanopore Technologies of Oxford, UK. They licensed the patent, but the patent actually is a University of California patent.

Portable sequencing and the MinION

1:11:15>> Okay. It was developed in uh UC Davis and UC Santa Cruz. Um, the fundamental research comes from David Demer who he started in UC Davis and then Santa Cruz poached him. He's like, "Yeah, I'll go I'll go live in Santa Cruz. It's kind of nice. >> Yeah, >> it's it's kind of nice. >> And I I really do think that this is um this is something that is Nobel Prizew worthy because it's it is now the foremost way of not just doing methylation but also just sequencing DNA right? >> In general, >> in general like this is now it's super fast because you go right and then and then have a computer just read the whole thing. Um and and these ultra long reads are just good >> regardless, >> right? For any number of contexts. We're we have a specific focus for this

1:11:56episode, but the applications >> the applications are endless. And and um Oxford Nanoport Technologies, they created something called a mini on sequencing device. It's like a tabletop sequencing device. So you can just like have it it it's not like the giant machines that you used to be. It's just a tabletop. Just stick your pipet in and then it'll just do the thingy. Is it analogous maybe to the sort of the phase shift from vacuum tubes to like desktop personal computer or desktop to mobile in the I would say like like uh yeah desktop to like laptop. >> Okay. Desktop to laptop. >> You know what I mean? The laptop I can now like go anywhere. >> I don't have to be plugged into a wall somewhere. >> Exactly. And things like that. Um and so I think it's it's a very big deal. And they actually took one to the

1:12:37International Space Station cuz they do like weird genetics experiments up there with like plants and like how they deal with microgravity and it makes sense, right? Like how does bacteria deal with microgravity? Cuz ultimately if you want to extend life to several years in space, you need to understand genet how like does the genetics at at the molecular biology level do they care? Probably they shouldn't because the gravitational potential difference between like one end of the cell and the other shouldn't be that much. But, you know, you never know with biology, right? You got to Yeah. Like, >> is the factory going to shut down? >> Yeah. Like, just because I took out like a tiny bit of wind effectively, right? That's like going in one direction. So, the ISS is using a mini ion sequencing

1:13:18device on it. >> That's really cool. >> Yeah. So, now finally with this, we can get to the paper at hand. An hour in, an hour into our episode, this is the paper

The Nature Genetics mouse paper

1:13:28that we were talking about. Okay. Non-Mandelian inheritance of DNA methylation patterns in mice. It was out in Nature Genetics. It was during my paternity break and I was like, "Oh, this is really cool." >> But now I can read that title and understand why this is a big deal. >> That's right. And you miss me. >> Yeah. Like this is [laughter] ladies and gentlemen, the greatest. This is why it's the greatest. But like and it's it's important because these words have meaning. A lot of times people see these titles and they're just like, "Ah, >> it's just big words. They don't mean anything." There's actually real Even in the short title. >> Even in the short title, you get it. And it's in mice, not transgenic mice, not like special mice, just mice, just plain old mice. That's why it's very important. You're doing it in mammals,

1:14:08right? >> Because this is from the 2006 one. This is basically the next stage, the next development there. >> Yeah. The um one of the key authors, Andrew Fineberg, he's from Johns Hopkins. Okay. He has a career in disease genetics and epigenomics. He's like one of the epigenomics guys at the conferences, right? Like that's like giving the presidential lecture or whatever. Um and then David um Threadgill at Texas A&M, he's been studying humanlike complex genetics in mice. So they decided that they wanted to collaborate about 10 years ago um trying to study epigenomics in the mouse model and they're trying to compare methylation patterns in response to diet in these inbredad strains. And they realized that in order to do that they

1:14:49what they really want to observe is alals specific epigenomics. Meaning this alil came from the mom, this al came from the dad. How is the methylation changing? All of that kind of stuff, >> which this methodology we just talked about before is an enabling layer to that specific research question. >> Exactly. Yeah. And so now we can we can start doing that. The model that they

Collaborative cross mice

1:15:09chose was something called the collaborative cross model. This is key here because what this collaborative cross mouse model is is it's derived from eight distinct founder strains. So the founder strains are kind of like your PE generation in the Mendals like the true breeding. But because now you're combining these eight different models, you get a lot of genetic diversity. And so it's much more closer. It's much closer to like, you know, normal organisms, but they're still lab in the sense that I still have very nice sequencing data about them. So I can still do very nice nitty-gritty comparisons. Okay. >> So that's the strains they use. uh specifically one the strains that they

1:15:51used was the CC019 and the CC037. Those are the two specific like sort of F2 or in this case like FN generations, right? There's so many that you can make and the experimental design is actually

The experimental design

1:16:03quite simple. It's kind of like Mandelian experiments. Okay. What you do is you take your um your you take your CC019 and your CC037 those lines very well established what the epigenetic markers are there and what the genetics are there. So even though they're not like true breeding in a sense you have a good understanding of like what the genetics are. Now you cross them and then you cross those again right just like in Mendle's experiments. But in this case, what we're looking at is the methylation pattern on the chromatin instead of the actual genetic sequence. Y >> okay. So the genetic sequences could be the same, but depending on whether this chromatin came from the mom, this one

1:16:45came from the dad, all of these things are now going to start changing. >> Okay, this is very very and and it and it makes sense now why it would be changing. One, because we understand the sex chromosome, so you get one from each. two because the methylation is going to change what proteins are actually produced or what's suppressed. And so now with all of that understanding and background and context and the ability to actually >> detect and sequence the methylated C um >> nice >> like that that is they can now do real statistical analysis that's meaningful uh in this because they've done they have the correct they've done the mice work they've done all the other

1:17:26background work anyway. So that I think it's all kind of just >> and one final thing that I want to mention before we get into the results is again about methods because we do want to focus on methods in this. So we've got the >> the you've got the model mouse models of

Building a pseudo-hybrid reference genome

1:17:40CC19 and CC37. >> Now when you sequence the offspring's DNA, right? Usually when you want to put together even when you've got these long reads, you've got to have a reference genome to put stuff together to. But we don't really have a reference genome for the offspring of these two lines, right? And it's not great to just use one or the other because you really you're going to have to have like some middle ground. And so one thing that I do want to talk about is like in traditional bioinformatics pipelines, right? You've got these and I think um photo 30 will show that in a traditional bioinformatics pipeline, right? you've got fragmented DNA, even if they're long, you sequence the DNA, then you get

1:18:21all these unaligned sequences and then you try to align those sequences to a reference genome. Okay? And the reference genome is something that you get like if you've got a human genetics, right? You've got the human genome project and you align your own DNA to that because there's not going to be that many differences, right? But here, those tiny differences are going to matter in this study, right? And so what they did was they actually solved it by constructing a pseudohybrid intermediate genome which is I think very cool that they were careful enough you know to create this kind of custom software that constructs um a synthetic reference genome for every single cross right and um it includes all of the strain specific insertions of the parent

1:19:02genomes but it's like unbiased analysis of what the >> um what the kids are going to be showing. Mhm. Mhm. >> In terms of methylation. >> And that this this is important because again that reference genome is otherwise you're kind of you have no you have literally no reference. >> Yeah. Exactly. And then it's impossible but you can't use one or the other. You got to use this like hybrid. And so they were careful enough to do that. I thought that was quite cool. >> That's a that's an important and again shows the the they're really trying to do it in a robust >> Yeah. very meticulously >> uh fashion especially also from a replication perspective. >> Exactly. Yeah. So now we can finally get to the results figures. Okay. Yes. >> So, um let's talk about the control.

The Mendelian methylation baseline

1:19:41Okay. So, Mandelian baseline. 93% of the time the epigenetics is doing what Mendle's laws say. Here's how we're going to read these figures. Okay? All of the subsequent figures are going to be the same way. Um so, the pink is coming from the mom. The green is coming from the dad. What we're looking at on the y-axis is the percent methylation, the amount of methyl methylation, meaning how much of the C's have a methyl attached to it. Okay, 100% would mean every single C has a methyl group attached. Zero means none of the C's have a methyl attached,

1:20:22right? And what we're looking at on the X-axis is just along the DNA. >> Okay? So along the DNA, you can see that there's a certain region where the mom has almost no methyl groups attached to the C's and the dad has a bunch. >> Mhm. >> Okay. The solid green lines and the solid purple lines are the parent generation and then there's dotted green lines and dotted purple lines for the kids. The key thing to see here is that the dotted green is on top of the solid green and the dotted purple is on top of the solid purple. Meaning the the the methyl pattern of the kids is the same

1:21:02as the the moms or the dads. Okay. Nothing's changed. Like I got the chromatin, I got the methyl. Nothing changed. Nothing weird happened in between. So this is the mandelian baseline. >> Yes. >> Okay. And they they they actually use two different um tissues from the liver and from the muscle >> to see how like if there's any organ dependent effects that are happening. >> That's actually good. That's nice. >> Yeah. So this is this is this is like normal. >> Okay. This is something that um we thought should happen every single time. >> Yes. >> All right. Now, let's look at our first anomaly. >> And because and what we're saying is 93% of the time, Mandelian genetics holds up. >> Yeah. >> But there is the 7% outlier where it doesn't. And that's what >> And that's the

1:21:43>> that's weird. >> Yeah. >> And that's where the weirdness is. Okay. Now, let's look at non-dominant

Non-Mendelian methylation anomalies

1:21:48transacting um methylated. What is it? something some something QTLs I I forget what the the full form is what but the me is the methylated part okay >> here what we're looking at >> is let's look at the liver which is the first figure um the the first sort of middle figure okay at the top >> over there what you're seeing is the top line is the pink solid >> the bottom line is the green solid so that's the mom >> methylation and the dad methylation you can see the mom has a lot of methylation in this region the dad has almost no methylation in this which is an invert of what we just >> Yeah. Yeah. But that's not what's important because this this part of the

1:22:28gene might be different. >> What's important is the dotted lines are all in the middle. They're not coinciding to one or the other. >> Meaning that the the I got the DNA from them, >> but then the methyl parts are half and half. >> They're blended. The methylation is blended. That's fascinating. >> That's nonmandelian. That's what we're looking at. Okay. The offspring, some of the methylation is there. Some of the methylation is not. >> That's interesting. Some of the some of the female chromosome is getting more methylated or sorry, no, some of the female chromosome is getting less methylated and some of the male chromosome is getting more methylated. >> Yeah, cuz because based on where they are, they're in they're in >> again the the male is the one that's almost has none, but the the the

1:23:10offspring are blended. And so >> yeah, that's why the dotted lines are all in the middle. >> In the middle significantly higher and the the higher and the opposite of her. Very interesting. Okay. >> Okay. >> Okay. >> Now, let's go to the next one. This one's weird. This is the CAP N11 gene.

CAPN11 and paramutation in mammals

1:23:24What we're looking at here is effectively paramutation. >> Okay. Okay. >> So in this one, in this particular region, >> the mom has let's say intermediate methylation. The solid pink line is like 50%. >> The dad is all the way down to like 10%. Okay, those are the solid green line that's way down there in that highlighted region. and the mom is down. There's a dip, but it's only 50%. The dotted pink line and the dotted green line are all on top of the green. None of the mom's effects of methylation have come through in the in the

1:24:05subsequent offspring. Okay, so that's that top part. >> Now, let's look at the F2 generation, okay? Which is in the bottom. Every single offspring has the methylation pattern of the dad. >> It's like the mom's methylate. Like obviously the genes are there, >> right? But the mom's methylation pattern is completely gone. The mom's epigenetics have been completely silenced >> in both F1 and F2. >> Yes. And and and in F2 subsequently. Yes. >> Yeah. >> F2 is there to show that like whatever happened to F1, it didn't recover. >> Right. >> Right. What whatever happened in that first generation, the grandkids now just get no influence from the mom's epigenetics. All of the epigenetic influence is coming from the dad. >> That's in this particular.

1:24:46>> Right. Right. Right. Right. >> Right. Right. This is very weird. >> This is very weird because what >> this is something that we saw in the maze, right? Where it's like it's like even when when I crossed the the purple with the green, >> it was only green. >> Even the grandkids all were all green. >> This was the suppression thing we talked about there. >> This is and now the the the alil is completely suppressed. >> And so we're now we're seeing this in animals as well. We had seen it in the the maze before, but now we're seeing it in more complex Yeah. >> biology, which is >> fascinating. And there there's some very cool like consequences of this that we'll talk about at the very end. Okay. Um the last few figures that I want to talk about um this next one, figure

1:25:27number 34, this is I think figure six

Emergent epigenetic patterns

1:25:30and seven. This shows um some emerging epigenetic patterns. Again, the main thing to see is that the dotted pink and green lines are different from the solid ones. The one on the left, figure six, that shows something very weird, which is that the offspring sometimes just have more methylation than either of the parents. So that I don't even know how that got there. >> You and Neither of your parents had this. It's not even a blend or one of the parent is dominant over the other, >> which would it make almost more sense. >> Yeah. Yeah. This this one's just like >> this doesn't >> Yeah. That's why they're calling it emergent epigenetic, you know? It's just like >> put it in that bin. >> Yeah. We we'll come back to that later. >> Yeah. Yeah. It's like it's like this

1:26:10happens um and we report it. So now you got a size [laughter] >> and then and then on the right hand side we've got genomic imprinting. This is um again this is similar to the mom and dad thing but here so in the in the mom and dad one um it didn't actually matter which um chromosome which if the if the alil came from the mom or if the alil came from the dad because both sets of alals if they were from the mom or the dad it was alil specific. Here it's actually mom and dad specific. It's a process where certain genes are expressed in a parent of origin specific manner. In this case, the epigenetics is

1:26:51expressed in a parent of origin matter. Okay. So, if the methylation is with the mom, only then is there going to be methylation in the kid. >> Mhm. >> Okay. >> Doesn't matter what type of alil it is, >> which is actually an important distinction. >> Yeah. >> Um Oh, this. >> So, it's a parent of origin. So there's can both be alil specific divergence in methylation uh in you know the F fn generations. Uh and that can be true on top of the fact that there's like this genomic imprinting like they're not necessarily independently true. >> Yeah. So it's super super

1:27:33complex. >> Yeah. Because the the combinatorics >> becomes the com Yeah. Exactly. >> Becomes quite difficult. >> The last one I thought was actually really really cool. Um, I mean I I think

Organ- and sex-specific methylation

1:27:42all of this stuff is really really cool, but here what we're seeing is a difference in one organ dependent methylation. So the same region in the liver versus the muscle. The muscle has about 80% methylation in both males and females and in the liver the males have 80% methylation but the females have something like 50% methylation. >> This is crazy. >> Highly significant. >> This is crazy. Okay. >> So you can also have divergence across >> organs on top >> and on top of sex. Now why is this important? This was found so it's hyperthylated in females and then not that much in males, right? Why is this

1:28:23important? Well, it's found exclusively in the liver. What does the liver do? One of the big things that the liver does is um dictate tissue specific like it dictates um hormonal environments. It dictates how drugs are detoxified. So, this could be one of the main reasons why certain drugs work one way in one sex >> and then not >> in another sex. >> Yeah. >> Right. >> Right. >> Cuz that's a known effect. >> Right. We know that. >> That's kind of mysterious. >> This could be it. >> Like the epigenetics is different in the liver but not in other other places. That's a really important potential insight among many in this is that

1:29:05>> there is this organ specific epigenetic difference in methylation in the liver which would affect drug delivery >> um >> or a drug like like efficacy >> efficacy right right >> kind of crazy >> I yeah oh my I'm thinking about so many things but I I want to be not we we will

Clinical genetics and evolutionary implications

1:29:28talk for the next three hours. >> I mean, obviously, this has very deep implications. >> That's that's the main headline. >> And um what what it's really saying is look, >> future clinical genetics is now going to need to focus on genetics and epigenetic risk. Okay? If we want to start charting, you know, like how an individual's genome is going to affect their life and so on and so forth, right? There's also some very cool just like fundamental science things that are happening here. um that have to do with like for example evolution right the foundational science of evolution there used to be this theory called the Wington's theory of genetic assimilation basically it's saying that

1:30:08environmentally induced traits can become hardcoded into the DNA right this is not very Darwinian Darwinian is just um natural um natural selection survival of the fittest it's like the offspring get a random assortment and then they live their lives and then if they survive they procreate. Right? What Wington's theory is saying it's it's more Lamarian in the sense that your life is going to dictate the genetic your genetic makeup. Now for a long time this was discredited and for good reason because genetics is like as I said the DNA part is like very hardcoded right but now there's a link between the software

1:30:49and perhaps the hardware. >> Yeah. because methylated cytoines which are um the C's with the methyl groups those are inherently chemically unstable. >> Okay. So what that means is they frequently mutate into thymine T's. So if I have more methylation I'm going to have more mutations and I'm going to have more T's where there should be C's at at three times a higher rate. So what's the conclusion? That means that if among the inherited epigenetic traits, right, if my life is changing the methylation pattern, that methylation pattern could change the

1:31:30hardware itself because of this 3x difference in mutation rate. >> Yeah, it's it's a it's a recursive self-improvement or not improve >> or not improve. Yeah, it could go either way. >> It could go either way. >> Kind of crazy. >> It that's that's a really, you know, it's always been the conversation about

Nature versus nurture becomes nature and nurture

1:31:45nature versus nurture. It's more like nature and nurture and it's there's this combination between the two >> and as this sort of continues to >> permeate as now posing some very difficult questions um there is and obviously the sort of epigenomics and epigenetics conceptually have now been around for some time. These are the kind of uh big results that I think put us into a new uh frame, you know, a a new what do they call it? um the the Overton window on this is moving a little bit

1:32:25>> um to now really think about okay because I think your point is right over the course of your life >> if your your life itself is impacting the methylation on these cytoines that then become go from C to T and your offspring fundamentally get different genetics as a result of that that's pretty meaningful >> yeah that's that's pretty huge right um I I mean even even in terms of disease

Disease risk and silenced healthy alleles

1:32:51risk right >> this is a big deal right um because you can explain now how a mutated alil could epigenetically silence a healthy alil >> right so it's not just all about genetics even if you're a hetereroygote and you've got the correct alil to like >> survive the disease >> if you've got some shenanigans going on like this >> and the healthy alil just doesn't even get expressed >> you're biologically null for that gene Right. >> This makes me think about things like um um like anemia being more prominent in like Mediterranean or uh African populations

1:33:32as opposed to and it's like is there >> Well, that one that one is actually a single nucleotide polymorphism. Yeah, that's actually there's like a straight up hardwired genetic difference. That's not an epigenetic thing. Yeah. And that one's well documented because the the the mutation is I believe in the >> that's great >> in the heem protein or something like that that like affects the shape of red blood cells. >> Yeah. Where where you cannot store the um uh hemoglobin as well. Your hemoglobin is uh >> it's like it's like in a weird shape. Some of them are in a weird shape. So then that makes the cell a weird shape. So but there's so many other things, right? And this is like there there are traits I forget which but like there's some traits where like the there's like

1:34:14weak evidence that shows that the grandmother's exposure to stuff >> alters the disease risk of grandchildren. Okay. And maybe that's another episode that we could do. But like this is this is now getting to that question, >> right? And we can now ask we can actually probe at the probe at it um a

Looking for paramutation in humans

1:34:33much more um in a much more robust fashion. >> Yeah. um not just create a framework or have things that we can't quite then follow up with empirical data. >> Yeah. And I mean the next step the next clear step and this is something that Fineberg and his colleagues are doing um next is to do this long read sequencing stuff for humans. >> Yeah. >> Right. And paramutation in humans >> which makes total sense. So because if it's like 7% in mice, it could even be higher in humans because humans are a relatively recent um evolutionary organism, right? And our mutation rate is hella high and that mutation rate we've only we're really talking at the

1:35:14hardware level. If the hardware level is already high, >> imagine what the mutation rate at the software [laughter] level is. You know, >> this is fascinating. A big big return

Final thoughts

1:35:24episode for our resident PhD Krishna Chowy. New rules for uh this idea of non-Mandelian inheritance of epigenetics. I mean there's so much here uh that we again >> we can't cover everything in these pods there. There's a lot of detail that we can't quite dive as much into but hopefully we gave a nice overview uh for folks who are interested in this conversation. And again, like I mentioned, there's so many, you know, social cultural conversations around this idea of quote unquote generational trauma and its impacts on your your actual um physical outcome. And we're starting

1:36:06to be able to actually poke at some of these areas in interesting ways. Um, do we want to leave because this is a long one. So, if you've made it this far, uh, congratulations. Uh, you are a lifelong

Comment prompts

1:36:17learner like the rest of us. Do we want to have any questions for folks to leave in the comments for this episode? >> Oh, yeah. Well, I was going to say what we what you guys should do is um tell us what books to put on the as you said in the the thing, but if you made it this far >> um >> and do you have any advice for for a new father? >> That's a good one. >> Even if you're single and you don't have kids, just give me some like really terrible advice. I want to see like the the worst advice you can think of. [laughter] >> Um my name is Lester Nar joined as

Outro

1:36:53always by my co-host and our resident PhD and welcome back to Zatti Krishna Chowdery. Um it's great to have you back. This is always so fun to be back. It's good to be back. >> Um we got uh some fun ones coming up for you guys uh here in the next couple of weeks as we get back on our regular scheduling cycle. We appreciate you all for staying with us and we will see you all next week.