S2E07 - Genotype (Genetics) | Gaming with Science

#genetics #genotype #GeniusGames #mendel #peas #BoardGames #Science

This month we're talking about Genotype, by Genius Games, where you get to play a field assistant to the father of modern genetic, Gregor Mendel. We'll talk about who Mendel was, why his peas were so important to biology, how he got a bit lucky, and how many different ways there are to break a gene. (Also, why it's weird that some humans can drink milk as adults, and why cats and borrowed board games don't mix.)

Timestamps

00:00 Introductions
01:30 New paper on Mendel's Peas
04:46 Overview of Genotype Game
08:16 The Meatball Incident
13:45 Who was Gregor Mendel?
16:08 The seven pea genes
20:36 How to break a gene
27:47 The Modern Synthesis of biology
31:04 Dominant and recessive genes
38:22 Mendelian genes in humans
44:59 Nitpick corner
48:40 Final grades

Full Transcript

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Jason 0:01
Brian.

Brian 0:06
Hello and welcome to the gaming with science podcast where we talk about the science behind some of your favorite games.

Jason 0:13
Today, we will be talking about Genotype by genius games.

Brian 0:19
Hey, I'm Brian, and I am joined by a very special guest today, an expert in plant genetics. Jason Wallace, yay!

Jason 0:26
Hey everyone. So I know you already know who I am, but this is, like, today's topic is what I do for my bread and butter. This is my research area. So we figured we'd run with this. It's been a while since it's been just us for a full episode. So

Brian 0:38
yeah, it has. This is gonna be, this is gonna be harder work than we normally have to do, but, you know, but you are the expert today, so you are going to talk about it, and I'm going to be here to ping you with questions,

Speaker 1 0:47
yeah, which means I probably should give a little bit of background, because I'm not sure I've ever done that. So we're both researchers at the University of Georgia, both associate professors. My background is in genetics and molecular biology and informatics, which basically means studying very small things and how they get passed down from organism to organism in bacteria and now plants. And my specific area, which we may talk about later, is quantitative genetics, which is complex traits, but not actually the very simple traits, like we're going to talk about with Mendel's peas for today in the game genotype, but traits that are controlled by many, many, many genes and that have more complex interactions.

Brian 1:28
Cool, cool, cool, cool.

Jason 1:30
Let's go ahead and start off with a fun science fact. And Brian, I'm going to throw this to you, because I'm going to be talking a lot this episode

Brian 1:35
Yeah. I mean, totally, totally fine. There was a paper published recently in Nature, where they described and identified the genes responsible for the last three of Mendel's seven traits. So could not be more appropriate for this game. Four of the genes were known, so Mendel studied seven different traits.

Jason 1:54
We'll talk about that later, and we'll probably talk about this paper a lot later. Yeah,

Brian 1:59
we probably will. Honestly, I'm hoping you can explain it to me, because I study bacterial genetics, and it's way easier than plant genetics, but basically, the four of the genes had been described previously, three of them had not. And this study was a massive genome sequencing effort across a huge diversity of domesticated and wild pea species, and they were able to do something called a genome wide association study. So they looked to see which plants had a particular phenotype, they looked at their genotype, and we're kind of able to say it's like, well, if we look at this sort of mathematically, we can see that everything that has this feature seems to be pointed down to this region of the genome. And we're able to identify these last three genes and and really it's interesting, right? Because we knew about genetics way earlier than we understand how heredity actually worked, how DNA worked, how any of that stuff worked, because it follows simple mathematic principles. And actually, what's interesting is a lot of times it's about how genes get broken. And this study in particular was sort of understanding the for the most part, the way that these traits were associated with breaking these seven genes in very specific and very different ways. It's a real smorgasbord of different ways that genes get busted, like lots lots of transposons interrupting genes, lots of premature stop codons interrupting protein sequences. It's just every single one of them seems to tell a unique story of all the ways that you can break a gene.

Jason 3:25
Brian, you just throw out so much vocabulary I have to define for people now.

Brian 3:28
Sorry, sorry.

Jason 3:28
So we'll go over some of this later. So genotype, phenotype, codon, transposon, like, if you don't know what those mean, that's okay. But basically, the idea of the studies, they looked at like 700 different peas. And then they did math, essentially to figure out, okay, we can see a bunch of ways that these are different from each other at the genetic level, which of these differences actually shows some sort of association with the traits we care about? And that's how they were able to narrow down on them. And they found a bunch of different ways that, like Brian said, genes can be broken basically, because most of these are the original plant, which biologists call the wild type. It's something got broken at some point, and humans said, Hey, I like that. And so we kept it. It became more common in some of our varieties that we cultivate. And so now it's common in, say, our domesticated peas that people grow in gardens, or in some varieties of them, but not in the wild ones. Usually, not always,

Brian 4:24
yeah? So, like, and again, this is kind of a weird science fact, because this is actually going to blend in with our discussion of the game, right? But, like, yeah, okay, so like, flower color, like, there's, there's a series of gene. Have we talked about that DNA really doesn't do very much. Maybe, I feel like, maybe this is the wrong story, because honestly, discussing this paper is discussing this game, so maybe we should just let ourselves move ahead so we can talk about it in more detail.

Speaker 1 4:46
I think so probably yes, let's, let's let it go. All right, so let's talk about this game then. So genotype by genius games, basic stats, it's for one to five players, obligatory first player or single player mode takes about an hour to play. Okay, ages 14 and up, but again, depending on your kid, it can be younger. I had a my nine year old played it with me several times, and she actually quite enjoyed it. So it is, it is kind of complicated. There are a lot of moving parts to be aware of. Suggested retail price is about $60 which may be a bit on the pricey side, but they have a bunch of custom components. You get a bunch of custom dice, bunch of custom punched out tokens, and some trowel shaped meeples, which I think are just lovely and such, because the whole point of this game, the conceit of the game is that you are playing assistants to Gregor Mendel, who is essentially the father of modern genetics. And we'll talk more about him in a bit. At Thomas Abbey, way back in the 1800s and you are essentially his field assistants going out doing the work to try to get the data and validate these traits he's studying in peas. And so you have your little trowel meeples, which represent the work you're putting in. You've got dice, which are the genes. And because reproduction is a little bit of a random process, you roll the dice to figure out what types of plants you get every generation. The game is basically a combination of a worker placement game and a drafting game, because it goes into few phases. In the first phase, you place your little trowell meeples to indicate what sort of stuff you're doing. Most of this is actually just set up for the second phase, where you roll dice, and then you take turns picking those dice to be able to mark off your plants and score points from them. And then there is a third phase where you can buy upgrades that will let you do these things better in future rounds. There's only five rounds, so the game goes pretty fast, and the goal is to get as many points as possible, which most of which happens from marking off these pea plants, although there are a few other things, partially competed. Plants are worth a few points. You can pick up these little coin resources that are also worth points, but generally they're probably better spent buying upgrades and other things, just because the pea plants are really what give you the most points.

Brian 6:56
One of the things that I've noticed because, you know, there's an entire ecosystem of of teaching people how to play games on YouTube and everything, I had a really hard time finding good videos teaching how to play Genotype because that first round, that setup round, doesn't make a lot of sense if you don't understand what you're doing in the second part, where you're actually planting and and while I understand the desire and the impulse to well, "you should start at the beginning. It's a very good place to start." Actually, you should not start at the beginning. You should start at the two things so that you understand what you're doing. And it took a very long time for me to wait, what are we even doing here? Why are, what does any of this mean? You got to explain what it means before you can understand how those setup activities even do anything.

Jason 7:39
But yeah, when I was explaining this to my kids, I would do with a high level overview, like, this is what you're doing. Here are your plants. You're going to be taking these dice in order to mark these off and do the broad scope of the entire game. And then I would zoom in, like, Okay, here's round one. Here are your options in round one. Here's round two. Here's what we do here. So I give that overview first, and it sounds like that's what the videos may be missing.

Brian 8:01
I think we could put out a good how to play genotype video. Maybe we should do that. I don't know.

Jason 8:05
I have now explained it to my children twice, so I've got practice. So Okay, put that together if you want.

Brian 8:10
I mean, let's do it. Why not? It'll be a bonus thing. Can I tell an anecdote about this game?

Jason 8:15
Sure

Brian 8:16
When I first got introduced to genotype, it was on Jason and I's list of things to play for a long time, and we went to our public library. A lot of your public libraries actually have pretty good collections of games. So it's like, oh, this is so excited. I wanted to play this anyway, and now I don't have to buy it, right? So we we checked it out, we brought it home. I read the book, I watched the videos. It was getting late, so what I did was I got the entire board all nicely set up, taught my wife how to play, and then we just put a blanket down over it. It's like, okay, well, it's too late to play this tonight. We're going to play it in the morning. We put a blanket down to protect it from our very wonderful, very over affectionate and very Cat, cat who does like to knock things over. Some of you can probably suspect where this is going. The blanket did not dissuade him. We wake up in the morning and every component has been scattered to the four winds in every corner of the room. We had to search the entire house to figure out where Meatball, which is the cast I'm had put everything we found, every meeple, we found every little cardboard token. We found everything except for three of these custom dice that we still have not found. They are hiding somewhere in the house. Remember, I checked this out from the library, so I had to buy a whole copy of genotype so that I could return an intact copy to the library. So the copy that we played is our replacement copy with a couple of like, generic, faceless dice that I had to draw the little symbols on. So anyway, thank you, Meatball for that good story. We did get meatball from a local animal rescue called odd paws that specializes in special needs cats and neonates. So if you happen to live in Georgia or the Athens area and you would be interested in having a truly wonderful animal who will destroy your board game experience, check out odd paws.

Jason 9:58
Yes, and we're not being paid for that. Like,

Brian 10:00
absolutely not

Jason 10:01
Brian had a good experience, and wanted to give them a plug. Yeah. So before we go on to the science, I want to talk a little bit about the game and playing the games. Like the game went pretty fast. I thought it was enjoyable because it seemed to have a good mix of like, control and randomness. So there is some amount of randomness there, but within the constraints of that, there are decisions I can make to position myself in better positions, and that's kind of the mix I like, is where it's not fully under my control, because then things tend to get kind of staid and they get predictable, but it's not too random for me to think that I have no power.

Brian 10:36
Yeah, that makes sense.

Jason 10:37
And in the vein of all good work replacement games, there's always more things you want to do than you can

Brian 10:41
so many more.

Jason 10:43
It's like, you want to buy all the upgrades. You want to place all the meeples and all that sort of and of course, one of the upgrade you can buy is additional meeples, which is I always went for. But, man, those upgrades are expensive, and the more they get bought, the more expensive they get. So it's hard. There are definitely some rounds. It's like, I want an upgrade and I have no money, therefore I must look at them sadly and pass

Brian 11:03
we should play this with a higher player count, because one of the things about worker placement games that two, just two players, is that you don't really that sort of like competing for sparse resources, doesn't come out as severely like in some of these like every time you buy a resource, there's a little thing that makes that more expensive, a little abacus that clicks up one die. So like, if you're not first, it really puts more emphasis on there's something that you can do to make sure that you'll be the first player in a round, and that becomes very important. The other thing is that, like, you get series of assistants that come out that have special abilities, you have tools that come out that have special abilities. Those will only be there for that round. If there's something cool out there and you don't get it right away, you may completely miss the opportunity. There's a huge FOMO associated with playing this game.

Jason 11:55
Oh yeah, this game is built around FOMO is, like, every turn, all the pea plants, all the tools, all the assistants, they get wiped and reset. And so, like, if you don't grab it this turn, it's gone, and depending on the deck and how many players, it may not come back.

Brian 12:09
So lots of replay value. But man, you really feel constrained with this one. This is a very, very worker placement. Like, the idea of worker placement, as you always have to make hard decisions here, and they always feel hard,

Jason 12:22
yeah, but I'll say I had a lot of fun. Like I really enjoy it. The game is beautiful. It's got very high quality art and like tactile design. The pieces the back of the game board is this beautiful watercolor of Thomas Abbey in the Czech Republic. They definitely put in their work to make it a nice looking game, and in a game that is nice and physically good to play, but also has a lot of strategy and tactics. Like I enjoyed the game.

Brian 12:45
They're sort of blending science and history in an interesting way. I know some of their they have a game called first in flight now, where they're talking about the Wright brothers and the first airplanes. And I can kind of see they're sort of edging in this direction. This is a wonderful, wonderful way of blending these two things together.

Jason 13:00
Plus, you probably figured there's only so many scientific concepts that concepts that readily lend themselves to a game,

Brian 13:04
boo, no, that's not true. There's an infinite number of scientific concepts that lend themselves to games. We just, we just reviewed a game that was completely based on a single study. I think. No, no, no, no.

Jason 13:15
Okay, fair. It does broaden their palate, though. Yes, now they can. Now they can appeal to history buffs and not just science buffs. Now, being a genius Games Game This, of course, did half my work for me. It comes with a nice insert that actually explains a lot of the background about Gregor Mendel and genetics and all that stuff. I am not going to just regurgitate that insert here, like if you want to read that, buy the game, read the insert. They'll tell you stuff. We're going to be talking about other kind of broader picture things here, but we will give some context. The core of this game is about Mendel and genetics, and so we really need to give a little bit of background about that. Now, you probably learned about Gregor Mendel in your like high school biology, because he is the father of modern genetics. He is arguably second only to Charles Darwin in terms of the foundations of modern biology. Mendel was a Christian monk. He lived in the mid 1800s he actually studied math and physics at Vienna, which is probably why he took this mathematical approach to biology. And the thing he's most famous for is this work at Thomas Abbey, which is in Brno in the Czech Republic, where he studied these seven different traits in pea plants over the course of like, eight years. And he basically wanted to figure out, Okay, how are these inherited? Because this was an active debate during his time, and it was actually an active debate for like, 50 years after his time, maybe a bit more, because Mendel's work was unfortunately forgotten for decades. He would publish it in sort of like a mid tier journal. Didn't get that much press, and apparently one of the issues was that people didn't like really think it applied outside of peas. It's like, okay, that's cute for pea plants, but what does that mean for humans and dogs and all these other things? And he got a little bit unlucky, because he did try to replicate it with a different species, um hiratium. Common name is Hank weed. I'd never heard of this.

Brian 15:10
Hank weed interesting.

Jason 15:11
Never heard of it. Don't know why it was picked.

Brian 15:13
Is it pretty?

Jason 15:14
It has a nice little orange flower that I saw. Okay, but he there's a problem with Hank weed in that. Now we know that a lot of Hank weed and the ones he studied are something that are called apomictic, which means that they make seeds without going through sexual reproduction.

Brian 15:31
That would be a problem.

Jason 15:32
Yes, it is very problematic. It's basically the plants do not really undergo fertilization as normal, and so a lot of the offspring are basically clones of the parent. Even though they're seeds, they are clones, which completely throws all of Mendel's work out the window because he was looking at inheritance through normal sexual reproduction, and didn't realize that the second plant he picked doesn't actually do that.

Brian 15:57
So he got really unlucky with his second pick, and insanely lucky with his first pick. I don't even know how to explain. I'm trying to decide what level of detail we want to go into here the seven traits, right? Yeah.

Jason 16:08
So the luck with pea plants is they study these seven traits, and the things that came out of Mendel were called the laws of segregation and independence assortment. This basically means, if you have varieties for a trait, they go independently of each other, and that they can move off in a different offspring. A very non technical definition there. But the idea the independent one, especially, is that Mendel thought every trait was independent of every other trait. They did not care about each other. Now we know that's incorrect, because all our genes are on the DNA. DNA is a long string. It's in chromosomes. Genes that are close together on a chromosome are actually not independent. They tend to travel together. And in fact, that's the basis of the genome wide association study that was mentioned in this in that paper at the beginning is that you use the fact that DNA that is close to the gene you care about tends to travel with it in order to track it.

Brian 17:01
What a wonderful modern paradox that the very study that allowed us to identify these genes breaks the rules that Mendel thought controlled genetics.

Jason 17:09
Yeah, basically. But the luck that Mendel got is that he picked seven traits that happened to either be all on separate chromosomes, in which case they are independent or very far apart on the same chromosome, far enough apart that they act like they're independent, because within a chromosome, there is a little bit of breaking and shuffling that happens between the genes you got from your your biological parents, and so there's a little breaking and reshuffling. So if you're far enough apart on a chromosome, you are actually independent, and the ones he picked were far enough apart. There is one exception, there are two of his traits that might be close enough. And this gets into a thing we don't actually know which varieties of peas Mendel was working with, so people have tried to figure this out based off of what varieties were available. What's out there in the populations that big study Brian mentioned, which we're going to keep coming back to, found that for most of these traits, there really is only one variation out there. And so that's what Mendel was working with. But some of them have a few different ones. And so one of the traits, I believe it, is whether the pod is edible or not.

Brian 18:12
Yeah, the edible pod, they found, there are two genes that control that, and they don't know which one he had.

Jason 18:17
They don't know which one he may have actually had both, because they may have come from different ones. One of those is actually close enough to the plant height gene that they are linked. So if he worked with those, and if he looked at that particular combination, then he might have seen that linkage show up, that they are not independent. But it seems like either he didn't have that version, or he didn't look at that combination very much, and so that his things about the Independent Assortment hold for all the ones he worked out. They hold in general, we've just now know that, as always, biology is a lot more complicated than you think at first, but in general, that does pass, that does hold weight still.

Brian 18:54
Can we talk about the seven traits and what they were?

Jason 18:56
Yeah, sure. So seven traits, the game only includes four of them. So the game has the round and wrinkled peas. So whether your pee is round and plump or whether it's shriveled and wrinkled when you dry it out, they have tall and short plants, which is probably one of the most famous ones you get in high school biology. It has whether the pea pod is green or yellow, and it has whether the flowers are purple or white. And then the other three traits he looked at was whether the seed is green or yellow, whether the pod is edible or the technical one was like whether it's inflated or constricted. So inflated is kind of like the normal pea pod you'd see, and constricted or flat are like the snow peas, where the pod is, like a little flat thing, and you could actually see the peas poking out through it.

Brian 19:45
Yeah, I think they're like, missing some kind of papery parchment layer that is unpleasant to eat. So those are, like, basically just the vegetable peas. You pull them right off the plant and eat them, and they're quite delicious.

Jason 19:55
And then the last one is about flower position. Basically, do you have flowers kind of going all up the stem, or are they all in one big group at the top of the stem? And those are his seven traits.

Brian 20:05
Where did Mendel get his peas from? They had seed catalogs in 18 in the 1800s and these seven traits were listed and being used by by pea breeders. Yeah,

Jason 20:16
that's still a valid thing. I know the person who works in the lab next to me studies tomato fruit shape. And when she was starting her lab, she just looked through the seed catalog like, Oh, that was a cool looking tomato. Let's order that. The fascinating thing is, I say, we now know what every one of these things does. We've known about the traits for 150 years. Breeders were using them for decades before Mendel got a hold of them. But it's only now we actually know the chemical basis, the actual molecular change that happened, because every one of these is tied to some sort of change in the DNA, but the nature of that change is very different, and actually it's kind of cool with that study, most of these have different mechanisms for changing, so almost all of these are using a different way to break a gene. One or two of them have a big chunk of DNA that got inserted in the middle of it. Some of them are these, what we call selfish elements, or transposons, jumping genes. Jumping genes, you may have heard they're basically like even below a virus. They're just a short stretch of DNA, maybe only a few 100 or a few 1000 base pairs long. A base pair is one A, G, T or C, so very, very short, that they basically only code for enough proteins to cut themselves out or copy themselves out and stick them somewhere else. They're not even a virus level, but they are selfish, and they will jump around your DNA and your body thankfully has many, many systems in place to stop them from doing that, because it's generally bad when a random piece of DNA goes into some other part of your genome because it usually breaks things

Brian 21:45
well, they can't be doing too good of a job. I mean, a huge percentage of our genome and plant genomes are transposons, right?

Jason 21:51
Yeah. So if you've heard of how much of our genome is junk DNA, a lot of that are the remnants of these, these selfish elements, and they are doing a very good job. It's just when you're talking over evolutionary time, then you only have to let one or two through per generation, and you get a lot. I don't know what the rate is of those, suffice it, the mutation rate in the game is way higher than happens in normal life.

Brian 22:17
I'm sensing a nitpick when we get to the end of the episode

Jason 22:21
The game designers pointed out. So it's not really a nitpick anyway. So you've got big chunks of DNA that will sit down in some of these genes and break them. The round, wrinkled pea is due to one of those. One of these jumping genes went into a, I think it's a gene that controls starch, starch production, and jumped into that. Also the yellow versus green seed one, I think there's one there. It didn't jump into the gene itself. It jumped nearby, and it broke how it's regulated. So when it's turned on and when it's turned off.

Brian 22:49
Have we had a chance previously to talk about DNA and how DNA works at all, or is this our first time doing it on gaming with science?

Jason 22:56
I think it's our first time.

Brian 22:57
Okay? I think we should just take a quick minute and just talk about that, and at least try to and try to make an analogy. I'm sure we've all heard these analogies before. What I think is interesting about DNA is we talk about DNA a lot. DNA, on its own, really doesn't do very much. It just stores the information.

Jason 23:13
It's kind of like the hard drive on your computer. If you have just a hard drive, you can't do all that much.

Brian 23:18
So it codes that information in sort of like Jason talked about base pairs, those As G, C's and T's, when you're in a gene region, every three bases codes for like a letter corresponding to one of the 20 amino acids that make up your proteins. So when the DNA gets read out, it's copied into a strand of messenger, RNA, just a single stranded DNA-like copy that then gets translated by the ribosome into each of those amino acids, which gets turned into little, a little chain of these things that folds up into the protein that actually does the thing.

Jason 23:51
If you want to hear more about that process, go see our episode on cytosis, because that's basically the core of that game. Is you have your start from your DNA, very true, or your RNA, you go to protein and all those sorts of other stuff there. Yeah.

Brian 24:03
So if you imagine that like your your little gene is sort of a sentence or word, right? And then somebody takes a whole nother sentence and jams it into the middle of it. It the sentence doesn't make any sense anymore. You've broken it, right? So it's going to start just fine. It's like a lorem ipsum. And then it turns into, you know, absolute garbage. And say, when you try to make the protein from that gene, you don't get a protein that works. You get a little busted up piece of something that doesn't do anything.

Jason 24:30
Yeah, it'd be like, if you have your, like, your book library on the shelf and, like, you open it up to complete works of William Shakespeare, you open up to a sonnet, and then you paste in the middle of that, like

Brian 24:40
Dr Seuss

Jason 24:40
12 lines, yes, 12 lines from Dr Seuss, like, you've broken the sonnet. It doesn't work anymore, but this is the basics of it stores information. That information gets moved out. But because it's so complicated, there's various ways that can be broken. So we talked about the selfish DNA coming in and either breaking the gene itself or breaking how. When it's turned on and when it's turned off.

Brian 25:01
Yeah, which kind of can do almost the same thing. It's like, if the gene is there but never gets turned on, then you never get the protein, and it might as well not be there.

Jason 25:10
Yep, there's a few of these. So the tall, short mutation for Mendel's peas is due to a single letter change in one gene that controls a plant growth hormone called gibberellin. That's sort of the smallest mutation you can have, is you switch out one letter for another. I think it's an A to a G, but I could be wrong about that.

Brian 25:29
Yeah. So this is changing dear into bear, right? Big change in meaning by changing the one letter,

Jason 25:35
wait, deer into bear? Those are two letters

Brian 25:36
Like, Hi, my dear.

Jason 25:38
Oh, okay. I was thinking two animals. I was like, there's two letters difference. There not one. I thought you could turn in Deer into beer.

Brian 25:46
Yeah, we could do that too. Okay, definitely a bigger change in meaning at that point.

Jason 25:52
Anyway, you got those little individual letter changes. There's one that is another letter change. But instead of changing the protein that comes out, it actually changes the way that that the RNA, the secondary one that's made, gets cut and pasted together. So it gets cut and pasted together, wrong?

Jason 26:08
Oh, man, we are not going to talk about exons and introns, are we?

Jason 26:10
No, we are not

Brian 26:11
okay.

Jason 26:12
Suffice to say, in us and most other complex organisms, the DNA is not read directly into a protein. It goes to the RNA. The RNA gets cut apart and then re glued together. And if something goes wrong there, it can also mess up the protein.

Brian 26:26
It's so unnecessarily complicated I don't understand. Like bacteria really have this on lock. It's just the gene looks just like the mRNA and gets made into protein. It's so simple. I don't I don't know what happened to you. Eukaryotes drive me crazy. Humans, everything with a nucleus drives me crazy.

Jason 26:46
It's thought that cut and pasting is one reason why we can get away with only like 20 or 25,000 genes is because they can be cut and pasted in different ways, and that's actually really important for our brain development. So don't knock it too bad.

Brian 26:57
Okay, okay, well, I guess I needed exons and introns to have a brain complicated enough to almost sort of understand exons and introns.

Jason 27:06
Other things are some small deletions. So little sections get removed. And like Brian was saying, since you have groups of three bases make essentially one amino acid, if you remove anything that's not a multiple of three, you mess up everything from there on out, and it usually just completely screws up the protein. So all of these different, these are all the different ways you can mess up your DNA. It's, it's actually kind of like those Co Op games where there's only one way to win and so many different ways to lose. A little bit. There are so many ways to mess up your DNA.

Brian 27:37
And peas seem to these seven traits seem to cover, like, again, a huge spectrum of the opportunities to break a gene. Yes,

Jason 27:43
so like, they show not every way, but they show a lot of ways you can break genes, which is really cool. Mendel was studying these traits in peas, and he gathered a bunch of data, and he published it, and it kind of got neglected and forgotten for like, 50 years. But then around the beginning of the 20th century, there were actually three different people who rediscovered them at the same time. It was Hugo de Vreis, Carl Correns, and Erich von Tsermach, people who were all working in genetics at the time. I guess they were all looking for similar stuff, results, and so they all found it, and within, like, a year, they'd all shared it with people, and they rediscovered Mendel's genetics. This did not actually solve the problem of genetics, which is what you may have heard in biology, because there was a raging debate going on about the nature of genetics, and it lasted for another like 10 to 20 years, which was how inheritance actually worked. And this actually goes into play with Charles Darwin and evolution, because one of the big issues with Darwin's publishing evolution by natural selection is that it was an explanation, but had no mechanism.

Brian 28:48
Yeah, Darwin didn't know how genetics worked. Nobody did

Jason 28:51
yeah, and he had some speculation. It turns out his speculation was wrong. He he was a he was in favor what's called the blending model. And this makes sense when you look at like how humans behave. If you have a tall human and a short human, and they have a child together, you don't end up with only a tall human, only tall children, or only short children, or only children that come in exactly two heights. They tend to be somewhere in the middle. And humans don't come in exactly two heights. We have all sorts of different heights, and The Offspring tend to be a blend of the characteristics of their parents.

Brian 29:23
So the blending model, if you had a plant with a red flower and a plant with a white flower, you would get a pink flower. That's what the blending model would predict,

Jason 29:30
yes, and that was Darwin's idea about how it worked. But the problem is that if you do a little bit of math, you realize that completely undermines evolution by natural selection, because pretty soon everything is average and you have no variation for evolution to act on. The reason why Mendel's work is so important is because it brought back the idea of discrete genetics. And I believe this was floating around beforehand, but it actually gave data to support that. Yes, this is true is that genes are discrete units that get passed down wholesale, and so the. There is still variation there, and there was argument between the people who did the blending and the people who did the discrete stuff for a while, although some mathematicians showed relatively quickly that all you need is a bunch of genes that affect the same trait and you can end up with something that looks like blending, and that is essentially where we are today. This is called the modern synthesis of biology where we have genes as the basic unit of heredity and information, they're all discrete, although some of them are sometimes you have a single trait that is controlled by many, many, many of them, and that natural selection is the dominant, although not the only, force that changes which genes get passed down which ones survive in populations over time. That is the modern synthesis of biology. It is essentially what all modern biology is built off of, and it is extraordinarily powerful. It's what's behind pretty much all, maybe not all. I'm sure there's some exceptions, but it's between behind the vast majority of biology research being done today.

Brian 31:00
You used one of the trigger words. You said dominant. So I think we should talk about Punnett squares.

Jason 31:04
Yes. Oh, okay, all right. Well, let's back off from the big picture. Then about large scale biology. Let's talk about what Mendel actually found. Because what he found is he found the pea plants he were working he was working with. He had tall ones and he had short ones. And when he crossed a tall one with a short one and a cross is basically he took pollen from one and put it on the pistol, the female part of the other, and made seeds. So basically he made offspring from a tall parent and a short parent. All of them were tall 100%. the short. It looked like this short trait had been erased, except when he then took those, all those tall parent, those tall offspring, and he let them self pollinate so they fertilized themselves, which is what peas normally do, the offs their offspring. So the grandchildren of the original cross actually came in both tall and short varieties, and they had about three times as many tall ones as short ones.

Brian 31:57
You ever heard the old adage about things skipping a generation? Yeah,

Jason 32:01
that's basically what's going on here. And the the term that came out of this is dominant and recessive. So we need to define some vocabulary right here. A gene is a section of DNA that controls a trait and that is good enough for us.

Brian 32:14
I'm realizing that us both like this, having it be specifically in our area of expertise is not helping us, sort of like skip jargon,

Jason 32:23
I know we're doing what the best we can bear with us, please gentle listeners as we geek out about our own fields. So anyway, that is your gene, a section of DNA that controls a trait, an allele, is a variation at that gene that has different trait values. So we have the height gene here in the peas, and it can have a tall allele and a short allele, so a tall version and a short version. And then what Brian was getting at is that you have a dom, you can have a dominant or a recessive one. So dominant means that it kind of overrules The other option. So in this case, tall is dominant to short. If you have a tall allele, then it will mask the short allele, whereas short is recessive, where essentially you need to be pure short. Because the math of this is that all the peas had two copies,

Brian 33:14
one from mom and one from dad.

Jason 33:16
Yeah, the original parents were either pure tall or pure short. The first generation offspring were a mix. They were 50/50, tall, short, but because tall is dominant, they were all tall. The offspring from that are a random mix of that you get randomly, one from the paternal line, one from the maternal line, one from mom, one from dad. When you're self fertilizing, like in peas, mom and dad's the same thing, but it's still random which one you get. It's basically a roll of the dice, which is why they have you rolling dice here in the game. And so you have a 50% chance of your first one being tall and 50% of being short, and also the second one tall and short. You work out the math. Three quarters of the time you'll have at least one tall gene and you'll be tall. One quarter of the time you'll have both short genes, and you'll be short and that math is reflected in the game. They actually have what's called a Punnett Square, named for Dr Punnett, who, I guess, used or popularized these that shows the gene combinations you have, and that shows the probability based on the die rolls of what you what sort of trait you get out and it's part of the game. You can actually adjust those squares by essentially picking different parents to go into your cross to make the ones that you want more likely and or to make the ones that your opponents want less likely or even impossible.

Brian 34:32
Would it be okay if we dig into that just a little bit? Because I think we've talked about broken genes and not broken genes and alleles, but I think the idea that the inheritance the dominant recessive is tied to that in an interesting way, is something that a lot of people sort of don't get introduced to. It's very common for people to learn about a Punnett Square and a dominant and recessive gene. But let's talk about that, what that means, and let's we can use specifically the example of the tall and short to do so, right? Jason already said that the tall plants are able to make, is it a receptor for the plant growth hormone, gibberellin, or is it the actual synthesis itself?

Jason 35:05
I think it's the actual hormone gibberellin itself.

Brian 35:08
Let's just, let's just assume that it is, because it's easier to discuss it that way. So if you've got the functional, wild type version of the gibberellin gene, you're making this plant growth hormone, which is why you're able to grow tall, right? If you have the broken version of the gene, you're not making that hormone, so you stay short, right? So if you imagine this, it's like if you're getting a wild type copy of the gene from one parent and a broken copy of the gene from the other, you still have one working copy. You're still making the gibberellin. So you look like the wild type strain, right? So that's why the one with the mixture ends up being tall because it has one copy of the working gene, and that's all you really need.

Jason 35:45
And important to point out, in this specific instance, one copy is enough. There are other instances where it's not where you would if you had one copy, you would be medium height because you had more than the short one, but less than the tall one.

Brian 35:56
Another example of how Mendel got lucky, because all of his traits were these traits where you had a clear one copy is enough,

Jason 36:04
yeah. And so that's how dominance and recessive genes work. Most genes are not strictly dominant or recessive. Again, Mendel was a little lucky, or maybe he was wise in which traits he picked. A lot of them actually show independent stuff. So there are definitely examples where you cross a red flower and a white flower plant, you get a pink flower out, or maybe you get like a light pink one out, or a dark pink one out. Like there's different gradations here. And then, of course, there's the traits that are actually controlled by many, many genes, the quantitative traits, as we call them. Now this is what my area, my research area, focuses on, which can be controlled by hundreds or 1000s of genes. I was just looking at before this recording what the current estimate is of human height. So human height is very quantitative, lots and lots of genes there. The most recent study I found, found like 12,000 possible mutations that were associated with it in like 8000 spots on the genome. And the fact is, there's probably even more than that, because each one of these is controlling such a minuscule amount of the of what's going on. Like we're talking one of these genes, a big effect from one of these genes might be like a millimeter of height difference. That'd be an enormous effect for most of these.

Brian 37:18
Well, thank goodness. Mendel identified a good, simple model system so that you could define the rules that then your area could go on to understand and break and understand the true complexity.

Jason 37:30
Yeah, that's the importance of model systems in biology, we know that a lot of our systems are not reflective of the messy complexity of the real world, but they let us figure out fundamental principles. And that's what Mendel's peas did, is that they let us figure out fundamental principles. Real life is much more messy than this, with a lot more complicated genes we there's also the fact that, you know, most traits are also influenced by environment. Going back to human heights, we are taller than people were 200 years ago, not because our genetics have changed, but because we eat better, we have better nutrition. And so this is nature versus nurture issue, and we're not going to get into that debate, because when talking strictly speaking about biology, you can usually actually figure out what it is.

Brian 38:12
Yeah, it's not a debate. It's just something you can measure.

Jason 38:15
Yeah, and we measure it, we calculate it out. And I do that all the time for the work I'm on, and they range all over the place. So some some traits are nearly 100% genetic, some traits are nearly 100% environmental, and a lot of them are somewhere in the middle this core of looking at these peas and these very simple traits is a good, a good way of simplifying the system and being able to make it tractable. I actually looked up for this, what Mendelian traits, so traits that follow this sort of simple, dominant, recessive pattern, what sort of traits like this humans have? And turns out most of them are diseases, because basically something important gets broken, and then that disease follows a a Mendelian pattern, because you either have a broken gene or you don't.

Brian 39:05
Oh, this is, this would be hemophilia in the royal families of Europe,

Jason 39:09
hemophilia, sickle cell, anemia, Tay sachs disease, albinism. A lot of these are recessive. So, like, if you have one working copy, you're probably fine. Some of these may be, like, partially dominant, so that if you have one copy, you're like, okay, but not great. Technically, sickle cell is like this. So if you have one sickle cell and one not sickle cell allele copy, technically, at the molecular level, you do have traits, and that's what gives resistance to malaria. You've probably heard that the reason sickle cell sticks around is because it does provide resistance to malaria. One copy does that, but it's not enough to actually cause disease symptoms, but it is a single gene trait, and we know exactly the gene mutation that caused that, an interesting one on this list, lactase persistence, so that's the fancy scientific way of saying you can continue to drink milk as an adult. Hmm, for people in the West, you may not realize this, but the ability to drink milk as an adult is actually really weird and uncommon in biology

Brian 40:08
and recent in human history, right?

Jason 40:10
Yes, it's actually one of the best examples of human evolution, like human evolution of traits, because when you look at at the ability to drink milk as an adult. What happens is, everyone, unless something's really broken, can drink milk as an infant, because that's how human infants are reared. You drink milk, especially historically, before formulas and stuff like that, was it. You had to drink mother's milk or get a wet nurse or something, or you died.

Brian 40:37
Yep, you are a mammal, believe it or not.

Jason 40:40
Yes. So, but once the infant was weaned, there's no reason to keep making all the the proteins and enzyme needed to keep drinking milk, especially lactose, which is the sugar in it. And so your body would turn that off, because that's just a waste of energy to make that. There's no point making all this protein that is trying to digest something you're not drinking. However, once humans started keeping animals for dairy, then it started becoming advantageous to be able to keep drinking milk. The thought is that it started with fermentation, so like cheeses and yogurts and stuff, stuff where you let bacteria digest the sugar first, so we didn't have to deal with it. But under those conditions, if someone had a mutation that let them continue to drink milk into adulthood, they could suddenly access this entire other nutrient resource that all of their peers couldn't, or at least, they could access it better. They could get more out of it, which I believe there was a study a few years ago showed that that meant they left like eight times as many offspring as people who didn't have it in these cultures. Whoa, which is insane.

Brian 41:45
That is a huge that is a huge advantage.

Jason 41:49
That is an enormous selective advantage, which is why lactase, persistence, the ability to continue to drink milk as an adult, is so common in cultures that have a long history of dairy production, because it spread through the population, because it was so beneficial, and it is apparently down to a single gene. And at least according to this list I'm looking at, it is dominant. So if you have one copy of it, you're fine. You can continue to drink milk into adulthood, just fine.

Brian 42:14
Very, very cool.

Jason 42:15
I assume anyone listening to this already knows if you can or not. So whether you have one copy or two, I don't know, you'd have to get gene tested for that, but you, if you can, you probably have at least one copy. Yeah,

Brian 42:25
this is the problem with recessive genes. Is they like to hide, right? You can't always tell that they're there. This is why a lot of these, well, you mentioned a lot of these diseases in humans, so a lot of very problematic ones are genetically based, and a lot of them are recessive. So for certain diseases, that's why genetic screening can be important to tell if your child will have the risk of inheriting one of these extremely detrimental diseases.

Jason 42:49
Yes, especially there are certain ethnic groups that have that are known to have elevated frequencies of some of these diseases, and so it's recommended to get testing there if, like you and your spouse are both of that, or if you know that you have a family history of this, it's worth testing to see, do I have this mutation, and especially, do I have it, and does my spouse have it, so that we can see, okay, what are the odds that we will have a child who inherits it's both broken copies and thus ends up with some sort of genetic disease? All right, so we really need to start wrapping this up. I'm sure we could keep talking about this for another for another hour, because, again, this is our specialty. We suffer the Curse of the specialist is there's so much stuff we want to talk about, we want to share, and we can only squeeze stuff in one hour. So dear in the best we can. Dear

Brian 43:33
listener, please let us know. Did how did we do? Did we actually talk this at a level that was appropriate, or did we, like, forget ourselves, because we were too much of a specialist in this.

Jason 43:44
Anyway. The take home from this, though, is that genes are the fundamental unit of information in biology. They're what pass information from parent to offspring. They're the raw material on which evolution acts, and Mendel is the one who found the first evidence of that. There's one little interesting aside here is that ever since Mendel's stuff was rediscovered, there's been an argument raging on whether he cooks the books a little bit, because people have pointed out the numbers he get are a little like, a little too close, or a little closer to what his theory would predict than you'd expect by actual random chance. But they're not so close as like, oh, okay, he definitely just fudged the numbers. And so people have argued back and forth for a century now over whether Mendel may have, like, fudged numbers just a little bit to make them fit a little bit better. But suffice to say, the theories that came out of the models that came out are correct and are the basis of modern biology and genetics. So that's the thing to take home.

Brian 44:40
Also, if he was, if he was cooking the books, then his Hank weed experiments, kind of throw that into some sort of like what I mean, he did a whole careful things, learned something really important, and then the second time he did it, it all fell apart. Maybe he would have picked something different, or, I don't know, whatever. It just doesn't seem like the act of someone who's putting their thumb on the scale. To me,

Jason 44:59
I agree. Yeah. So, all right, let's get down here. So, so nit pick corner, which I always feel bad calling the nitpick corner. I just like the, let's call it the improvement corner or something.

Brian 45:09
I think nitpicks are fine. It's just, again, we're very positive about these games, but I think it's, it's nice to have an opportunity to complain about things that are put I want to be reviewer two.

Jason 45:17
Okay, all right, Brian, reviewer number two, what would you change about the game?

Brian 45:22
No comments. It's perfect. Well, actually, no, I, I'm just getting in terms of comments about the game. The mutation die. The mutation rate is not only high, but the problem is that it is. It is a completely appropriate game mechanic, and that is why it exists. The problem is, is, if the real biology worked that way, and you were randomly mutating things that happen to look like your phenotypic trait, it wouldn't be the real Gene. And that whole idea of discrete genetics, you'd actually break the entire game. If you were really getting mutations that way and generating your traits, you would not be confirming it, because, again, we talked about all the different ways to break a gene. You're not going to break it the same way twice. You're going to make a new break, and maybe it's in the same gene, and it would be fine, but I don't know that that this is my nitpick, is the way that they're using mutation is real and completely inappropriate for the specifics of this game.

Jason 46:12
Yeah, and probably one of those decisions that was made for the sake of gameplay, like they wanted to represent mutation somehow, I don't think they wanted a one in 10 million chance of actually having a mutation. Because I don't think that's like at that point. Why even have the mechanic?

Brian 46:26
No, no, no, no. Yeah. I mean, you're right. Of course, I understand, and there's always that compromise for the sake of having an enjoyable game.

Jason 46:33
Yep, mine is, it's almost more of a curiosity question. So in genetics, when you have these traits and these alleles, you usually represent them by a letter and on the game board, it has the letters for these different traits, and it's usually like a capital for the dominant one and a lowercase for the recessive one. So like the round one is big R and little r, the flower color is big F and little f. The thing is, these aren't the symbols that are used by scientists. No, they're not. So R is the same for the wrinkled and round, but like the flower colors at the A locus, is that the A position? So these big A and little a, or the tall is not big T, little T, it's Le. For some reason, I don't know why green and yellow pod is actually Gp, instead of just g, so I would, I'd be interested why. I assume this is another one of like, let's make it easy. Because why on earth would flower color have A as a letter? I suspect it was just to make it easy for the people playing it. I just they never mentioned that in their little insert. And I'm kind of curious about that, because I never saw them referred to by the games ones anywhere, either.

Brian 47:42
No. I mean, you're right, it is, it is A and I guess, I mean, there is an answer. I just don't know it. I mean, I would guess anthocyanin perhaps, yeah, because anthocyanins

Jason 47:51
are one of the common pigments in plants, they're usually the ones that are kind of your purples and pinks and bluish ones.

Brian 47:57
So they, they use the same type of way that we would represent a dominant and recessive, which is the uppercase versus lowercase, but they didn't use the real gene names because or gene designations because it's confusing.

Jason 48:10
That's what I'm guessing. Yeah,

Brian 48:12
but would it have really been that confusing, though, because it's on all the cards. They could have just done it right.

Jason 48:17
They could have, but thinking with my game designer hat on that could be a friction point, and at least as a designer, unless it's important for the game, my goal is to remove as many friction points as possible, okay? And I think that particular one does not affect the game. It doesn't affect the science they're trying to portray. So I can agree with them changing

Brian 48:36
that, okay, all right, fair enough. Well, I mean, hey, oh, I guess we got to do our grades then, huh?

Jason 48:41
Yep, final grade. So how about you for gameplay? What do you think about gameplay here?

Brian 48:46
Gameplay? Um, I think I it's gonna get docked just a little bit as a game. That's actually kind of hard to learn. And I don't really, I don't really know how to get around that. I mean, everybody has a hard time learning just from the book. Do you primarily learn how to play games by reading the rule book? Is that your approach?

Jason 49:03
That's the first pass Yes, I'll either read. I'll read the rule book. I will watch how to plays. Sometimes the order of those, which one I do do first, which one I do second changes. But yeah, I will usually read through the rule book.

Brian 49:14
Okay? I usually watch the videos first, then read the rule book, and then kind of lay everything out to try to understand how it's going this one's way harder to learn than you'd expect for a game that once you've got it plays very quick and easily. I think I'm going to dock it just a bit for that, because the teach is difficult. I'm just going to give it a, B. They can argue with me if they feel like that's an undergrad. What about you?

Jason 49:34
Well, I'll argue with you. I was going to think about an A, but I think you bring up a valid point, that it is a little challenging to teach because of the moving parts and the way the order that the game happens is not the best order to actually teach it in. So I'm going to just say A minus, because I thought this was really fun to play. I enjoyed it. I managed to get my nine year old to play it multiple times, so she enjoyed it. So like, the game's fun. I like, once I get past that, once I get past. Has to learn. Once I understand what's going on, it plays relatively fast and fun.

Brian 50:04
I think if we're grading for the Wallace girls, we're really grading the rest of society on our curve, though you've been training them from like, you know, for as soon as they could talk how to play games. I think maybe, maybe they're not exactly at the mean on that particular bell curve?

Jason 50:22
I don't know, but I am very proud when I hear my 14 year old talking about, like, choosing the optimal play for the games we're playing. It's like, there you go.

Brian 50:30
Yeah. Well, she is your clone, let's be honest. She definitely got that trait from you.

Jason 50:34
Okay, all right, science, so give me a moment to think about this science grade for what it's trying to portray here. I think I'm going to go with an A minus again for the science grade. I think the core of it like, Oh, here's genetics and your Punnett squares and rolling the dice. I think that's fine. The place I'm going to dock it is actually in some of the ancillary stuff, some of the like, the tools you can use to accomplish certain things, and the like, some of the assistants, where, mechanically, they make perfect sense, they're giving you some access to an additional resource, or an additional thing to do that helps make your moves more powerful. But logically, it doesn't necessarily make sense. Like, why does the rake do this particular effect? I'd understand. Why does a pruning shear let me take another die, or something like that. I forget what all the tools do. The one that makes sense is the pollen brush, where you basically pick up the pollen and you brush it along all your different plants like that. One actually makes sense, yeah. And so that's it's like, it's that there's a little bit of a disconnect of the metaphor for me in those positions that said I do like the fact that one of the spots on the board is basically you paying the university money to do your research for you. So, yeah, I'll give it another A minus there.

Brian 51:49
Yeah, I think I'm actually comfortable with an A, and I'm gonna give it an A for the use of the Punnett Square and setting the parental genotypes to create the dice drafting system. I've seen other games do genetics in different ways. This is the only one I've seen where they're actually trying to replicate that process of genetic inheritance in a way that mimics how it happens in nature. Usually, there's just sort of a very, sort of a vague approach to it, but this is much more specific, and that practice with the Punnett Square is really useful. It's kind of in the same way that, like if you play cytosis and then go take cell biology, oh, well, you already know all the principles here. If you play genotype, you're going to understand how to do a Punnett square, because that you're just going to be doing it a bunch of times. You're going to be getting a ton of practice using Punnett squares and manipulating Punnett squares in a fun way.

Jason 52:37
Yeah, I'll agree with that. So I definitely think it would give a good foundation there. I wonder, because of the age range, this is ages 14 plus. So you're talking middle school already. I think many of those students have already been exposed to Punnett squares by that point, which may make the game easier to pick up. Who knows?

Brian 52:51
But, yeah, probably. But, I mean, like, again turning Well, that's not a bad thing. If they know how to use a Punnett square, it's just helping to reinforce it, right? Yeah, probably.

Jason 52:59
And, I mean, let's, let's face it, I mean, how much stuff does your average sixth grader remember by the time they get to eighth grade? So it's like a refresher, like this would be helpful. All right, I think we're going to wrap it up there. Keep an eye out. We may do a how to play genotype if you want to see more of that. If you're interested in the game, go pick it up from genius games or your friendly local game store. And with that, have a great month and have great games.

Brian 53:21
Have fun playing dice with the universe. See ya.

Jason 53:25
This has been the game of the Science Podcast, copyright 2025. listeners are free to reuse this recording for any non commercial purpose, as long as credit is given to Game of the science. This podcast is produced with support from the University of Georgia. All opinions are those of the hosts, and do not imply endorsement by the sponsors. If you wish to purchase any of the games we talked about, we encourage you to do so through your friendly local game store. Thank you and have fun playing dice with the universe. You.

Transcribed by https://otter.ai

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S2E07 - Genotype (Genetics)

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