so today we're going to continue with genetics and we're going to talk about the rules or laws of inheritance I expect that many if not all of you have been exposed to these rules before and so what I really want to do today is make the connection between these laws and the behavior of chromosomes such that when you're thinking about genetics and inheritance pattern you're thinking about chromosomes undergoing meiosis okay and I want to start just to make the point that there are a number of human traits and human diseases that show clear sort of inheritance patterns and what's shown up here is what's known as a pedigree okay so this is a pedigree I'll just block this off I'm showing you a pedigree which shows relationships and a family tree and so what you can see what these symbols denote are if you have a open box that is an unaffected male and so openbox is an unaffected male and what I mean by unaffected is and usually it means they don't have the disease that we're talking about okay circles represent females and so an open circle would be an unaffected female [Music] and finally if you have one of these symbols either male or female and it's shaded in that by convention represents an affected individual so that's an individual that has the disease or trait so this is an affected individual okay so this is an example of a disease that you've already heard about from Professor Imperioli this is a family tree that's indicative of a type of inheritance that's seen in families with a disease called phenylketonuria okay and you'll remember from Professor and Perry Ali's lecture this is a disease where there's a mutation or allele in which there's a defective enzyme that can't process the amino acid female v + O alanine and so patients with this disorder have to be very careful about their diet such that they don't in take too much phenylalanine okay and what you see about this this trait or disease is that it's skipping multiple generations and then it manifests itself down here I'm not getting any arrow so I'm just gonna use this pointer here so here you see there are several individuals there's a male and a female with the disease and its results from a relationship between two first cousins so only in this case does the disease sort of appear and you can think of this as a recessive trait in this case it's autosomal recessive so for PKU this is exhibiting what's a type of inheritance known as autosomal recessive and the reason that it's recessive is because if an individual just has one copy of a functional enzyme then they don't have the disease okay so you can see there's only individuals that have both defective versions which are labeled lowercase a here that exhibit the disease okay so in the case of PKU lowercase a represents the defective enzyme and uppercase a denotes a functional enzyme now it's not shown here but it's possible that our ancestors sort of like above this parental generation also exhibited this disease such that there would be a sign that this is being inherited across generations so that's not as obvious in this disorder because it's a very rare genetic disorder but more common disorders such as colorblindness show a more clear clear inheritance from generation to generation so um is anyone anyone here colorpoint I asked just to know how to set up my slides as well no one's colorblind okay we have a that's good then you'll all see the difference between the image on the left on the image on the right so if you have normal vision that's what you see on the left from this fruit stand but for those that are missing the red photo pigment in your cone cells you're you exhibit colorblindness and you had this fruit stand would look like the image on the right okay so this is a clear example of an inherited trait in humans and this is an example of inheritance pattern that would be similar to human color blindness and here you can see a clear example where you have an affected individual and affected Mal here that now has five daughters none of which exhibit the phenotype or disease but several of those daughters give rise to progeny sons that have the disease okay so in this case you see this trait skips a generation but essentially the grandfather here has passed on the trait to his grandsons okay and so color blindness is a little bit different from PKU not only in the fact that it's more frequent so it's about 10% of mouths exhibit color blindness in the population but also you see with PKU you had both a female and a male affected and in this case you're seeing a preponderance of affected males which seems to be not random okay and so this colorblindness exhibits a different type of inheritance pattern which is known as sex linked recessive and I'm going to come back to this inheritance pattern at the end of the lecture because it's actually this type of inheritance pattern which helped researchers about a hundred years ago make the connection between the unit of heredity the gene and chromosomes okay so we'll talk about a another example of this type of inheritance pattern at the end okay so for today what we're going to talk about is we're gonna start with some of the basic laws of autosomal inheritance and so we're gonna talk about Greg Ulm regor Mendel and his seminal studies in the pea plant and then towards the end of the lecture we're going to talk about sex linkage and I'm going to tell you about work done in fruit flies and specifically their eye color trait which led to the linkage between the behavior of genes and the behavior of chromosomes okay so that's what we have in store for today okay so first I'm gonna tell you a little bit about what enabled Mendel's theory I guess I could start over here so what enabled Mendel's theory and I presume that most of you have heard about Mendel before so there might be a little bit of a reminder for you but I also hope that we kind of make a very clear connection connection between Mendel's theory and the behavior of chromosomes so Mendel did his seminal studies using the pea plant and one aspect of pea plant biology that was really essential for Mendel's theory is that you can both self pollinate pea plants meaning you can take the male gametes from a pea plant and made it to the female gametes from the same pea plant so it's entirely within the same plant okay so you can self pollinate meaning you do a cross you basically cross a plant to itself which obviously we can't do with humans you can't do with many organisms or you can cross pollinate meaning you take the the male gamete from one plant and you combine it with the female gamete from a different plant okay and as we go through Mendel's experiments you'll see how this was used to define the rules of inheritance another property of the of the pea plants and something that Mendel took advantage of was he chose traits of pea plants that exhibit exhibited a very clear dominant or recessive phenotype okay you sure I'm okay so he used visible traits visible traits with a very clear dominance or recessive nasai and if we go back to our example of PKU you can see how this human disorder the genes that determine this disorder the alleles have a very clear dominance or recessive miss on the dominant allele is often odd denoted with a capital letter in this case for PKU we used capital letter a or the in this case the disease allele was lower cased heir a and that's recessive and if an allele has dominance what that essentially means is that being homozygous for the dominant allele is equivalent to having just one copy of that allele okay and so I think if you think of the PKU example this is very clear because the the disease phenotype results from a defective enzyme right so if you just have one copy of the enzyme that's functional then the the human can have wild-type or normal function okay so in order to really lack function of this enzyme you need to be homozygous for the non-functional allele okay so you need to not have any normal copy of that enzyme because if you just have one copy of that enzyme you're okay because you have an enzyme that's functional and will carry out that function in the cells of your body okay the last point I want to make is that Mendel did his experiments starting with what are known as pure breeding lines okay so started with pure breeding lines and what I mean by pure breeding are these are lines that if you take these plants and just self cross them over and over again generation to generation they will only give rise to plants with traits that reflect the parental generation okay so there's basically no variation and you'll see in just a moment that another way to denote pure breeding means that for a certain trait you have an allele combination which is homozygous okay so another way to think of pure breeding lines are these are plants that have a homozygous allele composition homozygous meaning that either they have two copies of one allele or two copies of the other allele okay okay I just want to make the point that Mendel had to overcome a number of hurdles in order to get these results and Mendel is not exactly you're sort of like you know clear clear example of the success story okay so Mendel applied to get a teaching certificate in University and he failed out okay and I'll quote one of instructive his instructors who said I quote he lacks in sight and the requisite clarity of knowledge okay so that guy feels stupid so next so Mendel did his experiments and and the significance of his work was never recognized throughout his lifetime he did his experiments in the 1850s and 60s he died in 1884 he died not knowing at all what the significance of his work was because his work was then found again in the early 1900s by the likes of Thomas Hunt Morgan and others and they made the connection between Mendel's laws of inheritance and chromosomes and it was really then that Mendel became the father of genetics right because then then there was a physical model for how inheritance was working and but he died before that happened right so he didn't realize that he was the success that we now know him to be another interesting story he started his work with mice he wanted to like breed mice with different coat colors but he got in trouble with with his bishop because his bishop didn't approve him of promoting sex among these mice luckily his bishop doesn't didn't take a plant biology course because of course plants also have sex but he had to under come a number of hurdles but he took advantage of his garden and I was talking to someone in my lab the other day and she said you know what's great about Mendel he had a garden and he just didn't put it on Instagram so you know he used his garden to his advantage and so with his modest garden he came up with what are now known as the rules of inheritance and I'll start with Mendel's first law so Mendel's first law is that every adult has a pair of genes for a given trait and these are now what we refer to as alleles and we now refer to them as genes as well Mendel did not use the term gene he just had these abstract sort of units of heredity okay so his first law states that every adult has two sort of units of heredity they can be different and that they split during the formation of the gametes okay and the probability that Gami will have a given allele or a given unit is equal probability okay so what I hope you can see is that this law which is stated up there is a direct result of the segregation of homologous chromosomes during meiosis 1 ok Mendel did not know that but now looking back we can see how this manifests itself and so during metaphase during meiosis 1 you recall that the homologous chromosomes here line up at the metaphase plate and they line up opposite each other such that some of the gametes will get the capital Y allele shown here and the other half of the gametes will get this lower case Y allele okay so there's a 50% probability of a gammy either having one or the other okay and of course in meiosis one this is referred to as a reduction older vision because the Hama homologs are split and so the genetic content of the gametes are divided into half okay so Mendel's first law the evidence for it were the results of a what is known as a monohybrid cross okay so Mendel did what is known as a monohybrid cross where he took pea plants that pure bred for two were pure breeding for two different traits well one was their pea color so his yellow peas versus green peas and he made a hybrid where he takes a yellow plant that arises from yellow peas and crosses it to a and from green pea okay and this is known as the parental generation and so the result of this cross is that all of the peas were yellow so a hundred percent this this cross results and eat a hundred percent yellow peas this is known as the first filial generation or the f1 okay and that should indicate to you which of these traits is dominant because if you take yellow peas and you cross it to green peas and you get yellow peas that means that the trait for yellow peas is dominant okay so for the rest of this I will denote the gene allele that confers yellow peas as capital y and the gene allele that encodes for green peas is lowercase Y and you see what I'm doing here is I'm putting the phenotype and describing the phenotype there which is just what the trait is that manifests in the organism but the genotype which is the combination of alleles of in the organism I'm showing beneath the phenotype okay and if these gene alleles are splitting during gamete formation and then recombining during the formation of a new plant then in this case this hybrid plant is going to be it's going to have one allele that's capital y and one allele that's lowercase Y and because these two alleles are different this situation is known as heterozygous so this is a heterozygous plant you can think of sort of pure breeding being analogous to homozygous because if you cross yellow pea plant to itself you will only get back yellow peas so it breeds true you can think of a hybrid as being equivalent to heterozygous because there are two gene alleles okay so then what Mendel did is he didn't stop there he self he self crossed or self pollinated he's f1 plants and looked at the resulting seeds and so in f2 generation what he found is that he got back both the parental phenotypes so 70% 75% of the progeny were yellow had yellow peas and 25% had green peas okay so there's this three-to-one ratio here okay now we can think of this if we think about this in terms of Mendel's first law where there's a segregation of these alleles during the formation of gametes and there's an equal probability of having either one of these alleles if we think about this cross here these plants both the male and female side are producing gametes that are either big Y or little Y so this would be the female here and so because they're separating and there's there's a 1/2 probability of having either the capital y or little Y allele for the male and there's also a 1/2 probability of having either of these alleles for the female okay so if you look at the possible combination of gametes that could give rise to the f2 generation you have some that will be pure breed yellow okay and the probability here would be the joint probability of having this gammy and this gammy which is 1/4 you then have two classes here that have one copy of the dominant allele and one copy of the recessive allele all right so these will have the same genotype and these three will have the same phenotype they'll all be yellow peas right and so if you add up the probabilities of all three of these you can see that 3/4 will be yellow so 3/4 of the progeny will have the yellow phenotype and you can see that another quarter of the progeny have the chance of getting two copies of the recessive allele and therefore will be green ok so just by considering this as a probability problem which is what Mendel did you can explain the ratios of the progeny that Mendel observed in his crosses okay and I want to point out the parallels between this simple cross with peak with our peas and the inheritance pattern shown by PKU or phenylketonuria so notice here you have green peas in the parental generation but Greenpeace skips a generation and only appears again in a subsequent generation okay so that's a lot like PKU right where you can see there's multiple generations that go by where the trait doesn't manifest itself but then it pops up again in that later generation where you have inbreeding in this family okay so there there's a clear connection between the results that Mendel got in cases of human disease okay now we're gonna go on and talk about Mendel's second law [Music] so Mendel's second law which is often referred to as the law of independent assortment and another fortuitous thing in thinking about Mendel's experimental design and set up which was fortuitous he didn't know it at the time he chose traits that actually were present on different chromosomes of the pea plant okay so the traits didn't exhibit what is now known as linkage where they're physically connected on the chromosome okay so this law of independent assortment can also be explained by thinking about how chromosomes behave during meiosis where the alignment of homologous chromosomes chromosomes at the metaphase plate of meiosis one is essentially random okay so if we take a look at this example here you can see I've drawn one particular configuration for the chromosomes and I'm using sort of one gene pair here and another gene allele pair here and so if the chromosomes were aligned this way then when they segregate during meiosis one you'd get two classes of gametes some that are capital y capital R and another class that's lowercase Y and R okay so that's one possibility but what's equally probable during the alignment of chromosomes during meiosis one is that the chromosomes line up like this so rather than having the the dominant alleles all on one side of the metaphase plate you the dominant allele for one homologous pair on one side and the other dominant alleles on the other side okay so how they arranged how these homologous chromosomes arranged during meiosis is totally random okay and if they arranged like this you'd get alternative types of gametes you get gametes that are uppercase Y lowercase R and lowercase Y uppercase R okay so this law of an independent assortment is can be completely explained by the behavior of the chromosomes during meiosis one okay so now I'm going to take you through the experiment that will illustrate this and this type of experiment is what is known as a dihybrid cross and so a dihybrid cross is now a cross where you're taking plants that differ in two traits rather than just one okay so dye stands for two and in this case we're going to consider both pea color again the pea colors are yellow and green but now we're also going to consider P shape so you can have peas that are round and peas that are wrinkled all right I'm gonna make use of this board again so let's consider the round wrinkled case if you set up a cross between a plant that was from a round seed and a plant that was from a wrinkled seed and let's say the round phenotype or the round allele is dominant what would you expect to see in the f1 so you have yes Carlos you'd see all round exactly right okay so let's go through now this cross so we're gonna have a parental cross where Mendel took two pure breeding lines one of them is has yellow round peas and he crossed the plant from a yellow round pea with a plant that was derived from a green wrinkled pea okay and we already know yellow is dominant and as Carla Carlos just pointed out if round is dominant then you'd expect all the peas to be round as well so in the f1 generation what you get what Mendel found is you have a hundred percent of the progeny that are yellow round piece okay and then similar to the monohybrid cross Mendel self crossed this these f1 plants and by self crossing them he observed a number of different he observed a number of different classes of progeny so he got back the parental types yellow round he also got back this other parental type green wrinkled okay so these because these were the same combination of traits that were present in at least one of the original parents are known as parentals their parental they have the same parental phenotype as one of the original parents but what Mendel observed was two other classes of progeny which were different combinations of these traits that weren't present in the original parental generation so those were yellow wrinkled peas and green round piece so you'll notice that this combination of traits yellow and wrinkled is not one of not present in the parental generation this is all f2 this is f2 continued you also see green and round we're not present in the parental generation so these are referred to as being non parental so these this non parental class is a unique combination of traits that wasn't present in the original parents ok and what Mendel noted was that in these dihybrid crosses he always got a stereotypic ratio of 9 to 3 to 3 to 1 for these different classes of combinations of traits okay now we have to think about the probability what what leads to this characteristic ratio and again we can think about this just in terms of probabilities and these different gene pairs segregating independently of each other so we already talked about for a monohybrid cross for p color 3/4 of the progeny is yellow right because they at least have one dominant allele for color and 1/4 are green okay so the probability of having this phenotype is 3/4 the probability of being green is 1/4 and you can consider peed shape as just a sin just a separate monohybrid cross where the round the dominant phenotype is also going to be present at 3/4 probability so three quarters are going to be round and 1/4 is going to be wrinkled okay so now if we just consider these different classes of progeny here we can consider two monohybrid crosses and what's the joint probability of being both yellow and round ok so the joint probability of being yellow and round is 3/4 times 3/4 so if we have 3/4 times 3/4 that's going to equal 9/16 okay now if we consider yellow and wrinkled that's the joint probability of 3/4 and 1/4 so this probability is being 3/4 times 1/4 which is equal to 3/16 green and round is similar it's 1/4 probability of being green and a 3/4 probability of being round so again you have 1/4 times 3/4 which equals to 3/16 and the least probable class is being homozygous recessive for both allele alleles because there's a 1/4 probability of being recessive for each so the joint probability of having all recessive alleles as 1/4 times 1/4 or 1/16 okay so you could draw a massive punnett square and also derive this but really you can just consider it as two separate monohybrid crosses and then just calculate joint probabilities okay any questions on Mendel before I move on I'll just point out one thing about Mendel's second law this is this is a rule that I'm gonna break now in just a minute and this law of independent assortment assumes that there is no linkage in an other war in other words it seeing this type of inheritance pattern really depends on the two genes not being physically connected to each other on the chromosome okay now we're going to talk about fruit flies and specifically we're going to talk about a certain trait in fruit flies which is their eye color I brought some pets to class today and so we're going to talk about the white mutant phenotype where the fruit flies have a white eye color so I have three pairs of vials here and one of them there's the white mutant and you're gonna see that has white eyes and then there's also a corresponding sort of normal red-eyed flies and the other vial so I'll just pass these around hopefully there's enough light that you can see the eye color you're able to see the eye color Jeremy is yeah you might have to come up to the board lights at the end of class if you want to see it really well okay so we're gonna fast forward from Mendel now and talk about researchers who picked up on Mendel's work in the early 1900s and specifically I'm going to tell you about research done in the lab of Thomas Hunt Morgan who had a fly lab at Columbia so we're going to talk about Thomas Hunt Morgan and actually we're gonna focus a lot on work done in Morgan's lab in the next couple lectures because it turns out his lab also made the first genetic map and we'll talk about that in Friday's lecture so what the type of inheritance that Morgan defined is what is now known as sex-linked inheritance where a given trait isn't a sorting independently of an organism sex but is somehow connected to it okay and I want to sort of return your attention to this example of human color blindness where there appears to be some sort of connection between the disease phenotype in this case colorblindness and the gender of the individuals right so you see this disease is only affecting males okay and this type of inheritance pattern while observed in humans was really explained by work done in flies on this white mutant that you're carrying and through the class okay so sex-linked inheritance the explanation for that is this is a trait that's carried by a special type of a chromosome known as a sex chromosome okay so fortunately for us flies like humans have a similar set or we have male flies and humans have an X in a Y chromosome okay so it's the inheritance kind of is similar between flies and humans when considering sex linkage and females have two x's okay so the presence of these sex chromosomes was known in the fly and it was known that if a fly had an X in a Y chromosome it would be a male fly and if a fly had two x chromosomes it would be a female fly and normally normal flies have red eyes but Morgan's lab was interested in variation in organisms and they searched and searched for flies that had abnormal characteristics or traits and what they found in Morgan's lab was a mutant fly it was a spontaneous mutant but this fly had white eyes and it was male so they find found a single white-eyed male which they continued to study for some time so they sort of defined some of the rules of its inheritance so what Morgan and his lab did was they set up a set of crosses that that look a lot like Mendel's crosses okay so you have a white-eyed male they took a white-eyed male and they crossed this white-eyed male to a red-eyed female okay and if you cross a white-eyed male to a red-eyed female what Mendel the result was actually similar to what Mendel had predicted which is that a hundred percent of the Flies had red eyes okay so that's similar what to what you would expect from a monohybrid cross where red eyes is dominant so I'm going to refer to the red-eyed allele as an X with a capital R and the white eyed allele is an X with a lowercase R okay because this gene is present on the X chromosome but it's not present on the Y chromosome okay so the Y chromosome is really small and so the X chromosome has all of its genes are basically present in one copy in the mouth okay and that's gonna manifest itself in that sex linkage okay so then they took this f1 generation where you have red eyed males and they crossed siblings so they did a sibling cross the one failing of flies as a genetic system is you can't they can't self cross you have to have a male and a female so they crossed two individuals in this f1 generation and what they found again similar to what Mendel would predict is that 75% of the Flies had red eyes and 25% had white eyes so this is behaving a lot like like the yellow trait in peas right except that all of the white eyed flies in this f2 generation all of these white I had felt when I'd flies were male so only the males were getting this trait of white eyes okay and you can see that that's very much reminiscent of colorblindness where you have a grandfather that has white eyes right and the grandfather is essentially passing on this trait to his grandsons okay so this pattern of inheritance that happens in the fly is very similar to that that happens in humans okay so now let's think about how this if we can explain this by thinking about chromosomes segregating so if we think about the this f1 generation we have red-eyed males or actually let's do the parental cross first where we have white eyed males and we have red-eyed females so all of the females are going to get their X from their dad and they're going to get a wild type copy of this gene from their mom so all the females are heterozygous for the white gene so I'm gonna call it the white gene because that's what it's called and flies if you when they name the genes based on the mutant phenotype so if you mutate it and it results in white eyed flies then they call it the white gene all the males are gonna have a functional copy of the white gene and thus all of these f1 flies are red-eyed okay so now these siblings are mated all the females are heterozygous for this gene the males all have a functional copy of the gene so they're going to make gametes that are either a functional X that's functional for this I color or the y-chromosome okay so now what you see is that all of the females are going to get this normal copy of the gene from dad and thus are gonna have red eyes whereas half the nails are gonna get a functional copy from mom and therefore have red eyes but the other half of the males are going to get this non-functional variant that can't produce red pigment and therefore are going to be white okay so this here is your white class and you can see because males only have one X chromosome the only class of progeny that's going to be white eyed here are those males that occur with a quarter of frequency okay one thing I want you to think about over the next couple days and I'll I'll sort of take you through it at the beginning of next lecture is what would happen if you set up a reciprocal cross here right what if you made it red I'd males to white I'd female okay and I want you to tell me what you expect would result so my question for next Friday is what if you took red eyed males and mated it to white eyed females so I want you to think about this and I want you to think how this is different from Mendel's experiment what if you did a reciprocal reciprocal cross for let's say the P color how would these two different crosses compare with each other okay and we'll talk about that at the beginning of Friday's lecture and we'll also talk about the first genetic map which was actually created by an undergraduate so stay tuned for that see you on Friday you