hello welcome to our online lecture for the course pathophysiology 1 in today's lecture we're covering genetic diseases in particular we'll be focusing on mutations chromosomal aberrations or alterations and then we'll finish up by talking about how genetic diseases are transmitted before we get into the pathophysiology of genetic diseases we should review some normal anatomy first of all if this DNA that you can see here in its super coiled form wants to replicate itself it needs to unwind and remember that DNA replication occurs during S phase of interphase during the cell cycle we want to replicate our DNA so that we have equal DNA in either cell after mitosis in order for DNA to replicate itself though it needs to unwind and unzip which you can see starting to happen here and you can see what it does is it exposes the nitrogenous bases and DNA has nitrogenous bases cytosine guanine adenine and thymine and when these bases are exposed it allows for its complementary match base to pair with it and recall that cytosine and guanine will always match with each other they are considered complementary base pairs and adenine and thymine as well will always match with each other and so what you can see happening with the help of DNA polymerase is we're going from one DNA strand to forming two DNA so we end up with a replication of DNA now just a few minutes now on transcription and translation which is different than DNA replication which we just spoke about so again DNA will replicate itself during S phase of interphase in order to prepare for cell division but what is the ultimate purpose of DNA well we know that it carries the genetic information to produce a variety of different I mean so many different proteins in the body but the first thing that has to happen in order to get ready to produce a protein and and and give the instruct proper instructions is it has to be transcribed so in the nucleus what ends up happening is a particular segment of DNA so we would call this than a gene is going to be made into a copy and that copy of that genetic information from that gene is going to be in the form of mRNA I'd like to remind you that that mRNA or RNA possesses the base uracil instead of thymine we have uracil and what will end up happening is this copy of that segment of DNA called mRNA once it's been edited and spliced and really finalized into its final final form it's going to leave the nucleus and you can see that happening here that it's leaving the nucleus and it's going to travel to a ribosome where protein that's synthesis will occur I'd like to remind you of the term codon a codon is a set of three nucleotides so just for example this could potentially represent a codon this could represent a codon and the ribosome is really going to be reading the RNA at three nucleotides or rather three nitrogenous bases at a time and that's called a codon and a codon is then part of RNA once that mRNA reaches the ribosome tRNA is now involved and tRNA is going to be bringing a specific amino acid to the ribosome and it's going to be a specific amino acid that's meant for a particular area of the mRNA you can also see that tRNA possesses what's called an anticodon and really it's the anticodon that will match perfectly with the codon at the level of the ribosome and you can see that happening here and then surely one by one as transfer RNA brings a different amino acid to the ribosome we end up forming a whole bunch of amino acids that are bound by peptide bonds and this forms our polypeptide and then once we get other polypeptides together we can form a protein but the most important thing to from this slide then is that in order for a polypeptide and then a protein to be formed properly it's dependent on the sequence of amino acids to be in a particular sequence and as soon as there's a change in the amino acid sequence in other words as soon as there's a change in what is actually originally coded for the development of that polypeptide or that protein then problems can arise and we'll talk about that on upcoming slides we'll start with mutations so a few important definitions that you need to know of with respect to the topic of genetics the first one being mutations a mutation is as stated on the screen a change in the sequence of a gene and there are over 20,000 genes in the human genome a gene as I already told you on the last slide is a segment of DNA and it contains very specific information coding for a particular polypeptide and subsequently a protein a mutation will involve any alteration of this genetic material or of this DNA and this can be something that's inherited but not necessarily it doesn't have to be inherited mutations are considered very rare events in the grand scheme of things now as a cell prepares to divide remember this includes the replication of DNA which happens during S phase several checkpoints exist in the cell cycle where the cell or or the DNA is going to be checked in order to make sure that it's normal and let's say DNA is discovered to have replicated abnormally or something's abnormal within the cell in a lot of cases our body can take that cell put it into a repair phase repair any of the issues repair the DNA and then let that cell re-enter the cell cycle to continue its process for cell division sometimes though we can't repair these errors and in these cases our body will hopefully undergo the process of apoptosis or programmed cell death in order to not allow that cell to divide once we realize it's no good and we can't fix it we don't want to be replicating it because once you once you divide and then we sell it will just continue to divide at that point and this is where conditions such as tumors and cancer etc can occur a mutagen this is an agent that's known to increase the frequency of mutation now not all mutagens are considered equally potent meaning that some are are more likely to cause problems than others and in lesser quantities potentially but mutagens can be physical an example is ionizing radiation so an x-ray they can be chemical an example of a chemical could be formaldehyde and sodium nitrate which have different potencies in terms of how mutagenic they are and they can also be biological such as certain viruses for instance HIV has the ability to dump it's infected DNA into a healthy cell infecting that healthy cells DNA causing mutations to occur but we're exposed to mutagens all throughout our lifetime and a lot of times they don't end up causing any problems but of course they still can they're generally speaking the effects of the mutation are commonly irrelevant to cell function and are therefore considered to be silent in a lot of cases so it doesn't change the function of the cell it's such a minor mutation so it doesn't have an any grand impact and so these silent mutations are ones that can't really be detected under most clinical situations so they're not very evident a genetic testing may yield that there's been some mutation but it's not otherwise obvious in other cases it could be sub-lethal it could be something that then could lead to a disease lethal mutations can cause for example miscarriages or stillbirths two main types of mutations exist we have base pair substitutions and frameshift mutations and we'll speak it with the specific types of each of these on upcoming slides I'll let you know now that we will not be elaborating anymore on silent base pair mutations because we've already really discussed them they don't really have a they're not obvious clinic and the reason that they're not obvious clinically is because it doesn't really affect the sequence of a gene okay so let's talk about just actually go back here for a moment for base pair substitutions we're gonna talk about my sense and nonsense base pair substitutions exist as relief three basic types but to our we're gonna focus on here and those are as I said my sense of nonsense my sense mutations occur when one base pair is substituted for another one base pair is substituted for another and this will cause a single amino acid change in most cases and I'll show you what that means in a moment on the image but because of the redundancy of our genetic code sometimes there's no consequence of this and and or there might not be any profound issues so let's have a look at this image here look at my pens that I can circle the example here you can see and we're gonna talk first normal DNA this is the normal mRNA copy of a gene and then here would be the polypeptide formation and remember that polypeptides are going to be amino acid test amino acid attached to amino acid by peptide bonds in this normal DNA sequence you can see that we have guanine and cytosine and mrna has taken a copy of guanine and then we have this codon here which consists of three nitrogenous bases and three nitrogenous bases will code for a very specific amino acid so their position in this order will code for a specific amino acid meaning net tRNA transfer RNA is going to be is going to bring a particular amino amino acid in this case this one to the ribosome where it sees this codon so it's attracted to this particular codon or group of 3 a nitrogenous bases but with base pair substitution what you can see happening is that GC is now substituted for 80 so GC that that complimentary bond gets kicked out and adenine and thymine move in nothing else though has changed if you compare both the normal DNA to this my sense mutation except for the fact that adenine and thymine as a base pair is substituted themselves in and so when mRNA makes a copy you can see that it now takes adenine as part of it and now here's our codon which has gone from AG C to AAC which means that transfer RNA is going to bring a different amino acid to that right to the ribosome and you can see that different amino acid here so all the other amino acids have stayed the same because of that one base pair substitution but because of that one change that leads to a potentially different polypeptide one that may not have the same function as it's supposed to have and that's called a my sense mutation and so the effect them will be dependent on how critical that particular amino acid is for the function of that polypeptide or that protein now in the next example of base pair of substitutions we're talking about nonsense mutations and nonsense mutations involve where one base pair is replaced to another but so replaced by another so very similar to what we just spoke about however this substitution ends up producing what's called a stop codon and we'll look at what that means in a moment and there are three different stop codons that exist which I'm highlighting at the bottom of the screen and what this ends up doing when there's a nonsense mutation is the stop codon will actually produce a premature stop in the mRNA in other words they're going to terminate the translation of the protein or the polypeptide and so our polypeptide or our protein will end up incomplete so what does that mean well once again let's look at we have normal DNA normal mRNA cop of a gene and then we have a polypeptide made up of the following amino acids and so what we're gonna look at here is CG cetas ena and guanine in a normal DNA strand when mrna takes a copy it has cytosines these 3 nitrogenous bases or this codon is going to code for this amino acid in a normal situation but in the case of a base pair substitution in a form of a nonsense mutation we've substituted adenine thymine which produces adenine in the mRNA strand and what this does of course has change the sequence and it now produces this UA a codon this is one of three potential codons that when present can put a stop in the amino eye or in the polypeptide chain and so instead of continuing on and with more protein with additional amino acids forming a polypeptide we end up with a premature stop so ultimately the protein is incomplete frameshift mutations are another type of mutation and they involve insertions and deletions frameshift mutations are a type of base pair substitution or rather they're not a base pair substitution they're a type of base pair insertion or base pair deletion so this really involves then inserting or deleting one or more base pairs into the DNA molecule rather than substituting it so you end up with a gain or a loss and so these mutations will change the entire reading frame of the DNA sequence because this deletion or insertion is not a it's not a multiple of three base pairs so it ends up causing a shift and we'll look at that in a moment and so what it does compared to our other examples is the amino acid sequence is going to be totally altered downstream from that point of the insertion or the deletion so let's look at an example and then I have another example on the next slide that should be helpful as well so this is an example of an insertion and you can see that if you compare to the normal DNA strand here you can see that cytosine and guanine were inserted so not substituting for another it's not like one base pair is removed and this one is added in its place it's completely just inserting itself and it's inserted and it's inserted in itself in between here and so what this will end up doing very similar to our other examples is it causes a shift it changes the sequence of amino acids afterwards so you can compare then to here and to here we have different amino acids but not just one but all amino acids downstream are going to be affected so let's look at and the same would apply with a deletion but we'll look at an example on this slide so that it hopefully makes more sense in the case of a frameshift deletion you can see here that I mean and adenine the space pair has been removed and when it's removed everything is going to shift downstream so if you looked up here this would have been a codon this would have been a code on all coding for a specific amino acid but now it's shifted where this is our new codon this is our new codon and so on and so forth and then the same applies with insertion which is an example we gave on the last page where we're just inserting guanine and cytosine again shifting the entire amino acid sequence downstream so this can have grand effects but in simple form if you think about if you're reading a sentence and and I removed or deleted words or maybe I inserted new words it's going to change the nature of the sentence that you're reading and what what it really means so let's look at another example of base pair substitution so we're going back to the first type of mutation we were referring to where we could have a silent or my sensor nonsense mutation here is a list of all of the different amino acids and then there are three letter code and you don't of course need to to know these but this group of twenty amino acids are going to in different orders create different polypeptides and different proteins so if you're looking at this normal DNA sequence here here's the normal mRNA sequence and it's going to form a normal polypeptide so you can see this codon is going to code for valine this codon and so on and so forth and then it produces this beautiful polypeptide chain that was originally designed by the DNA within our nucleus but if we look at another example in a silent mutation we have in this mutant DNA we've compared to normal we've had the insertion or substitution rather of adenine and thymine and so you can see the change here it substituted for guanine and cytosine and so the mRNA copy done is going to take is going to consist of adenine rather than guanine and so if these if these three let's erase that so it's clear if these three code for leucine with our base pair substitution now we have these three so we've gone from uug coding for leucine to uu a but look at that that codon still codes for the same amino acid and this is where the redundancy of our genetic code allows for certain things like this to happen without actually creating an obvious effect so it's considered a silent so we did not change you can see normal polypeptide we did not change the polypeptide in therefore the protein looking at the next example of sickle cell mutation will talk about sickle cell at a different point but just to show you an example so here's our mutant DNA compared to normal DNA and we have mutant RNA because of this substitution here which produced uracil as part of the mRNA strand so we have the codon of G UA which codes prevailing but what should have happened is adenine and thymine copy beam a we have G a a which codes for glutamine and so you can see that there's been a complete change in the amino acid and just this one change has had a great effect in creating it what's called sickle cell mutation so let's not speak about chromosomal aberrations or alterations an aberration is defined as our chromosomal aberration is defined as any change in the normal structure or number of chromosomes and this can often result in physical or mental abnormalities a few reminders of important terms for you about chromosomes human cells can be categorized as somatic cells and Gammy's somatic cells include all cells except your gametes so the gametes remember are your sperm and egg cells and each somatic cell has 46 chromosomes or we can say 23 pairs and we call these diploid cells and they have the term euploid and that's referring to them being in their normal state and with their normal number now each pair we know is donated one by mother and one and one by the father we know that that new cells are formed by the process of mitosis when it comes to somatic cells now a somatic cell that does not contain the normal number of chromosomes so 46 so if it has either less than or greater than 46 chromosomes it's considered not euploid which is normal but aneuploid we'll talk about those examples soon gametes which we know our sex cells are haploid they're also euploid and they're normal number and we know that one member of each chromosome pair is going to be so thick if it's the egg cell it's gonna be only the maternal DNA if it's the sperm cell it's only gonna be the paternal DNA but if there is a if a gamete cell contains less than or greater than 23 chromosomes in it so at a excel or sperm cell it's considered not euploid but aneuploidy so what reminder that this image here is showing you a karyotype and i want you to remember that the first it's gonna pen the first 22 so all of these here are autosomes autosomal chromosomes and they're present in both males and females and then this final pair here is the sex chromosomes which are going to vary depending on if you're male or female so xx for female XY z-- from XY for male and these all of these that I circle the first 22 are considered homologous autosomes they each pair is identical in terms of the information that they carry now this sex chromosome is only gonna be homologous if it's XX carrying the same information it's not considered homologous then if it's XY because the X and y chromosomes contain different information now everything I just said is summarized on on this page but we're going to now get into details as to why all of this information is important so I want you to remember that a euploid cell is normal so why is it important to look at differences in chromosomal number and structure well chromosomal abnormalities are the leading cause of intellectual disabilities as well as spontaneous miscarriages which usually occur before the 20th week of pregnancy they're common as well they occur occur in about 50% of early spontaneous abortions and in about one of 150 live births two different types of chromosomal aberrations exist we have numerical and structural when starting with numerical when a euploid cell so a normal cell is not a normal cell anymore and it contains more than the normal number of chromosomes it is said to be instead of euploid it's said to be polyploid or polyploidy and some examples if you have a zygote that has three copies of a chromosome rather than the usual two then this is a form of polyploidy called triploid II so 23 is the normal x 3 of each instead of 2 of each and that gives us 69 and nearly all triploid fetuses are spontaneously aborted or miscarried or occasionally is stillborn tetraploid is a condition where a euploid cell instead has a total of 92 chromosomes so referring to the four here four times the normal number of chromosomes we also have instead of two we also have pent employee so five times the normal number of chromosomes and hexaploid II is sick times triploid e and tetraploid e are the most really the most common of all of these triploid e and tetraploid e they account for about 10% of no miscarriages these these two numerical chromosomal abnormalities know a cell that has a an abnormal number of a single chromosome so going back here remember this condition of polyploidy is affecting all of the chromosomes so they have extras of all of the chromosomes so not just one or two but all of them now in the case of aneuploidy this is where there's an abnormal number of a single chromosome so in the case of aneuploidy it's important to consider the fact that it you could have an extra or you could have one less and the general rule of thumb is loss of a chromosome has more of a serious effect than duplication or having an extra chromosome the first example is monosomy autosomal monosomy so remember affecting the first 22 chromosomes or one of the first 22 chromosomes this is oftentimes lethal and so these individuals mono refers to one one of their chromosomes is missing so they might be missing this one or they might be missing this one this is usually lethal monosomy of the sex chromosomes if someone just has a why they won't survive we know how little that Y is and how little information it does contain so these individuals will not survive but monosomy of X can survive so if you have a female that that only has one X chromosome monosomy of the X chromosome she can survive trisomy try refers to three of the autosomes can exist and when you have trisomy of 13 so 3 of 13 or if you have three 18 or 3 of 21 these cases can survive these are known chromosomal abnormalities of Ave you played cell that can or an aneuploid cell that can survive tries me of the sex chromosomes so if you have a female let's say that has three x's and this is the only example I'm giving you often times this extra X is inactive so it ends up not being too much of a problem and these individuals can survive no structural problems also exist in a variant type we'll talk about deletions duplications and versions and translocations coming up so let's first look at an example of aneuploidy this is an example of trisomy in particular trisomy of the 21st chromosome so where we have if you look around we have you can see we have two of every chromosome in this karyotype but here we have three of the 21st chromosome and you would know then that this is caught this is Down syndrome because you've heard of tries to triz me of the 21st chromosome I'm sure this comes along with a lot of issues such as intellectual disability there's an increased risk that they're going to have problems with their heart from birth congenital is from birth immunosuppression is also common so they're more likely to develop conditions respiratory infections for instance they're also more likely to develop cancer of the blood so leukemia there's also an increased risk of Alzheimer's like or Alzheimer disease like symptoms after the age of 40 so if these individuals live until 40 or later they start showing Alzheimer like symptoms 97% of Down syndrome is caused by what's called nondisjunction so what does that mean well remember remember thinking back a year ago when you spoke about how chromosomes can when they when DNA replicates itself and we have these chromatids or sister chromatids that are attached by a centromere during during cell division in this case meiosis one and two these should be separated and pulled apart but sometimes they're not sometimes these sister chromatids don't undergo disjunction which is normal and if they don't undergo disjunction what ends up happening is instead of and this is just a very very simple example instead of one of these going here and one of these going here to a new cell what ends up happening is this entire thing ends up going into one cell which leaves nothing of that chromosome in the other cell so what you end up having let's say this is an egg cell is that a sperm cell that unites with this one is going to produce three because it's gonna give it's one copy there's going to be three in that final zygote of that particular chromosome and then if it's this one that happens to unite with a sperm cell what's gonna happen it's only gonna have one in it and so we all end up with cases of monosomy or trisomy depending on what which egg is fertilized so this is more commonly going to occur in females and if we look at this graph here you can see that this is maternal age you can see that the risk of Down syndrome or cases like this this nondisjunction it goes up with maternal age so chromosomal abnormalities are more common as a female ages and you can see that there's quite a spike after the age of 35 male sperm tend if they don't because they're produced all the time ongoing they don't undergo these same issues as frequently as females whereas a female her eggs are really as old as she is so 35 year old year old eggs so when they start to age they don't necessarily do what they're supposed to do all of the time and the last the last thing I wanted to mention about Down syndrome is the life expectancy is is 60 at most provided that they survive beyond ten years if a lot do not survive past the age of ten they also have a low IQ and this can constitutes their intellectual died disability in addition to the loss or gain of a whole chromosome parts of a chromosome can be lost or duplicated as gametes are formed and so ultimately this can change the arrangement of genes on a chromosome so altering them let's start with deletions so again we're talking about chromosomal structural alterations we just spoke about functional earlier with deletion some part of a chromosome can be broken off or lost essentially deleted so in this example here if this is normal in a structural alteration where deletion occurs this part here ends up being broken off and deleted and then what we're left with this combines over here is this here so we've lost genetic information this is considered unbalanced because of this loss similarly you can gain parts of a chromosome so for instance if this here is duplicated look how much extra information and the same thing applies with when I spoke about how you're better off having more of a chromosome than less in terms of number same thing with structure it's better to have more of or extra of than loss and so this duplication is considered a gain but of course it's still unbalanced now we have two other examples inversion and reciprocal translation with inversion this occurs when there are two breaks that take place on a chromosome followed by the reinsertion of that broken fragment at its original site but in an inverted order so let's show you one here so that makes a little bit more sense will we end up with is with inversion you can see B and D in this case are considered broken so B breaks D breaks then when they break off well then they read and up reinserting themselves but in the opposite order now unlike deletions or duplications as we spoke about earlier there's no loss in this case and there's no gain of genetic material so inversions are considered a balanced alteration of a chromosomal structure and oftentimes they won't have any major or at least apparent physical effects however some genes can actually be influenced by their neighboring genes in other words if B let's erase this if B has the ability to be influenced by a or C then it becomes a problem if B is now in a different place and this is called position effect when which is just a change in a genes expression caused by its position because of its influence of neighbor gene neighboring genes and so sometimes this can result in in obvious defects in nice in this individual though inversions can cause serious problems in offspring of individuals that carry the inversion so for instance if somebody carries this you may not even know it but then when they have a child that child is now at risk of duplications and deletions because they inherited the inverted gene translocations so this says reciprocal translocations I'm going to first tell you what translocations are a translocation so this is different than reciprocal translocation a translocation is the interchange of genetic material between non homologous chromosomes in other words one chromosome can be broken let's say chromosome one and it ends up becoming a part of let's say chromosome eight those are non homologous chromosomes they contain different information now reciprocal translocation as is as is the example listed here this occurs when breaks take place in two different chromosomes these homologous chromosomes and the material is exchanged so it's a translocation refers to think of it as moving from one area to another but with reciprocal translocation both chromosomes exchange their their genetic material so let's say for example we have this chromosome here in this chromosome here if part of this chromosome breaks off and ends up joining in with this chromosome that's called translocation but in another example let's say this part breaks off and this part breaks off let's say this is chromosome 1 and chromosome 7 then this part of the chromosome that breaks off joins chromosome 1 and this part of the chromosome that broke off chromosome 1 is going to join chromosome 7 and so that's called reciprocal translocation and you can see you can see on this next slide what that looks like so this is Philadelphia chromosome is an example of reciprocal translocation and what you can see happening in this image here is that we've had breaks of a chromosome so this is normal here you can see that there's been a break and in exchange and this in particular is affecting chromosome 9 and 22 so two non homologous chromosomes they break off a piece of their chromosome and then it migrates to the other chromosome and kind of fits in its place even though it's not supposed to be there and so this will end up with you end with this abnormal gene and so this abnormal gene product ends up having the effect of increasing cell proliferation and so Philadelphia chromosome is seen in leukemia in in most cases of chronic Milo CITIC leukemia but also seen in other types of leukemia as well so you can see it's it's clinical effect so we're talking about all of these genetic diseases and there's the thought that well if we can we know early on well people are starting to do genetic testing now even before they have kids but if someone is pregnant early on in the pregnancy genetic testing can be done so a prenatal diagnosis to see if there are any genetic abnormalities or chromosomal abnormalities and at that point a couple can decide if they want to carry on with the pregnancy especially if there's a major chromosomal abnormality detected and this child is very likely to not survive or not survive for very long if they are born then it gives parents an opportunity to make a very difficult decision so there's two examples on here amniocentesis and chorionic villus sampling or CVS with amniocentesis as you can see in this image a sample of the amniotic fluid is taken and this contains cells cells from the baby and these cells can be looked at to study to study the chromosomes to see what type of issues might be present do they look normal and this is one of the more common testing that's done especially for women that either have genetic diseases that run in their family and they want to know if their child has inherited that or if they're past a certain age where chromosomal abnormality odds increase then they might choose to do amniocentesis another examples chorionic villus sampling and this is where a sample of the chorionic villus is taken if you think back to our discussions on on embryology and this can this structure contributes to the placenta and it contains much more information much more cells but it's a trickier process it's a lot riskier you're more likely to cause problems especially when you're inserting through the cervix you can it's can lead to premature labor as just an example so these are these are risky but they do give us a lot of information as to whether or not that child has inherited a chromosomal abnormality and they should be done early early on so let's talk about transmission of genetic diseases now and how they can be inherited so let's go through some important definitions first of all the term genetically inherited and they're grouped here where these are relevant to each other but different relevant to each other bit different and so on and so forth genetically inherited is something that you would inherit from say your mom or from your dad it's some sort of gene alteration that can be transmitted to the next generation congenital this is something that you're born with so it could be something that's genetically inherited but not necessarily but it is present birth that's what congenital means now acquired in utero for example back in the 60s there was a drug called Follette amide that was used for things such as morning sickness and it was found to cause major congenital malformation of the limbs of these babies another example if a woman is exposed to a virus while they're pregnant this can also cause genetic malformation so the influence well while in utero of some sort of outside factor that gets into the mother and impacts the development of her baby and so this this isn't much commonly too common more common to happen early on in the pregnancy when development is happening autosomal these diseases you should know these are going to affect chromosomes 1 through 22 whereas sex linked diseases are going to affect a chromosome X or Y recessive this is a gene alteration in one allele that is clinically hidden so these people are considered a carrier so again with recessive remember back to talking about genetics and how we have what's called the genotype and this is just an example that I'm giving you so this here is a genotype and what you end up expressing ends up being your phenotype right the larger or capital letter represents a dominant gene whereas the lowercase letter represents a recessive gene the dominant gene dominates whereas the recessive gene there has to be two or recessive allele though has to be two present of these for it to actually take an effect and we'll look at an example on the next slide so somebody does possess a recessive disease but they're healthy allele dominates and takes over then this means that they are a carrier so they carry that recessive allele and could pass it on but it doesn't actually show up and they may never know if they don't have genetic testing done they may never know that they're actually a carrier because it doesn't actually show up in their phenotype and so I've already explained then what dominant is so that's gonna be representing and you know whatever letters were using the larger letter that will dominate over the smaller letter letter and so if you have a disease that's dominant and somebody has saved this genotype and the disease is dominant then they will express it versus the receipt the disease being recessive then they'll just be a carrier because that the dominant gene will take over so it really comes down to whether or not the disease is dominant or recessive and we'll look at a good example coming up the last two terms include penetrants and expressivity penetrance is the proportion of people that have the gene alteration and the clinical disease so in for example if you have a hundred people that have a specific gene alteration and if all of them so 100% of them actually show the disease say they have the gene alteration and they show the disease then we would call this 100% penetrance if you have a hundred people that have the gene alteration but only 50% of them show the disease then you would call this then 50% penetrance lastly expressivity this is a proportion of people with a gene alteration and varied severity of the disease so for example if somebody has a gene alteration and the severity of it so it's it's a very severe disease that they end up showing then we would say that they have high expressivity if somebody has a gene alteration but the effect is very the disease itself is very mild then we could say that it has low expressivity some examples for instance are cleft lip and cleft palate there's so many different degrees of severity you can have someone just with a cleft lip with both cleft lip and cleft palate you can have somebody with it unilateral or bilateral mild severe etc so this is a variance then in how its expressed and that's expressivity let's talk for a bit about how single gene diseases are inherited and the two examples that we have up on the screen here are retinal blastoma and cystic fibrosis remember again that a capital letter is going to be referring to dominant and the lowercase letter is going to be referring to recessive and each of these are alleles and collectively they form a genotype we have different types of genotypes so for instance homozygous dominant would be their homozygous meaning they're the same dominant meaning both letters are capital or dominant homozygous recessive they're the same meaning both are homozygous and both are recessive and then heterozygous is going to be hetero meaning different not the same where you have one of each so you can relate that then to our examples now in the top punnett square looking at retinoblastoma you can see this is is rare less than 1 in 500 infected but what I want you to be aware of is that this is a dominant genetic disorder autosomal affecting remember it's affecting the first 22 chromosomes so it's not affecting the sex chromosomes and it's and its dominant so in this case with our punnett square you can see that both parents are affected and you can see the parents genotypes listed here as db4 both cases that we know is heterozygous if this is a dominant disease then we know it's affecting the dominant allele so this is the affected and this is the affected and if you inherit that affected capital D or that allele then you will have the disease so if you have a two parents two affected parents they they know their genotype and they say we want to know what the odds are when we have children that they'll be normal or or affected and so you can create a Punnett Square and show them once it's created so D D gives us this D D gives us this and so on and so forth what you can see is that any time there's a capital D these people are going to be affected because it's a dominant disease so there is then a 3 at a 4 or a 75% chance that their offspring will inherit this disease of retinoblastoma and only a one in four chance that they will be normal because the smaller case D's in this case are representing the normal healthy allele because this dominant disorder will affect the capital the larger D and so this is important information to give to parents then so they have an idea of what their odds are and also important to know that it's not just this these dogs are not just applicable to their first child the same odds are applicable to every time they have a child now let's look at a case of autosomal recessive nests where both parents are carriers in this case so what this means is that with cystic fibrosis it's a recessive disease meaning that it's affecting the lower case allele and so this is really what you would have to inherit because it's recessive in order to get the disease because let's say you inherited this well if we know it's a recessive disease it's affecting this lowercase B or I should have done D sorry affecting this lowercase D then we know that this dominant allele is healthy and it's going to dominate so this person would be a carrier of it but not actually display the disease so if we look at the screen here in this example the capital DS we know represent normal because it's a recessive disease so this person is completely normal and not even a carrier whereas this person would be a carrier but not actually display the disease same with this person here but this is the situation where this would be displayed and this person would have cystic fibrosis and so we could say then that there's a three out of four chance that they won't have cystic fibrosis so one two three there's a one out of four chance that they will be perfectly healthy and not even a carrier and there is also a one in four chance then or 25% chance that their offspring will inherit cystic fibrosis you can see that this is even more rare and one in twenty five hundred but carriers are common this slide shows the continuum of the relative influence of gene alteration and human disease on the right here you can see that single gene diseases such as cystic fibrosis in hemophilia A are determined by genes or genetic factors and therefore they can be inherited so genetic factors then play the largest role and of course then you have the ability to pass these on to offspring because of their genetic involvement on the opposite end of this spectrum we have environmental diseases so things such as influenza and measles that are thought to be caused by our environment and our lifestyle what we get exposed to and and do we make good choices to our health to keep our immunity high etc so they're thought to really have no genetic influence over all and so they're called environmental diseases bring in the middle of the spectrum we have diabetes and heart disease these are considered multifactorial diseases in other words there's environment and lifestyle that impacts the development of diabetes and heart attack or heart disease and genetic factors can also play a role and multifactorial disease are the most common and so we're going to elaborate on that on our next slide which is our last slide continuing on with multifactorial inheritance so again the middle of the spectrum on the last slide these are caused by as already mentioned combinations of environment lifestyle and genetic factors they are polygenic in other words there's not just one single gene that is essential for this so for example with type 2 diabetes there are many different genes that could make somebody more prone to developing diabetes and so the polygenic nature of these paly of there's a polygenic nature then of these multifactorial diseases there's so many different potential influences within our genes risk is also going to vary from one population to another so just as an example Canada versus the versus Japan or there could be cultural ethnic environmental factors that differ amongst populations that can predispose somebody to this type of disease and then some important examples listed here of multifactorial inheritance include cancer include heart disease and cardiovascular disease as listed up on the screen diabetes as well as obesity Alzheimer's disease and then congenital malformations as well such as cleft lip and cleft palate and congenital heart disease so these are more common than multifactorial inheritance patterns and visit this website if you want to have your your own genome made into a piece of art I hope you enjoy the lecture thanks for listening