Genetics for the Perplexed Week 2 Part 1 Modifications of Mendel PDF

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Genetics for the Perplexed | Week 2 Part 1 | Modifications of Mendel...

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GENETICS FOR THE PERPLEXED WEEK 2 PART 1: MODIFICATIONS OF MENDEL LECTURE 03 Qu) What causes one allele to be dominant over another? BIG question with (fairly) complicated answer with different solutions. I would prefer not to go into too much depth, but in brief… The simplest explanation to dominance is when one of the alleles makes a broken protein. When this happens, the functioning protein is generally coded by the dominant allele. Thus in heterozygotes having one copy of the dominant allele produces enough protein for the normal phenotype. In homozygotes recessive, no functioning protein is produced leading to the mutant phenotype. This is the case in Tay Sachs syndrome. The hexosaminidase enzyme normally breaks down a lipid called ganglioside in the brain, and without the enzyme you get a build up of this substance. If you have one functioning allele you can still produce enough of the enzyme to break down the lipid and are phenotypically healthy. But this simple explanation in no way explains every pattern. In some cases, having one normally functioning allele does not produce enough protein for normal function. Two functioning copies is needed for a normal dose. This phenomenon is referred to by the term haploinsufficiency. This would be observed as a dominant mutation. Examples in human genetics include Marfan syndrome and polydactyly. And there are other scenarios. In the case of dominant diseases, the recessive allele codes for the normal allele and the dominant allele codes for the mutant protein. Here, the dominant allele may code for a protein which interacts with a different protein/molecule which causes the mutant phenotype. We call these types of mutations gain of function because the protein is doing something new. And there are many other examples, this paper below is a more detailed review: Zschocke J. 2008. Dominant versus recessive: Molecular mechanisms in metabolic diseases. Journal of Inherited Metabolic Disease, 31. Qu) What is the difference between incomplete dominance and codominance? The key is the expression of the phenotype in the heterozygotes. In incomplete dominance, the heterozygote phenotype is an intermediate phenotype of the two homozygote phenotypes. For example, in the 4 o’clock plant the colour of the flower is determined by the presence of the dominant R red allele and the recessive r white allele. So RR = Red flowered plant, rr = white flowered plant and Rr is an intermediate pink flowered plant. In codominance, the heterozygote expresses both alleles at a given locus equally. The classic example is blood groups, where the genotype AB means your phenotype is AB. Both red blood cell antigens are expressed equally.

Qu) What is pleiotropy? One gene mutation has an effect on many aspects of the phenotype. We talked about sickle cell; but it’s true for lots of conditions – cystic fibrosis, for example; normally talk about difficulties in breathing, but also severe problems with digestion, and sperm are less mobile. Qu) Can someone please explain the difference between pleiotropy and gene interaction? Could a gene not do both? This is a good question because in part because it is easy to confuse them, but also because in some cases it is not as clear cut as the definitions (or indeed the lectures) make out. Pleiotropy is defined as a single locus have multiple effects. You will encounter many examples on this course, for example the multiple phenotypes associated with sickle cell. The SS loci has multiple phenotypic effects. Epistasis is a situation in which the phenotypic expression of a genotype at one locus depends upon the genotype of another locus; a mutation that exerts its expression cancels out the expression of the alleles at another locus. The example covered in detail in this course is mouse colour, where the pigment which determines coat phenotype is determined by multiple loci, including a 'c loci' which determines whether any pigment is produced at all. A key difference with pleiotropy is that epistasis deals with 2 or more loci, whilst pleiotropy deals with 1 loci. However, it isn't quite that simple! The c loci in mice is actually a good example of a loci which behaves epistatically (because it masks the genotype at the a or b loci) and pleiotropically. The cc mice as well as being albino, have red eyes: http://www.ncbi.nlm.nih.gov/pubmed/16303920 and also behave differently, for example, apparently cc mice are apparently scared of heights: http://link.springer.com/article/10.1007%2FBF01507473#page-1 ie it is also having an effect on multiple phenotypes! In genetics, things are never so clear cut! Qu) What is a proto-oncogene? This can get a little technical, but let’s keep this simple for now. A proto-oncogene is any normal loci/gene which is associated with cell growth, cell lifespan and cell division. However, via mutation a proto-oncogene can become an oncogene which causes cancer. Most oncogenes are gain-of-function mutations; cause the upregulation of cellular division.

Qu) Why do we assume, in the recessive pedigree questions, that someone coming in from outside the family is homozygous for the dominant allele? Well it is an assumption; but for a really rare allele it is usually justified. In reality, we can take into account the probability of an individual joining a pedigree being a heterozygote, but we need to know the frequency of the allele in the population. We will cover this later in the course, in ‘Population Genetics’. So for now we assume individuals joining a pedigree are homozygous for the most common genotype, which would be AA for rare recessive diseases. A common mistake students make at this stage of the course is that because an induvial marrying into a pedigree could be AA or Aa, there is a 50% chance they are Aa. This is just not true for rare recessive diseases, because it is not the case that there is an equal number of A and a alleles in the population. Qu) Why is gene therapy for cystic fibrosis impossible? In truth, most (but not all) gene therapy in the strict sense – replacing a piece of damaged DNA – has not worked. The problem is getting it into the correct place and working at the correct rate; but, more important for CF, so many inaccessible tissues such as the pancreas are involved that you could never get access to them. The treatments that have worked are aimed at the bone marrow or retina, and hence at just one simple and specialised family of cells. Qu) According to the lecture slides, AB blood type has both A and B antigens on the red blood cell surface, and produces no antibodies in the blood plasma. The opposite is valid for O blood type. Therefore, when we add antibodies to the blood, the red blood cells in AB type will clump together for both anti-A and anti-B antibodies, and the opposite is again valid for O blood type. However, according to my own previous knowledge, AB blood type is the universal receipt and O blood type is the universal donor. Therefore, how can a patient of AB blood type receive blood from other blood types, when the anti-bodies from other blood types will cause clumping of the AB red blood cells? Even if we can only donate our blood without passing on the antibodies together, won't the foreign blood, say A blood type, produces B-antibodies after entering the receipt's body and cause clumping in the receipt's blood Antibodies and antigens; I still confuse them, but you are basically right. The key information is that there are 4 blood groups in humans that are defined by the ABO system (there are actually many other blood groups determined by different loci, but for now let's play it simple): • •

Blood group A has A antigens on the red blood cells with anti-B antibodies in the plasma Blood group B has B antigens on the red blood cells with anti-A antibodies in the plasma

• •

Blood group AB has both A and B antigens on the red blood cells, but no antibodies in the plasma Blood group O has no antigens on the red blood cells (again a simplification), but both anti-A and anti-B antibodies in the plasma

As you say, if you add blood from an AB individual to an individual with blood group O, their blood will clot because the individual has antibodies for both A and B in their blood plasma. Similarly, an individual with blood group O can donate to any individual because their red blood cells do not contain any antigens on their surface. This is why blood group O individuals are called universal donors. Blood group O is highly sort after by blood donation groups for this reason! Individuals who are blood group AB do not produce any antibodies. Therefore, they can receive blood from anyone regardless of their blood type; they don't have any antibodies! This is why are universal recipients. Individuals with blood group AB will only be able to donate to people with blood group AB. If an individual of blood group A receives blood from an individual with blood group B the blood will clump. This is because individuals with blood group A produce B antibodies and will recognise Blood Group B as foreign. Qu) I have a white rabbit with blue eyes. Can she hear or only white, blue eyed cats and dogs are deaf? A word on the association of white fur coloured - blue eyed cats being deaf. The white coat colour in cats is (in most cases) determined by a single dominant W loci. If a cat is Ww or WW they are guaranteed to be white coat coloured. Because 100% of individuals with the genotype express the phenotype (ie white coat colour), we call this complete penetrance. In the lectures you were told that all white fur coloured blue eyed cats being deaf. This is because the W locus is pleiotropic and causes the white eyed and deaf phenotypes. In fact, this is not quite true. MOST WW or Ww cats are blue eyed and deaf, but not quite all. Because the expression of this phenotype is less than 100%, we call the incomplete penetrance. See this paper for the stats on the strength of the association: http://www.sciencedirect.com/science/article/pii/S1090023306001699 Now onto your rabbit. Myself and Steve do seem to have an unhealthy obsession with cats and dogs, but sadly this obsession does not extend to rabbits and I'm not sure of the answer! Googling the problem links you to some rather choice rabbit forums discussing the topic and the consensus seems to be that it is not the case. Similarly a literature review does not bring up any such association, so I think we can assume your bunny is a ok. Qu) What is the difference between incomplete dominance and incomplete penetrance? And do incomplete penetrance and reduced penetrance mean the same thing?

In genetics, the penetrance of a disease is the proportion of individuals with a specific genotype who manifest that genotype at the phenotypic level. If penetrance is incomplete (or reduced, they do indeed mean the same thing to my knowledge) the proportion is less than 1. For example, if a disease has 0.9 penetrance that means 90% of individuals with the disease genotype will develop the disease and 10% will not. This is different from incomplete dominance (ID); in incomplete dominance the phenotype of the heterozygote is an intermediate value of the two homozygote phenotypes. ID is different for 2 reasons 1) in ID we have an intermediate value, whilst in penetrance there is no intermediate, you either have the disease or you do not have the disease 2) in ID there is a clear rule in homozygotes and heterozygotes, but the rules in penetrance depend on the specific disease. Qu) Did we look at an example of incomplete penetrance in the lectures? If not, could you please give us a few examples? There have been quite a few examples of diseases with incomplete penetrance in the course, but these were not explicitly pointed out. For example, many people with a mutation in the BRCA1 or BRCA2 gene will develop cancer during their lifetime, but some people will not. Specific figures show that breast cancer penetrance by age 80 was estimated to be 48% for BRCA1 mutation carriers (ie 52% of individuals carrying a mutated BRCA1 do not develop the disease) and 74% for BRCA2 mutation carriers. We cannot predict which people with these mutations will develop cancer or when the tumors will develop. In these cases, reduced penetrance probably results from a combination of genetic, environmental, and lifestyle factors, many of which are unknown. Qu) Is sickle-cell anemia an example of dominance, codominance or incomplete dominance? In fact, it is an example of every one of these! In respect to this course, sickle-cell anaemia (SCA) provides an interesting insight into complete dominance, codominance and incomplete dominance. The gene concerned affects the haemoglobin molecule, the three genotypes have different phenotypes as follows: HbA/HbA : Normal red blood cells; No SCA HbS/HbS : Abnormal haemoglobin causes red blood cells to have sickle shape; Severe SCA HbA/HbS : Red blood cells sickle only under low oxygen concentrations; No SCA In regard to the expression in the heterozygotes, the HbA allele is dominant to the HbS allele and the single functioning HbA allele produces enough functioning haemoglobin to prevent anaemia. In regard to the blood shape however, there is incomplete dominance, as shown by the fact that many cells have a slight sickle shape. Finally in regard to haemoglobin itself, there is codominance. The alleles HbA and HbS code for two different forms of haemoglobin differing only by a single amino

acid. Both forms are synthesized and expressed equally in the heterozygote. The A and S form can be separated by gel electrophoresis, a common if slightly outdated, means of diagnosis. And of course, it is an example of pleiotropy. The glutamic acid to valine mutation causes a change in the haemoglobin shape and changes its molecular properties. This changes the shape of the red blood cell, they sickle. This single change has many detrimental effects in the body. The blood cells can block small blood vessels. This can cause a wide variety of symptoms including anaemia, heart failure, paralysis, enlarged spleen, bossed skulls, brain damage, poor circulation - as well as malaria resistance in heterozygotes. Qu) Can you explain the Rhesus blood group system? My physiology lecturer told us there were implications for blood transfusions. On this course we have so far covered one blood group system (ABO). This is in fact a simplification of blood group genetics. There are 29 different blood group systems (as of 2007) of which the ABO systems and the Rh (Rhesus) system are but two. The Rh system is one of the most complex in terms of its genetics; it is determined by two loci (ABO is determined by one loci) and is associated with 49 different cell surface antigens! The antigens are located on two Rhesus proteins – RhD and RhCE which are found in the cell surface membrane of the red blood cells. The exact function of the RhD and RhCE proteins is still relatively unclear. At some point in our evolution, a deletion event occurred which resulted in the complete loss of the of the RhD gene. This causes most (but not all) of the Rh(negative) phenotype and is most common in European populations. Individuals with a functioning RhD gene have the Rh+ (positive) phenotype, this is the most common phenotype in the UK (85% of individuals according the to NHS). Broadly speaking, Rhcan be thought of as a recessive allele and Rh+ can be thought of as a dominant allele. The RHCE loci is responsible for 4 different rhesus antigens: C, c, E and e. The presence of the RhD protein has important medical implications. If a mother is Rh- and has an Rh+ child, the child can be recognised as a foreign body as a result of blood mixing during birth. The mother then carries Rh+ antibodies it means future pregnancies are likely to be aborted. However, today there are drugs that females can take after their first pregnancy to avoid this from happening. In cases of emergency medical transfusions in the UK, O Rh- (O-) blood is usually given because it contains no cell surface antigens at all. In some countries (eg Germany, not sure about the UK though) women of child bearing age who are Rh- do not receive transfusions from Rh+ blood to avoid likely anti Rh+ immunisation. To my knowledge, there is no implications of a male receiving blood from either an Rh- or Rh+ individual. Qu) When I was going through the third lecture (Modifications of Mendel I) I was quite confused about the Manx cat. My current understanding is that TT is a normal cat, Tt is a Manx cat and tt is lethal. One website said that lethal 'phenotype' is recessive and that tail-less phenotype is dominant. I somewhat

understand this, but then why do TT cat's not express Manx characteristics (and instead normal?) The tailless Manx phenotype in cats is produced by an allele that is lethal in the homozygous state. A single dose of the Manx allele, say M1, severely interferes with normal spinal development, resulting in the absence of the tail in the M1/M2 heterozygote. But in the M1M1 homozygote, the double dose of the gene produces an extreme abnormality in spinal development and the embryo does not survive development. So is the M1 allele really dominant? I would argue that it is completely arbitrary and depends on what trait you are looking at. In terms of having a short tail you could argue that it is dominant. This is because having one copy of the allele gives you a short tail. However, in terms of survival, the allele is actually recessive; heterozygotes M1M2 and homozygotes M2M2 both survive, but having two copies of M1M1 is lethal. Therefore, for survival it is modelled just like a recessive. Qu) Can someone please explain the difference between the following traits: Sex linked, sex influenced and sex limited? In the context of sex influenced and sex limited we have been guilty of incorrectly using them interchangeably on this course. Sex-linked refers to a specific loci which is located on the sex chromosome. This is most commonly discussed in the context of the X chromosome. In the case of rare Xlinked recessive alleles in humans (for example colour blindness or haemophilia), the trait is more likely to be expressed in males than females. This is because the wildtype X chromosome in female heterozygotes 'protects' the female. Loci on the Ychromosome (for example, SRY) may also be described as sex-linked. Diseases associated with mutations in Y-chromosome (for example, human male infertility) will only ever be expressed in the males, given the Y chromosome is never found in females. Sex-limited inheritance is when a trait is expressed in only one sex even though the trait may not be on the X (or indeed Y) chromosome. Here, the expression of the trait is completely limited to one of the sexes. For example, in domestic fowl, tail and neck plumage is often distinctly different in males and females:

So the expression of the cock-feathered phenotype is completely limited to one sex. However, in some cases, the sex of the individual only influences the expression of the trait. This is referred to as sex-influenced inheritance, defined as the phenotypic

expression that is conditioned by the sex of the individual. An example of this is sexinfluenced pattern baldness in humans, which is inherited in the following way:

So in this case, both males and females can potentially be bald, but the phenotype is far more prevalent in males than it is in females. But baldness is not limited to one sex. What does Prof Jones mean when he said that at a molecular level, there is no concept of dominance? The point that was being made here is that we can now look at the sequences of DNA and protein sequences at a molecular level. For most loci, at the molecular level, both alleles are expressed equally. Let's say we have a locus Aa, where it appears that A is dominant to a and a wild-type phenotype is produced. Infact, were we to look at the molecular level, you may find that two types of protein are produced: a and A. It is not the case that one allele is turned on (A) and one allele is turned off (a). You would be able to show this using a gel electrophesis which would separate out the proteins and you would see that there are both types of protein present. Remember the definition of codomi...