Rama Nada. - Belal Azab

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Lester Heath
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1 Moayyad Al Shafei - Rama Nada - Belal Azab 1 P a g e

In today s lecture we are going to understand the basic concepts regarding Pleiotropy, Epistasis, Polygenic Inheritance, and the The Environmental Impact on Phenotype.

2 In today s lecture we are going to understand the basic concepts regarding Pleiotropy, Epistasis, Polygenic Inheritance, and the The Environmental Impact on Phenotype. Then we are going to integrate the Mendelian View of Heredity and Variation. let s start the lecture.. Pleiotropy In Pleiotropy a single gene mutation produces a multiple phenotypic effects. Cystic fibrosis is an example in which the CFTR gene, which encodes for a Cl ion channel of the cell membrane, is mutated causing the Cl ion channels to be defected; consequently, Cl will be built up outside the cells. Due to this excess Cl, mucus is formed especially in the lumens and body cavities. You can see in the figure below that the airway with cystic fibrosis is filled with mucus. This mutation results in many manifestations in different organs which are: - The build-up of mucus in the airway, sinuses, trachea, and lungs, which lead to increase the risk of infections and difficulty in respiration. - Salty Sweating, we can do a classic test to test the presence of cystic fibrosis as chloride(salt quantity) is high in the skin. - The liver biliary ducts and the pancreatic ducts are blocked because they're filled with mucus, which impairs liver functions. - Intestines cannot propriety absorb nutrients as the mucus lines the lumen. 2 P a g e

3 - Male and female reproductive organs complications, because their lumens are filled up with mucus. Now you can observe the definition of Pleiotropy in the previously mentioned example, as a single gene mutation (CFTR) causes many phenotypic effects (multiple symptoms of certain hereditary disease) in different organs (respiratory tract, GI tract and reproductive organs). Also sickle-cell disease is another example. we are done with Pleiotropy. Extending Mendelian Genetics for Two or More Genes: Some traits determined by two genes, but other traits have a complex pattern of inheritance and result from several genes that interact with each other, examples about this idea are: epistasis and polygenic traits Epistasis (there is a question about it in the exam, most properly it will be a clinical scenario) It is a very big complicated field involves mathematical equations. But it is good for you to know that in Epistasis one gene at one locus (position on a chromosome) affects the phenotype of another gene at another locus. Example:. The coat color of Labrador retrievers(type of dogs) depends on two genes, one gene determine the pigment color and the other gene detemines whether the pigment will deposited in the hair or not. - The black color (B) is dominant over the brown (b), so we can expect that both BB & Bb genotypes will give a black color, but bb genotype will give a brown color (brown color gene is recessive). - The story didn t over, there is another gene somewhere else, other than the mentioned one, represented by E (from Edward) which allows the pigment (black or brown) to happen (when it is EE or Ee) or not (when it is ee).so when it's homozygous recessive (ee), it will prevent the pigmentation from happening; neither the brown nor the black color will be shown up and the dog is colorless. 3 P a g e

4 This is epistasis; one gene at one locus (Edward s gene) influences another gene at another locus (color gene).we are done with epistasis. Polygenic Inheritance We have talked about Tay-Sachs disease which is fatal within 4 years as Hex-A gene (single gene) is damaged causing an accumulation of lipids in the brain, and we have talked also about cystic fibrosis in which a single gene gives the manifestations. Actually, polygenic inheritance causes most of the diseases observed in the population such as: cancer, diabetes, vitiligo, etc. Those common diseases are not caused by one gene mutation, but multiple genes are involved, and this is the definition of polygenic inheritance. Quantitative variation* usually indicates polygenic inheritance, an additive effect of two or more genes on a single phenotype. * Quantitative characters are those that vary in the population along a continuum Example:. skin color(dark very light) is an example for these phyenotypes that are caused by multiple genes. There are 3 genes for skin color each has two alleles(allel gives the light color and the other gives the black color); each of them participates in skin color. There are a lot of possibilities creating a spectrum of colors some of them are: - If the 6 alleles for the three genes are light, the skin will be very light. - If the 6 alleles for the three genes are black, the skin will be very black. - Different combinations of those alleles will give different degrees of skin color. It is not binomial; not black or white. When discussing a disease like cystic fibrosis your probabilities are limited; either diseased(aa) or not diseased (normal carrier Aa or normal not carrier AA), we can t details mor than this. 4 P a g e

5 On the other hand, when talking about Polygenic Inheritance, there will be more than 3 probabilities and those probabilities take the normal curve distribution in the population (we remember the biostatistics yet). This is polygenes that are involved in a single phenotype. Nature and Nurture: The Environmental Impact on Phenotype Many phenotypes including cancer are influenced not only by multiple genes but also by the environment (this topic is very complicated). Let s study 100 smokers Vs 100 non smokers, lung cancer will affect the smokers more than the non smokers, but not every smoker will develop the cancer, he has only a higher risk to develop the cancer especially if his genes are susceptible to develope it, so the phenotype for this character depends on environment as well as genotype. Such characters are called multifactorial because genetic and environmental factors collectively influence phenotype. - It is important to know that the effect of genotype:environment is not 1:1. Usually scientists use identical twins to study this relation as their DNA are completely the same (here we are studying the environmental effect only). If they lived in different environments and one was affected while the other identical twin was not, then it is an indication of environmental contribution more than genetics. On the other hand, if they lived in different environments and they both were affected the same, then it indicats that the environmental contribution for this character is less than the genetic contribution. When I have a multifcatorial disorder, this means that many genes and environmental factors influence the phenotype. According to that the phenotypic range of a genotype influenced by the environment, and this is called The norm of reaction, those Norms of reaction are generally broadest for polygenic characters which result from additive effect of two or more genes. For example, hydrangea flowers of the same genotype range from blueviolet to pink, depending on soil acidity. 5 P a g e

6 Integrating a Mendelian View of Heredity and Variation An organism s phenotype includes its physical appearance, internal anatomy, physiology, and behavior reflects its overall genotype and unique environmental history. Human Genetics and Pedigrees Human genetics follow the pattern seen in other organisms which are the Mendelian ptternes of inheritance. Humans are not good subjects for genetic research for many resons: Generation time is too long Parents produce relatively few offspring Breeding experiments are unacceptable However, basic Mendelian genetics endures as the foundation of human genetics Pedigree Analysis (there will be many questions about it in the exam) - Pedigree is the family tree that describes the interrelationships of parents and children across generations, it is a concise summary of the medical family history; it is the symbolic language of clinical genetics and human genetics research. -It is an easy, fast, and efficient mean for recording a wealth of information about the family. From slides: -Inheritance patterns of particular traits can be traced and described using pedigrees - Pedigrees can also be used to make predictions about future offspring - We can use the multiplication and addition rules to predict the probability of specific phenotypes (will be discussed later). -The pedigree is composed of horizontal and vertical lines, the horizontal represent the generations and they are numbered by Roman numerals, meanwhile, the vertical lines represent the individuals and they are 6 P a g e

7 numbered by Arabic numerals within a generation. So, the marked is represented as (II-1). 1. the circle represents female, while the square represents male. 2. Place the oldest generation at the top 3. Use Roman numerals to identify generations 4. Use Arabic numbers to identify individuals within a generation 5. List siblings from oldest to youngest, from left to right 6. Male partner is usually placed to the left of the female partner 7. Record full name, current age and date of birth, or age at death for each individual 8. Record race and ethnic origin of each individual 9. Note health problems and/or cause of death for each individual 10. There are appropriate symbols to use for both adoption and assisted reproductive technologies In order to understand a pedigree, you have to be familiar with the points in the following figures This is his biological family, but he is not member of the family 7 P a g e

8 He is member of the family, but those parents are not his biological parents *Proband: (the point of contact) an individual that brings the family to clinical attention, typically (not always) the affected individual is the Proband and there may be more than one proband per family. The Gene is the Unit of Inheritance - The location of a gene on a chromosome is its locus. - Alternative versions of a gene at a particular locus are referred to as alleles, for each gene we have two alleles (except for sex chromosomes), if they are identical the individual is homozygous AA OR aa, if they are different, the individual is heterozygous Aa. - Compound heterozygote: two mutant alleles, but each allele s mutation is different than the other one, e.g. we have nonsense mutation in the first allele and the second allele has missense mutation. 8 P a g e

9 -The genotype at a particular locus and the environment in which it is expressed determines the phenotype or observed characteristics of an individual. - Traits that are determined by loci on one of the 22 autosomes are autosomal. Traits determined by loci on the X chromosome are X-linked, and those determined by loci on the Y chromosome are Y-linked. Gregor Mendel s Laws of Inheritance We talked about them at the level of chromosomes, but now we are going to talk about them at the level of genes. - Law of Unit Inheritance - parental characteristics do not blend because there is a unit of inheritance. Mendel s units are now known as genes or alleles (not mentioned by the doctor). - Law of Segregation Homologous chromosomes carry the same genes but not necessarily the same version of the gene (alleles), after meiosis, each gamete will carry only one allele of each gene; because the homologous chromosomes (which carry the versions of gene) have undergone segregation into different cells. So, there is one allele per one gene in each gamete. So, Law of Segregation - the two alleles at a particular locus segregate into different gametes. - Law of Independent Assortment - alleles at different loci(chromosomes) are transmitted independently of each other. Linkage is an exception to this rule. For example, if we have A gene at chromosome 8 and B gene at chromosome 10, due to the mentioned independency the gamete may carry AB, Ab, ab or ab. 9 P a g e

10 Dominant and Recessive Inheritance -Traits that are determined by loci on one of the 22 autosomes are autosomal. Traits determined by loci on the X chromosome are X-linked, and those determined by loci on the Y chromosome are Y-linked, both X-linked & Y-linked are called sex-linked (it is different than sexinfluenced or sex-related). Nomenclature: For dominant traits the capital letter (e.g. A) represents the mutant allele and the small letter (e.g. a) represents the normal allele. For recessive traits, the small letter (e.g. a) represents the mutant allele and the capital letter (e.g. A) represents the normal allele. Autosomal Dominant Inheritance: One mutant allele is enough to manifest the clinical features, in which the phenotype of the heterozygote and the homozygote for the dominant allele are the same, i.e., Aa and AA have the same phenotype (both are affected if we talk about a disease) where A=dominant allele. These traits are expressed when only one copy of the dominant allele is present. In practice, if the heterozygote expresses the trait, then the trait is classified as dominant, even if the phenotype of the homozygote (AA) and heterozygote (Aa) are different. So, AA &Aa both will be affected while aa will be normal. Types of Genetic Disease Chromosomal Single gene (Mendelian) Multifactorial Teratogenic Examples of Autosomal dominant diseases (they are for memorization): 1) Huntington disease: a progressive neurodegenerative disorder in which there is a damage in the brain neurons specifically in the basal ganglia, its consequences loss of motor control (deterioration), first there will be problems in moving then it progresses to problems in cognition. The onset of the disease is at late 30s early 40s, which means the first years of their life is normal, but at their 30s they will manifest the symptoms. 10 P a g e

11 It s a genetic disease but not congenital (the is no manifestation at the time of birth. noticing that their motor system is defective, however, the onset may be earlier but typically appears late. -It affects 1/20000 person of European descent -After the onset of the disease most patients die within 5 years. * Not all autosomal dominant disorders begin at birth. 2) Myotonic dystrophy: progressive muscle damage and weakness, it starts with facial muscle weakness. The onset and the expressivity (severity) are variable among individuals. 3) Neurofibromatosis type I (NF1): It is characterized by the presence of cafe-au-lait spots (hyperpigmented skin), Lisch nodules (which are benign growths on the iris) and variable expressivity (the severity varies dramatically among individuals) see the figures in the slides to notice this variability. And the individual may acquire a cancer in the peripheral nervous system. 4) Familial hypercholesterolemia: they develop Arteriosclerosis and Xanthomas, and their blood LDL (bad fat) is very high risking the blockage of arteries especially the coronary. The heterozygous patients develop increased LDL coronary heart disease in middle age, while, the homozygous patients develop (may de at embryo level) coronary heart disease in childhood. The age of onset for homozygous patient is earlier than it for heterozygous. 5) Marfan syndrome: they have a problems in the connective tissue, the clinical features of this mutation are many such as: I. They are tall with long limbs II. Narrow elongated face III. Lens dislocation and Myopia (the eye does not bend or refract light properly to a single focus to see images clearly) IV. The big problem here is due to the elasticity of their connective tissue which may lead to rupture of the 11 P a g e

12 aorta as it is exposed to high pressure, causing sudden death (aortic aneurysm). - The expressivity is variable and it s a pleiotropy disease (gene mutation causes multiple phenotypic effects; Marfan patients have problems in their skeleton, heart and the lens of the eye etc). 6) Achondroplasia: the most common form of dwarfism, affected individuals show many clinical features: I. Short limbed dwarfism II.Megalocephaly (prominent head) III.Lordosis and Kyphosis. IV.80% new mutations (de novo mutations/spontaneous not inherited); his/her parents are not affected (the parents don t have the mutation, it s developed spontaneously) V.Mutations increase with paternal age. An important note: if you see someone who is affected with a dominant disease, assume that this individual is heterozygous not homozygous, unless something else is proved. So, by default the dominantly affected individuals are heterozygous more than homozygous and this is due to the fact that the abnormal genes (dominant) are rare so it is unusual for a person to acquire both alleles. Don t forget to refer to slides Best of luck!!الع ج ب.. لغفلة الح س اد عن سالمة األجساد!! 12 P a g e

Chapter 14. Mendel and the Gene Idea

Chapter 14. Mendel and the Gene Idea Chapter 14 Mendel and the Gene Idea Gregor Mendel Gregor Mendel documented a particular mechanism for inheritance. Mendel developed his theory of inheritance several decades before chromosomes were observed