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PLEIOTROPY AND GENETIC HETEROGENEITY Questo documento è pubblicato sotto licenza Creative Commons Attribuzione – Non commerciale – Condividi allo stesso modo http://creativecommons.org/licenses/by-nc-sa/2.5/deed.it Genetica per Scienze Naturali a.a. 08-09 prof S. Presciuttini The complexity of the phenotype At one level, geneticists tend to think of genes in isolation. In reality, genes don't act in isolation. The proteins and RNAs they encode contribute to specific cellular pathways that also receive input from the products of many other genes. Furthermore, expression of a single gene is dependent on many factors, including the specific genetic backgrounds of the organism and a range of environmental conditions, temperature, nutritional conditions, population density, and so on. Gene action is a term that covers a very complex set of events, and there is probably no case where we understand all the events that transpire from the level of expression of a single gene to the level of an organism's phenotype. Two important generalizations about the complexity of gene action: 1. There is a one-to-many relationship of genes to phenotypes. 2. There is a one-to-many relationship of phenotypes to genes. Genetica per Scienze Naturali a.a. 08-09 prof S. Presciuttini One-to-many relationship of genes to phenotypes This relationship is called pleiotropy. Pleiotropy is inferred from the observation that mutations selected for their effect on one specific character are often found to affect other characters of the organism. This might mean that there are related physiological pathways contributing to a similar phenotype in several tissues. For example, the white eye-color mutation in Drosophila results in lack of pigmentation not only in compound eyes but also in ocelli (simple eyes), sheaths of tissue surrounding the male gonad, and the Malpighian tubules (the fly's kidneys). In all these tissues, pigment formation requires the uptake of pigment precursors by the cells. The white allele causes a defect in this uptake, thereby blocking pigment formation in all these tissues. Genetica per Scienze Naturali a.a. 08-09 prof S. Presciuttini The AY allele as an example of pleiotropy An important question is how can a gene controlling coat color cause death in an organism? Possibly in a single dose the allele causes a yellowing of the coat, but when expressed in two doses, the gene product kills the animal. Thus, this gene actually has an effect on two phenotypes. Pleiotropic gene - a gene that affects more than one phenotype In this example the gene that causes yellowing of the coat also affects viability and is termed a pleiotropic gene. Genetica per Scienze Naturali a.a. 08-09 prof S. Presciuttini Pleiotropy is the rule rather than the exception Pleiotropy: A given gene affects more than one trait. Examples of pleiotropy abound; in fact, probably every gene is pleiotropic to some extent. Some instances of pleiotropy are not surprising. Mice that are bred for larger body size also produce litters with more pups. It is not hard to understand how this can occur, since larger bodies have more room for young inside and can supply more nutrients to the young. A plant that lacks a functional gene involved in synthesis of abscisic acid has leaves that wilt easily and seeds that do not become dormant in the normal way. Genetica per Scienze Naturali a.a. 08-09 prof S. Presciuttini 5. Phenylketonuria (PKU) Another example is human phenylketonuria, in which loss of an enzyme involved in the breakdown of excess phenylalanine causes pleiotropic effects that include elevated phenylalanine levels in the blood plasma, urinary excretion of intermediate products of phenylalanine breakdown, severely reduced IQ, changes in hair color, and changes in head size. Figure. Frequency distributions of phenylketonurics (right) compared with controls (left). A: d/s = 13, where d is the difference in the means and s is the average standard deviation of the two distributions. B: d/s = 5.5; C: d/s = 2.0; D: d/s = 0.7 Genetica per Scienze Naturali a.a. 08-09 prof S. Presciuttini Gene mutations may affect apparently unrelated traits Often, pleiotropy involves multiple events that are not obviously physiologically related. For example, the dominant Drosophila mutation Dichaete causes the wings to be held out laterally but also removes certain hairs on the back of the fly; furthermore, the mutation is unviable when homozygous. This example shows a real limitation in the way dominant and recessive mutations are named. The reality is that a single mutation can be both dominant and recessive, depending on which aspect of its pleiotropic phenotype is under consideration. In general, genetic terminology is not up to the task of representing this level of pleiotropy and complexity in one symbol, and there is a certain arbitrary or historical aspect as to how we name alleles. Genetica per Scienze Naturali a.a. 08-09 prof S. Presciuttini Waardenburg syndrome in human In humans, heterozygosity for a gene called MITF causes a condition called Waardenburg syndrome type 2, which involves iris defects, pigmentation abnormalities, deafness, and inability to produce the normal number of mast cells (a type of blood cell). 1st quadrant = hearing loss 2nd quadrant = different colored eyes 3rd quadrant = white forelock 4th quadrant = premature graying of hair. Genetica per Scienze Naturali a.a. 08-09 prof S. Presciuttini Pleiotropy and variable expressivity in WS The Waardenburg syndrome was named for Petrus Johannes Waardenburg, a Dutch ophthalmologist (1886-1979) who was the first to notice that people with two different colored eyes frequently had hearing problems. In this disease, the skin pigment, the iris of the eye, the inner ear tissue, and the mast cells of the blood are not related to one another in such a way that the absence of one would produce the absence of the others. Rather, all four parts of the body independently use the MITF protein as a transcription factor. In addition to different phenotypes, WS is also characterized by variable expression of the various features. Genetica per Scienze Naturali a.a. 08-09 prof S. Presciuttini A major challenge in genetics Pleiotropy occurs when a mutation in a single gene produces effects on more than one characteristic, that is, causes multiple mutant phenotypes. In humans, this phenomenon is most obvious when mutations in single genes cause diseases with seemingly unrelated symptoms A major challenge in the analysis of pleiotropic genes is determining whether all of the phenotypes associated with a mutation result from the loss of a single function or of multiple functions encoded by the same gene. In addition to providing important information about gene function, distinguishing between these two models is important for devising effective treatments and analyzing drug side effects. Classical genetic analysis attempts to resolve such issues by isolating and characterizing multiple alleles of the same gene, with the goal of determining whether these phenotypically defined functions are genetically separable. Unfortunately, this type of approach is time consuming and often not feasible in a clinical setting, which relies on the identification of naturally occurring alleles. Genetica per Scienze Naturali a.a. 08-09 prof S. Presciuttini One-to-many relationship of phenotypes to genes This concept is based on the observation that many different genes can affect a single phenotype. This is easy to understand in terms of a character such as eye color, in which there are complex metabolic pathways with numerous enzymatic steps, each encoded by one or more gene products. Genetic heterogeneity is the term used to refer to a given condition that may be caused by different genes. One goal of genetic analysis is to identify all the genes that affect a specific phenotype and to understand their genetic, cellular, developmental, and molecular roles. To do this, we need ways of sorting mutations and genes. We first will consider how we can use genetic analysis to determine if two mutants are caused by mutational hits in the same gene (that is, they are alleles) or in different genes. Later, we will consider how genetic analysis can be used to make inferences about gene interactions in developmental and biochemical pathways. Genetica per Scienze Naturali a.a. 08-09 prof S. Presciuttini The complementation test The allelism test that finds widest application is the complementation test, which is illustrated in the following example. Consider a species of flower in which the wild-type color is blue. We have induced three white-petaled mutants and have obtained pure-breeding strains (all homozygous). We can call the mutant strains $, £, and ¥, using currency symbols to avoid prejudicing our thinking concerning dominance. In each case the results show that the mutant condition is determined by the recessive allele of a single gene. However, are they three alleles of one gene, or of two or three genes? The question can be answered by asking if the mutants complement each other. Complementation is the production of a wild-type phenotype when two recessive mutant alleles are united in the same cell. Genetica per Scienze Naturali a.a. 08-09 prof S. Presciuttini Performing the complementation test In a diploid organism the complementation test is performed by intercrossing homozygous recessive mutants two at a time and observing whether or not the progeny have wild-type phenotype. If recessive mutations represent alleles of the same gene, then obviously they will not complement because they both represent lost gene function. Such alleles can be thought of generally as a’ and a", using primes to distinguish between two different mutant alleles of a gene whose wildtype allele is a+. These alleles could have different mutant sites but would be functionally identical. The heterozygote a’/a" would be However, two recessive mutations in different genes would have wild-type function provided by the respective wild-type alleles. Here we can name the genes a1 and a2, after their mutant alleles. Heterozygotes would be a1/+ ; +/a2 (unlinked genes) or a1+/+a2 (linked genes), and we can diagram them as follows: Genetica per Scienze Naturali a.a. 08-09 prof S. Presciuttini Mutants that complement We now return to the flower example and intercross the mutant strains to test for complementation. Assume the results of intercrossing mutants $, £, and ¥ are as follows: From this set of results we would conclude that mutants $ and £ must be caused by alleles of one gene (say w1) because they do not complement; but ¥ must be caused by a mutant allele of another gene (w2). The molecular explanation of such results is often in terms of biochemical pathways in the cell. How does complementation work at the molecular level? Although it is conventional to say that it is mutants that complement, in fact the active agents in complementation are the proteins produced by the wild-type alleles. Genetica per Scienze Naturali a.a. 08-09 prof S. Presciuttini Complementation Three phenotypically identical white mutants, $, £, and ¥, are intercrossed to form heterozygotes whose phenotypes reveal whether or not the mutations complement each other. (Only two of the three possible crosses are shown here.) If two mutations are in different genes (such as £ and ¥), then complementation results in the completion of the biochemical pathway (the end product is a blue pigment in this example). If mutations are in the same gene (such as $ and £), no complementation occurs because the biochemical pathway is blocked at the step controlled by that gene, and the intermediates in the pathway are colorless (white). Genetica per Scienze Naturali a.a. 08-09 prof S. Presciuttini Complementation test for rare human genetic diseases Genetic complementation for rare and invalidating genetic diseases cannot be observed in human pedigree, because affected people do not marry However, some mammalian somatic cells can be cultured in a well-defined medium. In addition, cultured cells can be fused to produce somatic hybrids; although cell fusion occurs spontaneously at very low rate, it can be increased in the presence of certain viruses that have a lipoprotein envelope similar to the plasma membrane of animal cells. A mutant viral glycoprotein in the envelope promotes cell fusion. Cell fusion is also promoted by polyethylene glycol, which causes the plasma membranes of adjacent cells to adhere to each other and to fuse. Genetica per Scienze Naturali a.a. 08-09 prof S. Presciuttini Xeroderma pigmentosum Cell fusion is the basis for the complementation test in human; if a genetic defect is assayable in cultured cells, complementation analysis by cell fusion can be undertaken. For example, the autosomal recessive disease xeroderma pigmentosum (XP) involves defects in repair of UV-induced damage in DNA. Patients are abnormally sensitive to sunlight, developing skin cancer after relatively brief exposure. Multiple basocellular carcinomas on the face of an XP patient. Thick arrow points to a recent lesion, and thin arrow to a scar of an old lesion Genetica per Scienze Naturali a.a. 08-09 prof S. Presciuttini First demonstration of complementation groups in XP By fusing fibroblasts from various patients with XP, seven main complementation groups have been defined Genetica per Scienze Naturali a.a. 08-09 prof S. Presciuttini Different sensitivity to UV radiation of cells from different complementation groups Hypersensitivity to UV radiation of XP cells in culture. Here the cells from a number of complementation groups are shown. There is a variation between complementation groups, but all are more sensitive to UV radiation than are normal cells. The difference in UV photosensitivity between normal and diseased cells is evident from the survival curves of cultured cells treated with UV light Genetica per Scienze Naturali a.a. 08-09 prof S. Presciuttini