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1. From Genes to Phenotypes Mendel was fortunate to have chosen some of the most genetically simple of characters in the garden pea for his seminal experiments that laid the foundation for the science of genetics. Differences between traits were determined by single gene substitutions on different chromosomes, and each trait behaved as clearly dominant or recessive in this experimental system. This allowed Mendel to recognize the pattern of inheritance of the individual genes. However, the experimental situation devised by Mendel was rather a particular case, that of unlinked loci with biunivocal correspondence between homozygous genotypes and dichotomous phenotypes. Most of the major advances in genetics have come from laboratory studies on characters having a simple, one-to-one correspondence of genotype to phenotype. However, in natural populations, phenotypic variation generally shows a more complex relationship to genotype and not a one-to-one correspondence. Genetica per Scienze Naturali a.a. 05-06 prof S. Presciuttini 2. Interactions Between the Alleles of One Gene One important generalization of Mendel’s theory concerns the interactions of the different alleles of a locus in producing a phenotype A) Intermediate dominance Four-o'clocks are plants native to tropical America. Their name comes from the fact that their flowers open in the late afternoon. When a wild-type four-o'clock plant with red petals is crossed with a pure line with white petals, the F1 has pink petals. If an F2 is produced by selfing the F1, the result is Genetica per Scienze Naturali a.a. 05-06 prof S. Presciuttini 3. Intermediate dominance Because of the 1:2:1 ratio in the F2, we can deduce an inheritance pattern based on two alleles of a single gene. However, the heterozygotes (the F1 and half the F2) are intermediate in phenotype, suggesting an incomplete type of dominance. Inventing allele symbols, we can list the genotypes of the four-o'clocks in this experiment as c+/c+ (red), c/c (white), and c+/c (pink). Genetica per Scienze Naturali a.a. 05-06 prof S. Presciuttini 4. Incomplete dominance B) Incomplete dominance Incomplete dominance describes the general situation in which the phenotype of a heterozygote is intermediate between the two homozygotes on some quantitative scale of measurement. This figure gives terms for all the theoretical positions on the scale, but in practice it is difficult to determine exactly where on such a scale the heterozygote is located. In cases of full dominance, in the wild-type/mutant heterozygote either half of the normal amount of transcript and product is adequate for normal cell function (the gene is haplo-sufficient), or the wild-type allele is "up-regulated" to bring the concentration of transcript up to normal levels. Genetica per Scienze Naturali a.a. 05-06 prof S. Presciuttini 5. Codominance C) Codominance The human ABO blood groups are determined by three alleles of one gene that show several types of interaction to produce the four blood types of the ABO system. The allelic series includes three major alleles, i, IA, and IB, but of course any person can have only two of the three alleles (or two copies of one of them). There are six different genotypes, the three homozygotes and three different types of heterozygotes: In this allelic series, the alleles IA and IB each determine a unique antigen, which is deposited on the surface of the red blood cells. These are two forms of a single protein. However, the allele i results in no antigenic protein of this type. In the genotypes IA/i and IB/i, the alleles IA and IB are fully dominant to i. However, in the genotype IA/IB each of the alleles produces its own antigen, so they are said to be codominant. Genetica per Scienze Naturali a.a. 05-06 prof S. Presciuttini 6. Relativity of dominance relationships The human disease sickle-cell anemia gives interesting insight into dominance. The gene concerned affects the molecule hemoglobin, which transports oxygen and is the major constituent of red blood cells. The three genotypes have different phenotypes, as follows: In regard to the presence or absence of anemia, the HbA allele is obviously dominant. In regard to blood cell shape, however, there is incomplete dominance. Finally, in regard to hemoglobin itself there is codominance, as the two hemoglobin molecules HbA and HbS can be visualized simultaneously by means of electrophoresis Sickle-cell anemia illustrates that the terms dominance, incomplete dominance, and codominance are somewhat arbitrary. The type of dominance inferred depends on the phenotypic level at which the observations are being made, organismal, cellular, or molecular. Indeed the same caution can be applied to many of the categories that scientists use to classify structures and processes; these categories are devised by humans for convenience of analysis Genetica per Scienze Naturali a.a. 05-06 prof S. Presciuttini 7. Sickle cell anemia The red blood cells of people with sickle cell disease contain an abnormal type of hemoglobin, the oxygen-carrying pigment, called hemoglobin S. The deficiency of oxygen in the blood causes hemoglobin S to crystallize, distorting the red blood cells into a sickle shape, making them fragile and easily destroyed, leading to anemia. Electrophoresis of hemoglobin from an individual with sickle-cell anemia, a heterozygote (called sickle-cell trait), and a normal individual. The smudges show the posi-tions to which the hemoglobins migrate on the starch gel. Genetica per Scienze Naturali a.a. 05-06 prof S. Presciuttini 8. 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. 05-06 prof S. Presciuttini 9. 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. 05-06 prof S. Presciuttini 10. 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 inviable 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. 05-06 prof S. Presciuttini 11. 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. 05-06 prof S. Presciuttini 12. The discovery of PKU In 1934, Asjbørn Følling, a Swedish physician, recognized that a certain type of mental retardation was caused by elevated levels of phenylalanine in body fluids. He identified the disease as an autosomal recessive condition. In the 1940s, Lionel Penrose in the UK introduced the idea that PKU was not randomly distributed in human populations and could be treatable. In the mid-1950s, it was demonstrated that individuals with PKU had a deficiency of hepatic cytosolic phenylalanine hydroxylase (PAH) enzyme activity. Next it was shown that affected individuals responded to dietary restriction of the essential nutrient phenylalanine. During the 1980s, the human PAH gene was mapped and cloned, and the first mutations identified. In the 1990s, in vitro expression analysis was being used to study the effects of different PAH alleles on enzyme function and the crystal structure of PAH was elucidated. Genetica per Scienze Naturali a.a. 05-06 prof S. Presciuttini 13. Screening and treatment of PKU By the 1960s, a microbial inhibition assay was used for mass screening of newborns, providing early diagnosis and access to successful treatment. In the 1970s, it was discovered that not all cases of hyperphenylalaninemia (HPA) was PKU. Some forms of HPA were caused by disorders of synthesis and recycling of the cofactor [tetrahydrobiopterin (BH4)] involved in the phe hydroxylation reaction (genetic heterogeneity). HPA is treatable. Affected individuals can lead normal lives. Continuous efforts are made to improve the taste and convenience of the current synthetic dietary supplements. Research to improve the current treatment with restrictive phenylalanine diets, supplemented by medical formula, is still ongoing. Genetica per Scienze Naturali a.a. 05-06 prof S. Presciuttini 14. Distribution of blood phenylalanine concentration The phenylalanine tolerance test. A short time after administering a measured amount of phenylalanine to the subject, the concentration of phenylalanine in the blood plasma is measured. The level is usually substantially higher in people who carry one PKU gene (even though they show no signs of disease) than in individuals who are homozygous for the unmutated gene Genetica per Scienze Naturali a.a. 05-06 prof S. Presciuttini 15. The complexity of “simple” Mendelian traits Phenylalanine hydroxylase deficiency is a 'multifactorial disorder' in that both environment (dietary intake of phe) and genotype (mutation of the PAH gene) are necessary causal components of disease. Because each individual has a personal genome, even those with similar mutant PAH genotypes may not have similar 'PKU' phenotypes. Variability of metabolic phenotypes in PAH deficiency is caused primarily by different mutations within the PAH gene. Whereas the genotype does predict the biochemical phenotype (i.e., by phe loading tests), it does not always predict the clinical phenotype (i.e., occurrence of mental retardation). PAH deficiency is therefore a 'complex' disorder at the cognitive and metabolic levels. Genetica per Scienze Naturali a.a. 05-06 prof S. Presciuttini 16. A single amino acid substitution The compounded consequences of one amino acid substitution in hemoglobin to produce sicklecell anemia. Genetica per Scienze Naturali a.a. 05-06 prof S. Presciuttini