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(BQ) Part 2 book Genetics - A conceptual approad has contents: The genetic code and translation, the genetic code and translation, control of gene expression in eukaryotes, quantitative genetics, population genetics, evolutionary genetics, cancer genetics,.... and other contents.
CHAPTER 15 The Genetic Code and Translation The spleen, an organ found in the upper abdomen, plays an important role in defense against infection Isolated congenital asplenia is an autosomal dominant condition in which children are born without a spleen [Sebastian Kaulitzki/Shutterstock.] A Child Without a Spleen T he spleen is an often underappreciated organ Brownish in color and weighing about a third of a pound, it sits in the left upper part of your abdomen, storing blood and filtering out bacteria and old blood cells The spleen is underappreciated because it’s widely believed that you can live without a spleen Indeed, many people who lose their spleen to automobile accidents and other trauma survive, although they are at increased risk of infection But a young child without a spleen is in serious trouble A small group of children are born without spleens; these kids are highly susceptible to life-threatening bacterial infections, and many die in childhood This rare disorder, known as isolated congenital asplenia (ICA), is inherited as an autosomal dominant trait Except for the absence of a spleen, children with ICA are unaffected But their immune function is severely compromised When infected with bacteria that the immune system normally eliminates, these children develop raging infections that quickly spread throughout the body Even when treated with modern antibiotics, they often die In 2013, an international team led by scientists from Rockefeller University discovered the genetic cause of ICA Using the power of DNA sequencing, they examined all the coding DNA of 23 individuals with ICA and compared their DNA sequences with those of 508 individuals with normal spleens Statistical analysis pointed to differences in one particular gene that was associated with ICA, a gene encoding ribosomal protein SA (RPSA) The RPSA protein is one of the 33 proteins that make up the small subunit of the ribosome, the organelle responsible for protein synthesis How a defect in the RPSA gene results in the absence of a spleen is not known Diseases such as ICA, which result from defective ribosomes, are referred to as ribosomopathies Many, but not all, individuals with ICA have mutations in RPSA, indicating that other genes may also be involved in the disorder The researchers found several different types of mutations in RPSA associated with ICA: some caused premature stop codons, halting translation before a functional protein could be made; one was a frameshift mutation, a change that alters the way the mRNA sequence is read during translation; others changed the amino acid sequence of the RPSA protein One interesting but unanswered question is why a defect in RPSA affects only the spleen Inherited mutations in RPSA occur in every cell of the body, and protein synthesis—carried out by ribosomes—is essential for numerous life processes, yet these mutations affect only the development of the spleen Why aren’t other organs altered? Why aren’t numerous physiological functions affected? Scientists are still studying these important questions THINK-PAIR-SHARE Propose some possible reasons why mutations in the RPSA gene affect only the spleen and not other tissues where ribosomes carry out translation What are some possible reasons that researchers might be interested in identifying the gene that causes a genetic disease such as ICA? In other words, what benefits might result from this research? solated congenital asplenia illustrates the extreme importance of translation, the process of protein synthesis, which is the focus of this chapter We begin by examining the molecular relation between genotype and phenotype Next, we study the genetic code—the instructions that specify the amino acid sequence of a protein—and then examine the mechanism of translation Our primary focus is protein synthesis in bacterial cells, but we also examine some features of this process in eukaryotic cells At the end of the chapter, we look at some additional aspects of protein synthesis I 15.1 Many Genes Encode Proteins The first person to suggest the existence of a relation between genotype and proteins was English physician Archibald Garrod In 1908, Garrod correctly proposed that genes encode enzymes, but unfortunately, his theory made little impression on his contemporaries Not until the 1940s, when George Beadle and Edward Tatum examined the genetic basis of biochemical pathways in the bread mold Neurospora, did the relation between genes and proteins become widely accepted Beadle and Tatum’s work helped define the relation between genotype and phenotype by leading to the one gene, one enzyme hypothesis, the idea that each gene encodes a separate enzyme THINK-PAIR-SHARE Question The One Gene, One Enzyme Hypothesis Beadle and Tatum used Neurospora to study the biochemical results of mutations Neurospora is easy to cultivate in the laboratory, and the main vegetative part of the fungus is haploid, which allows the effects of otherwise recessive mutations to be easily observed (Figure 15.1) Wild-type Neurospora grows on minimal medium, which contains only inorganic salts, nitrogen, a carbon source such as sucrose, and the vitamin biotin The fungus can synthesize all the biological molecules that it needs from these basic compounds However, mutations may arise that disrupt fungal growth by destroying the fungus’s ability to synthesize one or more essential biological molecules These nutritionally deficient mutants, termed auxotrophs (see Chapter 9), cannot grow on minimal medium, but they can grow on medium that contains the substance that they are no longer able to synthesize Beadle and Tatum first irradiated spores of Neurospora to induce mutations (Figure 15.2) Then they placed the spores in different culture tubes with complete medium (medium containing all the biological substances needed for growth) These spores grew into fungi and produced spores by mitosis Next, they transferred spores from each culture to tubes containing minimal medium Fungi with auxotrophic mutations did not grow on the minimal medium, which allowed Beadle and Tatum to identify cultures that possessed mutations Once they had determined that a particular culture had an auxotrophic mutation, Beadle and Tatum set out to determine the specific effect of the mutation They transferred spores of each mutant strain from complete medium to a series of tubes (see Figure 15.2), each of which contained minimal medium plus one of a variety of essential biological molecules, such as an amino acid If the spores in a tube grew, Beadle and Tatum were able to identify the added substance as the biological molecule whose synthesis had been affected by the mutation For example, an auxotrophic mutant that would grow only on minimal medium to which arginine had been added must have possessed a mutation that disrupts the synthesis of arginine 15.1 Beadle and Tatum used the fungus Neurospora, which has a complex life cycle, to work out the relation of genes to proteins [Namboori B Raju, Stanford University.] 15.2 Beadle and Tatum developed a method for isolating auxotrophic mutants in Neurospora Adrian Srb and Norman H Horowitz patiently applied this procedure to genetically dissect the multistep biochemical pathway of arginine synthesis (Figure 15.3) They first isolated a series of auxotrophic mutants whose growth required arginine Then they tested these mutants for their ability to grow on minimal medium supplemented with three compounds: ornithine, citrulline, and arginine From the results, they were able to place the mutants into three groups on the basis of which of the substances allowed growth (Table 15.1) Based on these results, Srb and Horowitz proposed that the biochemical pathway leading to the amino acid arginine has at least three steps: They concluded that the mutations in group I affect step of this pathway, mutations in group II affect step 2, and mutations in group III affect step But how did they know that the order of the compounds in the biochemical pathway was correct? Notice that if step is blocked by a mutation, then the addition of either ornithine or citrulline allows growth because these compounds can still be converted into arginine (see Figure 15.3) Similarly, if step is blocked, the addition of citrulline allows growth, but the addition of ornithine has no effect If step is blocked, the spores will grow only if arginine is added to the medium The underlying principle is that an auxotrophic mutant cannot synthesize any compound that comes after the step blocked by a mutation Using this reasoning with the information in Table 15.1, we can see that the addition of arginine to the medium allows all three groups of mutants to grow Therefore, biochemical steps affected by all the mutants precede the step that results in arginine The addition of citrulline allows group I and group II mutants to grow, but not group III mutants; therefore, group III mutations must affect a biochemical step that takes place after the production of citrulline but before the production of arginine: TABLE 15.1 Growth of arginine auxotrophic mutants on minimal medium with various supplements Mutant Strain Ornithine Citrulline Arginine Group I + + + Group II − + + Group III − − + Note: A plus sign (+) indicates growth; a minus sign (−) indicates no growth 15.3 Method used to determine the relation between genes and enzymes in Neurospora The biochemical pathway shown here leads to the synthesis of arginine in Neurospora Steps in the pathway are catalyzed by enzymes affected by mutations The addition of ornithine allows the growth of group I mutants, but not group II or group III mutants; thus, mutations in groups II and III affect steps that come after the production of ornithine We’ve already established that group II mutations affect a step before the production of citrulline; so group II mutations must block the conversion of ornithine into citrulline: Chapter 22 Ada, G L., and G Nossal 1987 The clonal-selection theory Scientific American 257(2): 62–69 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UAA, UAG, and UGA are termination (stop) codons As we learned in Chapter 14, tRNAs serve as adapter molecules that bind particular amino acids and deliver them to a ribosome, where the amino acids... (see Chapter 7), they were able to demonstrate that mutations affecting any one step in a pathway always occurred at the same chromosomal location Beadle and Tatum reasoned that mutations affecting... for translation and all 20 amino acids A different amino acid was radioactively labeled in each of the 20 tubes Radioactive protein appeared in only one of the tubes—the one containing labeled