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Chapter 1 - Using pea plants Mendel revealed the...

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Unformatted text preview: Using pea plants, Mendel revealed the fundamental principles of transmission genetics. Work by others showed that genes are on chromosomes, and that mutant strains can be used to map genes on chromosomes. The discovery that DNA encodes genetic informationaand solving the structure of DNA and the mechanism of gene expression form the foundation of molecular genetics. 5-5 '3‘ The development of recombinant DNA technology revolutionized genetics and is the foundation for _'genome sequencing, including the Human fienome Project. o Biotechnology uses recombinant DNA technology to produce goods and services in a wide range of areas, including agriculture, medicine, and industry. The use of biotechnology has raised many legal and ethical issues involving the patenting of genetically modified organisms, and the use of gene therapy. {c‘an‘ilric‘isecr‘ \. " ' . tiny-.4tiffsjoirlen' ,-:'.T:3'f.‘€'i "‘ (Téi'l‘i'f'fii'fiifl'fi‘. - Model organisms have been used in genetics since the early part of the twentieth century. The extensive genetic knowledge gained from these organisms coupled with recombinant DNA technology and genomics makes these organisms useful as models to study human diseases. c Genetic technology is developing faster than policy, law, and convention in the use of this technology. Education and participation are key elements in the wise use of this technology. 3N0 saidvnj 2 Chapter 1 Introduction to GenetiCS rom our perspective early in the twentysfirst century, we can look back and ask when the interaction between ge— netic technology and society began to affect our lives. Did it begin when recombinant DNA technology was used to produce insulin, when the first food produced by genetic engi- neering reached the marketplace, or when gene therapy was first used to treat a genetic disorder? While each of these is an incremental step in using genetic knowledge in ways affecting society, we will focus on a case where the use of genetic tech— nology directly affects the citizens of an entire country. This case captures how genetics has a significant impact on society and provides a glimpse of future implications as more advances and applications are developed. In December 1998, a controversy affecting the 270,000 resi- dents of the island nation of Iceland was coming to a head. Fol- lowing months of heated debate, the Icelandic Parliament passed a law granting deCODE, a biotechnology company with headquarters in Iceland, a license to create and operate a data- base called IHD (Icelandic Health Sector Database) containing detailed information drawn from coded {to ensure anonymity) medical records of all Iceland residents. The law also allows de- CODE to cross-reference medical information from the IHD with a comprehensive genealogical database from the National ‘Archiyes. In additioggdigCQDEgan correlate information in - these two databases with results of DNA profiles collected from Icelandic donors. The combination of disease, genealogical, and genetic information is a powerful resource available ex- clusively to deCODE, which can market this information to re- searchers and companies for a period of 12 years. This is not a scenario from a movie such as Gottaca, but a real example of the interaction underway between genetics and society as we begin a new century. The development and use of these databases in Iceland has spurred the creation of simiw lar projects in other countries as well. The largest is the “UK Biobank“ effort launched in Great Britain in 2003. There, a huge database containing the genetic information of 500,000 Britons will be compiled from an initial group of [.2 million residents. The database will be used to search for susceptibil- ity genes that control complex traits. Similar projects to develop nationwide databases have been an“ nounced in Estonia, Latvia, Sweden. Singapore, and the Kingdom of Tonga, illustrating the global impact of genetic technology. In the United States, smaller-scale programs involving tens of thousands of individuals are underway at the Marshfield Clinic in Marshfield. Wisconsin; Northwestern University in Chicago, Illinois; and Howard University in Washington, DC. Why did deCODE select Iceland for such a project? Becauso for several reasons, the people of Iceland represent a unique case of genetic uniformity seldom seen or accessible to scientific investi- gation. This high degree of genetic relatedness results from the peopling of Iceland about 1,000 years ago by a small founding population drawn mainly front Scandinavian and Celtic sources, periodic population reductions by disease and natural disasters that further reduced genetic diversity and, until the least few decades, a lack of immigrants bringing new genes into the population. Thus, for geneticists trying to identify genes that control complex dis- orders, the Icelandic population is a tremendous asset. Because of the state—supported health care system, medical records exist for l cocled th all residents as far back as the early 1900s. Genealogical infor- mation is available in the National Archives and church records for almost every resident and for more than 500,000 of the estimated 750,000 individuals who have ever lived in Iceland. In spite of the associated controversies, the project already has a number of suc— cesses to its credit. Scientists at deCODE have identified genes associated with more than 25 of the most common diseases, iri— eluding asthma, heart disease, stroke, and osteoporosis. On the flip side of these successes are issues of privacy, con- sent, and commercialization—issues at the heart of many controversies arising from the applications of genetic technol- ogy. Scientists and nonscientists alike are considering the fate and control of genetic information as it is acquired, and the role of law and society in decisions about how and when genetic tech— nology is used. For example, how will knowledge of the complete nucleotide sequence of the human genome be used? More than at any other time in the history of science, addressing the ethi— cal questions surrounding an emerging technology is now as im— portant as the information gained from that technology. As you launch your study of genetics, remain sensitive to questions and issues like those just described. There has never been a more exciting time to be part of this science, but never has the need for caution and awareness of social issues been more apparent. This text will enable you to achieve a thorough understanding of modern—day genetics and its underlying prin- ciples. Along the way, enjoy your studies, but take your re- sponsibilities as a novice geneticist very seriously. From Mendel to DNA in Less Than a Century Because genetic processes are fundamental to the comprehen- sion of life itself, the discipline of genetics is thought by many to sit at the center ofbioiogy. Genetic information directs cel- lular function, largely determines an organism’s external ap- pearance, and serves as the link between generations in every species. As such, knowledge of genetics is essential to the thor- ough understanding of other disciplines, including molecular biology, cell biology, physiology. evolution. ecology, system— atics, and behavior. Genetics therefore unifies biology and serves as its core. Thus, it is not surprising that genetics has a long, rich history. Our starting point for this history is a monastery garden in central Europe in the 18605. Mendel’s Work on Transmi '5 garden (Figure 1—1 , conducted a decad l pea plants I ' f Trats g, 5%.,” . W _ i e further concluded that genes controlling a trait ex s "'1 pairs, and that members of a gene pair separate from each other during gamete formation. His work was published in 1866 but was largely ignored until it was partially duplicated and cited in papers by Carl Correns and others around 1900. Having been confirmed by others, Mendel's findings became FlGURE 1—1 The monastery garden where Gregor Mendel conducted his experiments with garden peas. In 1866, Mendel put forward the major postulates of transmission genetics. recognized as the basis for the transmi ‘ c . En The Chromosome Theory of Inheritance: Uniting Mendel and Meiosis 7_ Mendel did his work before the structure and role. of chromo- isornes lvais known. About twenty years after his work. advances in microscopy allowed researchers to identify chromosomes (Figure 1—2). and to establish that in eukaryotic organisms (those with a nucleus and cellular membrane systems). each species has a characteristic number of chromosomes called the diploid number (2:2). For example, humans have a diploid number of 46 {Figure 1—3). Chromosomes in diploid cells exist in pairs. called homologous chromosomes. Members of a pair are identical in size and location of the centromere. a structure to which spindle fibers attach during division. in addition, researchers in the last decades of the nineteenth century described the behavior of chromosomes during two forms of cell division, mitosis and meiosis. In mitosis (Figure 14). chromosomes are copied and distributed so that the two resulting daughter cells each receive a diploid set of 1.1 From Mendel to DNA in Less Than a Century 3 FIGURE 1—2 Colorized image of human mitotic chromosomes as visualized under the scanning electron microscope. FIGURE 1~3 A colorized image of the human male chromosome set. Arranged in this wayr the set is called a karyotype. FIGURE 1—4 A stage in mitosis (anaphase) when the chromosomes (stained blue) move apart. 4 Chapter‘l Introduction to Genetics I FIGURE 1—5 Chromosome l (the X chromosome) of D. melanogaster, showing the location of many genes. Chromosomes can contain hundreds of genes. scute bristles, 5c ' white eyes, w ruby eyes, rb _ e crossveinless ' wings, cv '5; 7 singed bristles, sn 7 chromosome-s. Meiosis is a form of cell division associated with gamete formation in animals and spore. for- mation in most plants. Cells produced by meiosis receive only one copy of each chromosomecalled the haploid lozenge eyes, lz a vermilion eyes, v i: - sable body, 5 (n_l_num_l_3_er of chromosomes. This reduction in chromosome number is r scalloped essential if the offspring arising from Win95: 50' two gametes are to maintain a con- ga, eyes, 3 stant number of chromosomes char— acteristic of their parents and other members of their species. Early in the twentieth century. Wal- ter Sutton and Theodore Boveri inde— pendently noted that genes and chromosomes have properties in com— mon and that the behavior of chroa mosomes during meiosis is identical to the behavior of genes during gamete formation. For example, genes and chromo- somes exist in pairs and members of a gene pair and members of a chromosome pair separate from each other during gamete formation. Based on these parallels, they each proposed that genes are carried on chromosomes (Figure 175). This proposal is the basis of the chromosome theory of inheritance. which carnation eyes, car little fly, if states that inherited traits are controlled by genes residing on' chromosomes that are faithfully transmitted through gametes. maintaining genetic continuity from generation to generation. Genetic Variation About the same time that the chromosome theory of inheriv lance was proposed. scientists began studying the inheritance of traits in the fruit fly. Drosophr'ln melanogrrsrer. Soon after. a white-eyed fly (Figure [—6) was discovered in a bottle cone taining normal [wild-type] red—eyed flies. This variation was produced by mutation. an. inherited change in the gene con trolling eye color. Chromosomal mutations affect the number and structure of chromosomes. Mutations, whether genetic or chromosomal are defined as any heritable change. and are the source of all genetic variation. The variant gene discovered in Drosophila represents an allele ofthe eye color gene. Alleles are defined as alternative forms of a gene. Different alleles may produce differences in the observable features. or phenotype of an organism. The set of alleles for a given trait carried by an organism is called the (W 5.3“ . FIGURE 1—6 The normal red eye color in Drosophila (bottom) and the white—eyed mutant (top). genotype. Using mutant genes as markers. geneticists were able to map the location of genes on chromosomes. The Search for the Chemical Nature of Genes: DNA or Protein? “fork on white-eyed Dmsophifa showed that the mutant trait had a pattern of inheritance that could be traced to a single chromosome. confirming the idea that genes are carried on chromosomes. Once this was established. investigators turned their attention to identifying which chemical component of f chromosomes carried genetic information. By the [9203, DNA and proteins Were identified as the major chemical components of chromosomes. Proteins are the most abundantcomponent in cells. There are a large number ofdifferent proteins and be- cause of their universal distribution in the nucleus and cyto- plasm. many researchers thought proteins would be shown to be the carrier of genetic information. In 1944. Avery, MacLeod, and McCarty, three researchers at the Rockefeller Institute in New York. provided experimental evidence that DNA was the carrier of genetic information in bacteria. This evidence, although clear—cut. failed to convince many influential scientists. Additional evidence for the role of DNA as a carrier of genetic information came from other re— searchers who worked with viruses lhat infect and kill cells of the bacterium Escherichia coir (Figure 1—7]. One of these viruses. called a bacteriophage. or phage for short, consists of a protein coat surrounding a DNA core. These experiments showed that the protein coat of the virus remains outside the cell. while the DNA enters the cell and directs the synthesis and assembly of more phage. This work was more proof that 1.2 Discovery of the Double Helix Launched the Recombinant DNA Era 5 FIGURE 1-—7 An electron micrograph showing T phage infecting a cell of the bacterium E. coli. DNA carries genetic information. Additional experiments over the next few years provided solid proof that DNA. not protein, is the genetic material. setting the stage for work to establish the structure of DNA. Discovery of the Double Helix Launched the Recombinant DNA Era Once it was accepted that nucleic acid in the form of DNA car- ries genetic information, efforts were focused on deciphering the structure of DNA, and the mechanism by which informa— tion stored in this molecule is expressed to produce an observe able phenotype. in the years after this was accomplished. researchers learned how to isolate and make copies of specific regions of DNA molecules. opening the way for the era of re— combinant DNA technology. The Structure of DNA and RNA DNA is a long. ladder-like molecule that forms a double helix. Each strand of the helix is a linear molecule made up of subunits called nucleotides. In DNA. there are four different nucleotides. Each DNA nucleotide contains one of four nitrogenous bases — A (adenine). G (guanine), T (thymine), or C (cytosine). These four bases comprise the genetic alphabet, or genetic code. which-in various combinations ultimately specify the amino acid sequence of proteins. One of the great discoveries of the twentieth century was made in 1953 by James Watson and Fran- cis Crick. who established that the two strands of DNA are exact complements of one another. such lhat' the rungs of the ladder in the double helix always consist of either A=T or GEC base pairs. As we shall see in a later chapter, this complement- ary relationship between adenine and thymine and between guanine and cytosine is critical to genetic function. This rela~ tionship serves as the basis for both the replication of DNA and for the basis of gene expression. During both processes. DNA b... .. c «t. .h _,«-- (36.: 3' I Sugar ‘ E (deoxyribose) h * Nucleotide * Phosphate Complementary base pair (thymine-adenine) FIGURE 1—3 Summary of the structure of DNA, illustrating the nature of the double helix (on the left) and the chemical components making up each strand (on the right). strands serve as templates for the synthesis of complementary molecules. Two depictions of the structure and components of DNA are shown in Figure [—8. RNA, another nucleic acid, is chemically similar to DNA. contains a different sugar (ribose vs. deoxyriboselin its nucleotides, and contains the nitrogenous base uracil in place of thymine. Additionally, in contrast to the double helix of DNA, RNA is generally single stranded. lmpbttantty,-tr can form complementary structures With a strand of DNA;- Gene Expression: From DNA to Phenotype As noted earlier. complementarity is the basis for steps in gene ex" pression. This process begins with the transcription of the Chem- ical information in DNA into RNA (Figure 1—9). OnggniRNA [UQchulecomplementary to one strand of DNA is transcribed. the RNA directs the synthesis of proteins. This is accomplished when the RNA%alled messenger RNA. or mRNA. for short— binds to a ribosome. The synthesis of proteins under the direc- tion omeNA is called translation ( bottom part of Figure 1—9). Proteins, as the end product of genes, are polymers made up of amino acid monomers. There are 20 different amino. acids in living organisms. How can information contained in mRNA direct the inser- tion of specific amino acids into protein chains as they are syn— thesized? The answer is now quite clear. The genetic code consists of a linear series of triplet nucleotides present in mRNA molecules. Each triplet reflects the information stored in DNA and specifies the insertion of a specific amino acid into the growing protein chain. This is accomplished by the action of adapter molecules called transfer RNA (tRNAJ_. Within the rtbosoiiiatRNAuecogtuaethejntormaumacedecl in the LRNA.lflpl€l§_E1Dd specii'thC properjmino acidfiirjascttion into theorem n_c.iur,i_ag,tt=_1_n§lation. As the preceding discussion shows. DNA makes RNA, which most often makes protein. These processes. known as the central dogma of genetics. occur with great specificity. Using Introduction to Genetics 6 Chapter 1 ):‘\ ,1 . . . [r l" l Transcrtptlon inRNA Translation complex Ribosome Translation l? rotei n FIGURE 1—9 Gene expression involves transcription of DNA into mRNA (top) and the translation (center) of mRNA on a ribosome into a protein (bottom). an alphabet of only four letters (A, T, C, and G). genes direct the synthesis of highly specific proteins that collectively serve as the basis for all biological function. Proteins and Biological Function As we have mentioned, proteins are the end products of gene expression. These molecules are responsible for imparting the properties that we attribute to living systems. The diverse na- ture of biological function rests with the fact that proteins are made front 20 different amino acids. In a protein chain that is just 100 amino acids in length, at each position there can be any one of 20 amino acids; the number of different 100 amino acid proteins. each with a unique sequence, is equal to 20lUU Because 2010 exceeds 5 X lOlZ, or more than 5 trillion, imagine how large 20100 is! Obviously. evolution has seized on a class of molecules with the potential for enormous structural divetu sity to serve as the mainstay of biological systems. The__large_s_t category 7 3f 7 proteins includes enzymes (Figure 1:10). Thelserrmoleeulesrserve as biological catalysm sentially allowing biochemical reactions to proceed at rates that FIGURE 1—10 The three—dimensional conformation of a protein. The amino acid sequence of the protein is depicted as a ribbon. sustain life under the conditions that exist on Earth. By lowers ing the energy of activation in reactions, metabolism is able to proceed under the direction of enzymes at body temperature. There are countgssprotiejns other than enzymes that are critical components of cells and organisms. These include hemoglo...
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