Basic Genetics PDF

1 Introduction to Genetics CHAPTER CONCEPTS Genetics in the twenty-first century is built on a rich tradition of discovery and experimentation stretching from the ancient world through the nineteenth Newer model organisms in genetics i...

1 Introduction to Genetics CHAPTER CONCEPTS Genetics in the twenty-first century is built on a rich tradition of discovery and experimentation stretching from the ancient world through the nineteenth Newer model organisms in genetics include the roundworm, ­Caenorhabditis century to the present day. elegans; the zebrafish, Danio rerio; and the mustard plant, Arabidopsis Transmission genetics is the general thaliana. process by which traits controlled by genes are transmitted through gametes from generation to generation. Mutant strains can be used in genetic O crosses to map the location and distance ne of the small pleasures of writing a genetics textbook is being between genes on chromosomes. able to occasionally introduce in the very first paragraph of the The Watson–Crick model of DNA initial chapter a truly significant breakthrough in the discipline structure explains how genetic that has started to have a major, diverse impact on human lives. In this edi- information is stored and expressed. This tion, we are fortunate to be able to discuss the discovery of CRISPR-Cas, a discovery is the foundation of molecular molecular mechanism found in bacteria that has the potential to revolution- genetics. ize our ability to rewrite the DNA sequence of genes from any organism. Recombinant DNA technology As such, it represents the ultimate tool in genetic technology, whereby the revolutionized genetics, was the genome of organisms, including humans, may be precisely edited. Such gene foundation for the Human Genome modification represents the ultimate application of the many advances in Project, and has generated new fields that combine genetics with information biotechnology made in the last 35 years, including the sequencing of the technology. human genome. Biotechnology provides genetically Although gene editing was first made possible with other methods, the modified organisms and their products CRISPR-Cas system is now the method of choice for gene modification because that are used across a wide range of it is more accurate, more efficient, more versatile, and easier to use. CRISPR- fields including agriculture, medicine, Cas was initially discovered as a “seek and destroy” mechanism that bacteria and industry. use to fight off viral infection. CRISPR (clustered regularly interspersed short Model organisms used in genetics palindromic repeats) refers to part of the bacterial genome that produces research are now utilized in combination RNA molecules, and Cas (CRISPR-associated) refers to a nuclease, or DNA- with recombinant DNA technology and cutting enzyme. The CRISPR RNA binds to a matching sequence in the viral genomics to study human diseases. DNA (seek) and recruits the Cas nuclease to cut it (destroy). Researchers Genetic technology is developing faster have harnessed this technology by synthesizing CRISPR RNAs that direct Cas than the policies, laws, and conventions nucleases to any chosen DNA sequence. In laboratory experiments, CRISPR- that govern its use. Cas has already been used to repair mutations in cells derived from indi- viduals with genetic disorders, such as cystic fibrosis, Huntington disease, 1 2 1 Introduction to Genetics sickle-cell disease, and muscular dystrophy. In the United by a succession of developmental events that eventually trans- States a clinical trial using CRISPR-Cas for genome editing form the egg into an adult. The theory of epigenesis directly in cancer therapy is recruiting participants, while proposals conflicted with the theory of preformationism, which stated for treating a genetic form of blindness and genetic blood dis- that the fertilized egg contains a complete miniature adult, orders are in preparation. In China, at least 86 patients have called a homunculus (Figure 1.1). Around 1830, Matthias already started receiving treatments in CRISPR-Cas clinical Schleiden and Theodor Schwann proposed the cell theory, trials for cancer. stating that all organisms are composed of basic structural The application of this remarkable system goes far units called cells, which are derived from preexisting cells. beyond developing treatments for human genetic disorders. The idea of spontaneous generation, the creation of living In organisms of all kinds, wherever genetic modification may organisms from nonliving components, was disproved by benefit human existence and our planet, the use of CRISPR- Louis Pasteur later in the century, and living organisms were Cas will find many targets. For example, one research group then considered to be derived from preexisting organisms and edited a gene in mosquitoes, which prevents them from car- to consist of cells. rying the parasite that causes malaria in humans. Other In the mid-1800s the work of Charles Darwin and researchers have edited the genome of algae to double their Gregor Mendel set the stage for the rapid development of output for biofuel production. The method has also been genetics in the twentieth and twenty-first centuries. used to create disease-resistant strains of wheat and rice. The power of this system, like any major technological advance, has already raised ethical concerns. For example, Darwin and Mendel genetic modification of human embryos would change the In 1859, Darwin published On the Origin of Species, describ- genetic information carried by future generations. These ing his ideas about evolution. Darwin’s geological, geo- modifications may have unintended and significant nega- graphical, and biological observations convinced him that tive consequences for our species. In 2017, an international existing species arose by descent with modification from panel of experts discussed the science, ethics, and gover- ancestral species. Greatly influenced by his voyage on the nance of human genome editing. The panel recommended HMS Beagle (1831–1836), ­Darwin’s thinking led him to caution, but not a ban, stating that human embryo modifica- formulate the theory of natural ­selection, which pre- tion should “only be permitted for compelling reasons and sented an explanation of the mechanism of evolutionary under strict oversight.” change. Formulated and proposed independently by Alfred CRISPR-Cas may turn out to be one of the most exciting Russel Wallace, natural selection is based on the observation genetic advances in decades. We will return later in the text to discuss its discovery in bacteria (Chapter 15), its devel- opment as a gene-editing tool (Chapter 17), its potential for gene therapy (Special Topic Chapter 3 Gene Therapy), and its uses in genetically edited foods (Special Topic Chapter 6 Genetically Modified Foods). For now, we hope that this short introduction has stimulated your curiosity, interest, and enthusiasm for the study of genetics. The remainder of this chapter provides an overview of many important concepts of genetics and a survey of the major turning points in the history of the discipline. 1.1 Genetics Has an Interesting Early History While as early as 350 b.c., Aristotle proposed that active “humors” served as bearers of hereditary traits, it was not until the 1600s that initial strides were made to understand the biological basis of life. In that century, the physician and anatomist William Harvey proposed the theory of epigenesis, FIGUR E 1.1  Depiction of the homunculus, a sperm contain- which states that an organism develops from the fertilized egg ing a miniature adult, perfect in proportion and fully formed.  1.2 Genetics Progressed from Mendel to DNA in Less Than a Century 3 that populations tend to produce more offspring than the The Chromosome Theory of Inheritance: environment can support, leading to a struggle for survival Uniting Mendel and Meiosis among individuals. Those individuals with heritable traits Mendel did his experiments before the structure and role of that allow them to adapt to their environment are better chromosomes were known. About 20 years after his work able to survive and reproduce than those with less adap- was published, advances in microscopy allowed research- tive traits. Over time, advantageous variations, even very ers to identify chromosomes and establish that, in most slight ones, will accumulate. If a population carrying these eukaryotes, members of each species have a characteris- inherited variations becomes reproductively isolated, a new tic number of chromosomes called the diploid number species may result. (2n) in most of their cells. For example, humans have a dip- Darwin, however, lacked an understanding of the loid number of 46 (Figure 1.2). Chromosomes in diploid genetic basis of variation and inheritance, a gap that left cells exist in pairs, called homologous chromosomes. his theory open to reasonable criticism well into the twen- Researchers in the last decades of the nineteenth cen- tieth century. Shortly after Darwin published his book, tury also described chromosome behavior during two forms Gregor Johann Mendel published a paper in 1866 show- of cell division, mitosis and meiosis. In mitosis, chromo- ing how traits were passed from generation to generation somes are copied and distributed so that each daughter cell in pea plants and offered a general model of how traits are receives a diploid set of chromosomes identical to those in inherited. His research was little known until it was partially the parental cell. Meiosis is associated with ­gamete for- duplicated and brought to light by Carl Correns, Hugo de mation. Cells produced by meiosis receive only one chro- Vries, and Erich Tschermak around 1900. mosome from each chromosome pair, and the resulting By the early part of the twentieth century, it became number of chromosomes is called the haploid number clear that heredity and development were dependent on (n). This reduction in chromosome number is essential if genetic information residing in genes contained in chromo- the ­offspring arising from the fusion of egg and sperm are somes, which were then contributed to each individual by to maintain the constant number of chromosomes charac- gametes—the so-called chromosome theory of inheritance. The teristic of their parents and other members of their species. gap in Darwin’s theory was closed, and Mendel’s research Early in the twentieth century, Walter Sutton and The- now serves as the foundation of genetics. odor Boveri independently noted that the behavior of chro- mosomes during meiosis is identical to the behavior of genes 1.2 Genetics Progressed from Mendel to DNA in Less Than a Century Because genetic processes are fundamental to life itself, the science of genetics unifies biology and serves as its core. The starting point for this branch of science was a monastery gar- den in central Europe in the late 1850s. Mendel’s Work on Transmission of Traits Gregor Mendel, an Augustinian monk, conducted a decade- long series of experiments using pea plants. He applied quantitative data analysis to his results and showed that traits are passed from parents to offspring in predictable ways. He further concluded that each trait in pea plants is controlled by a pair of factors (which we now call genes) and that members of a gene pair separate from each other during gamete formation (the formation of egg cells and sperm). Mendel’s findings explained the transmission of traits in pea plants and all other higher organisms. His work forms the foundation for genetics, the branch of biology concerned with the study of heredity and varia- FIGUR E 1.2 A colorized image of a replicated set of human tion. Mendelian genetics will be discussed later in the text male chromosomes. Arranged in this way, the set is called a (see Chapters 3 and 4). karyotype. 4 1 Introduction to Genetics F IGURE 1.3  The white-eyed mutation in D. melanogaster (top) and the normal red eye color (bottom). during gamete formation described by Mendel. For example, was established, investigators turned their attention to iden- genes and chromosomes exist in pairs, and members of a gene tifying which chemical component of chromosomes car- pair and members of a chromosome pair separate from each ries genetic information. By the 1920s, scientists knew that other during gamete formation. Based on these and other proteins and DNA were the major chemical components of parallels, Sutton and Boveri each proposed that genes are chromosomes. There are a large number of different pro- carried on chromosomes. They independently formulated teins, present in both the nucleus and cytoplasm, and many the chromosomal theory of inheritance, which states that researchers thought proteins carried genetic information. inherited traits are controlled by genes residing on chromo- In 1944, Oswald Avery, Colin MacLeod, and Maclyn somes faithfully transmitted through gametes, maintaining McCarty, researchers at the Rockefeller Institute in New York, genetic continuity from generation to generation. published experiments showing that DNA was the carrier of genetic information in bacteria. This evidence, though clear- cut, failed to convince many influential scientists. Additional ES S E N TIAL P OINT evidence for the role of DNA as a carrier of genetic informa- The chromosome theory of inheritance explains how tion came from Alfred Hershey and Martha Chase who worked genetic information is transmitted from generation to with viruses. This evidence that DNA carries genetic informa- generation. tion, along with other research over the next few years, pro- vided solid proof that DNA, not protein, is the genetic material, setting the stage for work to establish the structure of DNA. Genetic Variation About the same time that the chromosome theory of inheritance was proposed, scientists began studying the inheritance of traits in the fruit fly, Drosophila melanogaster. 1.3 Discovery of the Double Helix Early in this work, a white-eyed fly (Figure 1.3) was discov- Launched the Era of Molecular ered among normal (wild-type) red-eyed flies. This variation Genetics was produced by a mutation in one of the genes controlling eye color. Mutations are defined as any heritable change in Once it was accepted that DNA carries genetic information, the DNA sequence and are the source of all genetic variation. efforts were focused on deciphering the structure of the DNA The white-eye variant discovered in Drosophila is an allele molecule and the mechanisms by which information stored of a gene controlling eye color. Alleles are defined as alterna- in it produce a phenotype. tive 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 Structure of DNA and RNA the genotype. Using mutant genes as markers, geneticists can One of the great discoveries of the twentieth century was map the location of genes on chromosomes (Figure 1.5). made in 1953 by James Watson and Francis Crick, who described the structure of DNA. DNA is a long, ladder- The Search for the Chemical Nature like macromolecule that twists to form a double helix of Genes: DNA or Protein? (­Figure 1.4). Each linear strand of the helix is made up Work on white-eyed Drosophila showed that the mutant trait of subunits called nucleotides. In DNA, there are four could be traced to a single chromosome, confirming the idea ­different nucleotides, each of which contains a nitrogenous that genes are carried on chromosomes. Once this relationship base, abbreviated A (adenine), G (guanine), T (thymine),  1.3 Discovery of the Double Helix Launched the Era of Molecular Genetics 5 Gene P Sugar A T P (deoxyribose) DNA P Nucleotide C G P P 3' 5' G C TAC C AC A AC TC G P Phosphate P DNA template strand T A P Complementary Transcription base pair (thymine-adenine) mRNA 5' 3'  The structure of DNA showing the arrange- F I G U R E 1.4 ment of the double helix (on the left) and the chemical AUGGUGUUGAGC ­components making up each strand (on the right). The dot- Triplet code words ted lines on the right represent weak chemical bonds, called hydrogen bonds, which hold together the two strands of the DNA helix. Translation on ribosomes or C (cytosine). These four bases, in various sequence ­combinations, ultimately encode genetic information. The two strands of DNA are exact complements of one another, Met Val Leu Ser so that the rungs of the ladder in the double helix always Protein consist of A = T and G =C base pairs. Along with Maurice Amino acids Wilkins, Watson and Crick were awarded a Nobel Prize in 1962 for their work on the structure of DNA. We will discuss FIGUR E 1.5 Gene expression consists of transcription of DNA into mRNA (top) and the translation (center) of mRNA the structure of DNA later in the text (see Chapter 9). (with the help of a ribosome) into a protein (bottom). Another nucleic acid, RNA, is chemically similar to DNA but contains a different sugar (ribose rather than deoxyri- Protein assembly is accomplished with the aid of bose) in its nucleotides and contains the nitrogenous base adapter molecules called transfer RNA (tRNA). Within uracil in place of thymine. RNA, however, is generally a the ribosome, tRNAs recognize the information encoded in single-stranded molecule. the mRNA codons and carry the proper amino acids for con- struction of the protein during translation. We now know that gene expression can be more com- Gene Expression: From DNA to Phenotype plex than outlined here. Some of these complexities will be The genetic information encoded in the order of nucleotides discussed later in the text (see Chapters 15 and 16). in DNA is expressed in a series of steps that results in the for- mation of a functional gene product. In the majority of cases, this product is a protein. In eukaryotic cells, the process Proteins and Biological Function leading to protein production begins in the nucleus with In most cases, proteins are the end products of gene expres- transcription, in which the nucleotide sequence in one sion. The diversity of proteins and the biological functions strand of DNA is used to construct a complementary RNA they perform—the diversity of life itself—arises from the fact sequence (top part of Figure 1.5). Once an RNA molecule that proteins are made from combinations of 20 different is produced, it moves to the cytoplasm, where the RNA— amino acids. Consider that a protein chain c­ ontaining 100 called messenger RNA, or mRNA for short—binds to a amino acids can have at each position any one of 20 amino ribosome. The synthesis of proteins under the direction of acids; the number of possible different 100-­amino-acid pro- mRNA is called translation (center part of Figure 1.5). The teins, each with a unique sequence, is therefore equal to information encoded in mRNA (called the genetic code) 20100 consists of a linear series of nucleotide triplets. Each trip- let, called a codon, is complementary to the information Obviously, proteins are molecules with the potential for stored in DNA and specifies the insertion of a specific amino enormous structural diversity and serve as a mainstay of acid into a protein. Proteins (lower part of Figure 1.5) are biological systems. polymers made up of amino acid monomers. There are Enzymes form the largest category of proteins. These 20 different amino acids commonly found in proteins. molecules serve as biological catalysts, lowering the energy 6 1 Introduction to Genetics of activation in reactions and allowing cellular metabolism to proceed at body temperature. Proteins other than enzymes are critical components of cells and organisms. These include hemoglobin, the oxygen- binding molecule in red blood cells; insulin, a pancreatic hormone; collagen, a connective tissue molecule; and actin and myosin, the contractile muscle proteins. A protein’s shape and chemical behavior are determined by its linear sequence of amino acids, which in turn is dictated by the stored information in the DNA of a gene that is transferred to RNA, which then directs the protein’s synthesis. Linking Genotype to Phenotype: Sickle-Cell Anemia Once a protein is made, its biochemical or structural proper- ties play a role in producing a phenotype. When mutation FIGUR E 1.7 Normal red blood cells (round) and sickled alters a gene, it may modify or even eliminate the encoded red blood cells. The sickled cells block capillaries and small protein’s usual function and cause an altered phenotype. To blood vessels. trace this chain of events, we will examine sickle-cell ane- mia, a human genetic disorder. ES S ENTIA L POINT Sickle-cell anemia is caused by a mutant form of hemo- The central dogma of molecular biology -- that DNA globin, the protein that transports oxygen from the lungs is a template for making RNA, which in turn directs to cells in the body. Hemoglobin is a composite molecule the synthesis of proteins -- explains how genes control made up of two different proteins, a@globin and b@globin, phenotype. each encoded by a different gene. In sickle-cell anemia, a mutation in the gene encoding b@globin causes an amino acid substitution in 1 of the 146 amino acids in the protein. Individuals with two mutant copies of the b@globin gene Figure 1.6 shows the DNA sequence, the corresponding have sickle-cell anemia. Their mutant b@globin proteins mRNA codons, and the amino acids occupying positions 4–7 cause hemoglobin molecules in red blood cells to polymer- for the normal and mutant forms of b@globin. Notice that the ize when the blood’s oxygen concentration is low, forming mutation in sickle-cell anemia consists of a change in one long chains of hemoglobin that distort the shape of red blood DNA nucleotide, which leads to a change in codon 6 in mRNA cells (Figure 1.7). Deformed cells are fragile and break eas- from GAG to GUG, which in turn changes amino acid num- ily, reducing the number of circulating red blood cells (ane- ber 6 in b@globin from glutamic acid to valine. The other 145 mia is an insufficiency of red blood cells). Sickle-shaped amino acids in the protein are not changed by this mutation. cells block blood flow in capillaries and small blood vessels, causing severe pain and damage to the heart, brain, muscles, and kidneys. All the symptoms of this disorder are caused NORMAL B-GLOBIN by a change in a single nucleotide in a gene that changes one DNA............................ TGA GGA CTC CTC............ mRNA........................ ACU CCU GAG GAG............ amino acid out of 146 in the b@globin molecule, demonstrat- Amino acid.............. Thr Pro Glu Glu........ ing the close relationship between genotype and phenotype. 4 5 6 7 MUTANT B-GLOBIN DNA............................ TGA GGA CAC CTC............ mRNA........................ ACU CCU GUG GAG............ 1.4 Development of Recombinant Amino acid.............. Thr Pro Val Glu........ DNA Technology Began the Era 4 5 6 7 of DNA Cloning FI G U R E 1. 6 A single-nucleotide change in the DNA encod- The era of recombinant DNA began in the early 1970s, ing b@globin (ctc S cAc) leads to an altered mRNA codon when researchers discovered that restriction enzymes, (GAG S GuG) and the insertion of a different amino acid used by bacteria to cut and inactivate the DNA of invad- (Glu S val), producing the altered version of the b@globin protein that is responsible for sickle-cell anemia. ing viruses, could be used to cut any organism’s DNA at  1.5 The Impact of Biotechnology Is Continually Expanding 7 s­ pecific nucleotide sequences, producing a reproducible set of fragments. Soon after, researchers discovered ways to insert the DNA fragments produced by the action of restriction enzymes into carrier DNA molecules called vectors to form recombi- nant DNA molecules. When transferred into bacterial cells, thousands of copies, or clones, of the combined vector and DNA fragments are produced during bacterial reproduction. Large amounts of cloned DNA fragments can be isolated from these bacterial host cells. These DNA fragments can be used to isolate genes, to study their organization and expression, and to study their nucleotide sequence and evolution. Collections of clones that represent an organism’s genome, defined as the complete haploid DNA content of a specific organism, are called genomic libraries. Genomic libraries are now available for hundreds of species. Recombinant DNA technology has not only accel- erated the pace of research but also given rise to the bio- FIGUR E 1.8  Dolly, a Finn Dorset sheep cloned from the technology industry, which has grown to become a major genetic material of an adult mammary cell, shown next to contributor to the U.S. economy. her first-born lamb, Bonnie. New methods of cloning livestock such as sheep and cattle have changed the way we use these animals. In 1996, Dolly the sheep (Figure 1.8) was cloned by nuclear trans- 1.5 The Impact of Biotechnology fer, a method in which the nucleus of an adult cell is trans- Is Continually Expanding ferred into an egg that has had its nucleus removed. This makes it possible to produce dozens or hundreds of geneti- The use of recombinant DNA technology and other molecu- cally identical offspring with desirable traits with many lar techniques to make products is called biotechnology. In applications in agriculture and medicine. the United States, biotechnology has quietly revolutionized Biotechnology has also changed the way human pro- many aspects of everyday life; products made by biotech- teins for medical use are produced. Through use of gene nology are now found in the supermarket, in health care, transfer, transgenic animals now synthesize these thera- in agriculture, and in the court system. A later chapter (see peutic proteins. In 2009, an anticlotting protein derived Chapter 18) contains a detailed discussion of biotechnology, from the milk of transgenic goats was approved by the U.S. but for now, let’s look at some everyday examples of biotech- Food and Drug Administration for use in the United States. nology’s impact. Other human proteins from transgenic animals are now being used in clinical trials to treat several diseases. The biotechnology revolution will continue to expand as gene Plants, Animals, and the Food Supply editing by CRISPR/Cas and other new methods are used to The use of recombinant DNA technology to genetically develop an increasing array of products. modify crop plants has revolutionized agriculture. Genes for traits including resistance to herbicides, insects, and genes for nutritional enhancement have been introduced Biotechnology in Genetics and Medicine into crop plants. The transfer of heritable traits across spe- More than 10 million children or adults in the United States cies using recombinant DNA technology creates t­ ransgenic suffer from some form of genetic disorder, and every child- organisms. Herbicide-resistant corn and soybeans were bearing couple faces an approximately 3 percent risk of first planted in the mid-1990s, and transgenic strains now having a child with a genetic anomaly. The molecular basis represent about 88 percent of the U.S. corn crop and 93 for hundreds of genetic disorders is now known, and most percent of the U.S. soybean crop. It is estimated that more of these genes have been mapped, isolated, and cloned. than 70 percent of the processed food in the United States Biotechnology-derived genetic testing is now available to ­contains ingredients from transgenic crops. perform prenatal diagnosis of heritable disorders and to We will discuss the most recent findings involving test parents for their status as heterozygous carriers of more genetically modified organisms later in the text. (Special than 100 inherited disorders. Newer methods now offer the Topics Chapter 6—Genetically Modified Foods). possibility of scanning an entire genome to establish an 8 1 Introduction to Genetics individual’s risk of developing a genetic disorder or having of naturally occurring mutations or intentionally induced an affected child. The use of genetic testing and related tech- mutations (using chemicals, X-rays, or UV light as examples) nologies raises ethical concerns that have yet to be resolved. to cause altered phenotypes in model organisms, and then worked through the labor-intensive and ­time-consuming process of identifying the genes that caused these new phe- ES S E N TIAL P OINT notypes. Such characterization often led to the identifica- Biotechnology has revolutionized agriculture and the tion of the gene or genes of interest, and once the technology pharmaceutical industry, while genetic testing has had a advanced, the gene sequence could be determined. profound impact on the diagnosis of genetic diseases. Classical genetics approaches are still used, but as whole genome sequencing has become routine, molecular approaches to understanding gene function have changed considerably in genetic research. These modern approaches are what we will highlight in this section. 1.6 Genomics, Proteomics, For the past two decades or so, geneticists have relied on the use of molecular techniques incorporating an approach and Bioinformatics Are New referred to as reverse genetics. In reverse genetics, the DNA and Expanding Fields sequence for a particular gene of interest is known, but the role and function of the gene are typically not well under- The ability to create genomic libraries prompted scientists stood. For example, molecular biology techniques such as to consider sequencing all the clones in a library to derive gene knockout render targeted genes nonfunctional in a the nucleotide sequence of an organism’s genome. This model organism or in cultured cells, allowing scientists to sequence information would be used to identify each gene investigate the fundamental question of “what happens if in the genome and establish its function. this gene is disrupted?” After making a knockout organism, One such project, the Human Genome Project (HGP), scientists look for both apparent phenotype changes, as well began in 1990 as an international effort to sequence the as those at the cellular and molecular level. The ultimate human genome. By 2003, the publicly funded HGP and a goal is to determine the function of the gene being studied. private, industry-funded genome project completed sequencing of the gene-containing portion of the genome. ES S ENTIA L POINT As more genome sequences were acquired, several new Recombinant DNA technology gave rise to several new biological disciplines arose. One, called genomics (the study of fields, including genomics, proteomics, and bioinformat- genomes), studies the structure, function, and evolution of genes ics, which allow scientists to explore the structure and and genomes. A second field, proteomics, identifies the set of evolution of genomes and the proteins they encode. proteins present in a cell under a given set of conditions, and studies their functions and interactions. To store, retrieve, and analyze the massive amount of data generated by genomics and proteomics, a specialized subfield of information technol- 1.7 Genetic Studies Rely on the Use ogy called bioinformatics was created to develop hardware and software for processing nucleotide and protein data. of Model Organisms Geneticists and other biologists now use information in databases containing nucleic acid sequences, protein After the rediscovery of Mendel’s work in 1900, research sequences, and gene-interaction networks to answer experi- using a wide range of organisms confirmed that the prin- mental questions in a matter of minutes instead of months ciples of inheritance he described were of universal signifi- and years. A feature called “Exploring Genomics,” located at cance among plants and animals. Geneticists gradually came the end of many of the chapters in this textbook, gives you to focus attention on a small number of organisms, includ- the opportunity to explore these databases for yourself while ing the fruit fly (Drosophila melanogaster) and the mouse completing an interactive genetics exercise. (Mus musculus) (Figure 1.9). This trend developed for two main reasons: First, it was clear that genetic mechanisms were the same in most organisms, and second, these organ- Modern Approaches to Understanding isms had characteristics that made them especially suitable Gene Function for genetic research. They were easy to grow, had relatively Historically, an approach referred to as classical or forward short life cycles, produced many offspring, and their genetic genetics was essential for studying and understanding analysis was fairly straightforward. Over time, researchers gene function. In this approach geneticists relied on the use created a large catalog of mutant strains for these species,  1.7 Genetic Studies Rely on the Use of Model Organisms 9 opening photograph. Each species was chosen to allow study of some aspect of embryonic development. The nematode Caenorhabditis elegans was chosen as a model system to study the development and function of the nervous system because its nervous system contains only a few hundred cells and the developmental fate of these and all other cells in the body has been mapped out. Arabidopsis thaliana, a small plant with a short life cycle, has become a model organism for the study of many aspects of plant biology. The zebraf- ish, Danio rerio, is used to study vertebrate development: it is small, it reproduces rapidly, and its egg, embryo, and larvae (a) are all transparent. (b) Model Organisms and Human Diseases F I G U R E 1.9 The first generation of model organisms in The development of recombinant DNA technology and the genetic analysis included (a) the mouse, Mus musculus, and results of genome sequencing have confirmed that all life has (b) the fruit fly, Drosophila melanogaster. a common origin. Because of this, genes with similar func- tions in different organisms tend to be similar or identical and the mutations were carefully studied, characterized, in structure and nucleotide sequence. Much of what scien- and mapped. Because of their well-­characterized genetics, tists learn by studying the genetics of model organisms can these species became model organisms, defined as organ- therefore be applied to humans as the basis for understand- isms used for the study of basic biological processes. In later ing and treating human diseases. In addition, the ability to chapters, we will see how discoveries in model organisms are create transgenic organisms by transferring genes between shedding light on many aspects of biology, including aging, species has enabled scientists to develop models of human cancer, and behavior. diseases in organisms ranging from bacteria to fungi, plants, and animals (Table 1.1). The idea of studying a human disease such as colon cancer The Modern Set of Genetic Model Organisms by using E. coli may strike you as strange, but the basic steps of Gradually, geneticists added other species to their col- DNA repair (a process that is defective in some forms of colon lection of model organisms: viruses (such as the T phages cancer) are the same in both organisms, and a gene involved in and lambda phage) and microorganisms (the bacterium DNA repair (mutL in E. coli and MLH1 in humans) is found in Escherichia coli and the yeast Saccharomyces cerevisiae) both organisms. More importantly, E. coli has the advantage (Figure 1.10). of being easier to grow (the cells divide every 20 minutes), and More recently, additional species have been developed researchers can easily create and study new mutations in the as model organisms, three of which are shown in the chapter bacterial mutL gene in order to figure out how it works. This knowledge may eventually lead to the development of drugs and other therapies to treat colon cancer in humans. The fruit fly, Drosophila melanogaster, is also being used to study a number of human diseases. Mutant genes TABLE 1.1 Model Organisms Used to Study Some Human Diseases Organism Human Diseases E. coli Colon cancer and other cancers S. cerevisiae Cancer, Werner syndrome D. melanogaster Disorders of the nervous system, (a) cancer C. elegans Diabetes (b) D. rerio Cardiovascular disease M. musculus Lesch–Nyhan syndrome, cystic  Microbes that have become model organ- F I G U R E 1.10 ­fibrosis, fragile-X syndrome, and isms for genetic studies include (a) the yeast Saccharomy- many other diseases ces cerevisiae and (b) the bacterium Escherichia coli. 10 1 Introduction to Genetics have been identified in D. melanogaster that produce pheno- types with structural abnormalities of the nervous system 1.8 Genetics Has Had a Profound and adult-onset degeneration of the nervous system. The Impact on Society information from genome-sequencing projects indicates that almost all these genes have human counterparts. For Mendel described his decade-long project on inheritance example, genes involved in a complex human disease of the in pea plants in an 1865 paper presented at a meeting of retina called retinitis pigmentosa are identical to Drosophila the Natural History Society of Brünn in Moravia. Less genes involved in retinal degeneration. Study of these muta- than 100 years later, the 1962 Nobel Prize was awarded to tions in Drosophila is helping to dissect this complex disease James ­Watson, Francis Crick, and Maurice Wilkins for their and identify the function of the genes involved. work on the structure of DNA. This time span encompassed Another approach to studying diseases of the human the years leading up to the acceptance of Mendel’s work, the nervous system is to transfer mutant human disease genes discovery that genes are on chromosomes, the experiments into Drosophila using recombinant DNA technology. The that proved DNA encodes genetic information, and the eluci- transgenic flies are then used for studying the mutant dation of the molecular basis for DNA replication. The rapid human genes themselves, other genes that affect the expres- development of genetics from Mendel’s monastery garden to sion of the human disease genes, and the effects of thera- the Human Genome Project and beyond is summarized in a peutic drugs on the action of those genes—all studies that timeline in Figure 1.11. are difficult or impossible to perform in humans. This gene transfer approach is being used to study almost a dozen The Nobel Prize and Genetics human neurodegenerative disorders, including Huntington disease, Machado–Joseph disease, myotonic dystrophy, and No other scientific discipline has experienced the explosion Alzheimer disease. of information and the level of excitement generated by the Throughout the following chapters, you will encounter discoveries in genetics. This impact is especially apparent in these model organisms again and again. Remember each the list of Nobel Prizes related to genetics, beginning with time you meet them that they not only have a rich history those awarded in the early and mid-twentieth century and in basic genetics research but are also at the forefront in the continuing into the present (see inside back cover). Nobel study of human genetic disorders and infectious diseases. Prizes in Medicine or Physiology and Chemistry have been consistently awarded for work in genetics and related fields. The first such prize awarded was given to Thomas H. Morgan ES S E N TIAL P OINT in 1933 for his research on the chromosome theory of inheri- tance. That award was f­ ollowed by many others, including The study of model organisms for understanding human prizes for the discovery of genetic recombination, the rela- health and disease is one of the many ways genetics and tionship between genes and proteins, the structure of DNA, biotechnology are changing everyday life. and the genetic code. This trend has continued throughout DNA shown to carry genetic information. Watson–Crick model of DNA Chromosome theory of Recombinant DNA technology inheritance proposed. developed. DNA cloning Mendel’s Application of Transmission genetics begins work published genomics begins evolved 1860s 1870s 1880s 1890s 1900s 1910s 1920s 1930s 1940s 1950s 1960s 1970s 1980s 1990s 2000s 2010s............. Mendel’s work Era of molecular genetics. Genomics begins. Gene editing rediscovered, correlated Gene expression, regulation Human Genome Project using TALENS with chromosome behavior understood initiated and CRISPR/Cas9 in meiosis FI G U R E 1. 11 A timeline showing the development of research, medicine, and society. Having a sense of the history genetics from Gregor Mendel’s work on pea plants to of discovery in genetics should provide you with a useful the current era of genomics and its many applications in framework as you proceed through this textbook.  PROBLEMS AND DISCUSSION QUESTIONS 11 the twentieth and twenty-first centuries. The advent of therapy, and genetic privacy. Two features appearing at the genomic studies and the applications of such findings will end of most chapters, “Case Study” and “Genetics, Ethics, and most certainly lead the way for future awards. Society,” consider ethical issues raised by the use of genetic technology. This emphasis on ethics reflects the growing concern and dilemmas that advances in genetics pose to our Genetics, Ethics, and Society society and the future of our species. It is our hope that upon Just as there has never been a more exciting time to study the completion of your study of genetics, you will become an genetics, the impact of this discipline on society has never been informed, active participant in future debates that arise. more profound. Genetics and its applications in ­biotechnology are developing much faster than the social conventions, pub- lic policies, and laws required to regulate their use. As a soci- ES S ENTIA L POINT ety, we are grappling with a host of sensitive genetics-related Genetic technology is having a profound effect on society, issues, including concerns about prenatal testing, genetic dis- while raising many ethical dilemmas. crimination, ownership of genes, access to and safety of gene Mastering Genetics Visit for Problems and Discussion Questions ­instructor-assigned tutorials and problems. 1. Describe Mendel’s conclusions about how traits are passed from 10. Outline the roles played by restriction enzymes and vectors in generation to generation. cloning DNA. 2. CONCEPT QUESTION Review the Chapter Concepts list on p. 1. 11. What are some of the impacts of biotechnology on crop plants in Most of these are related to the discovery of DNA as the genetic the United States? material and the subsequent development of recombinant DNA 12. Summarize the arguments for and against patenting genetically technology. Write a brief essay that discusses the impact of modified organisms. recombinant DNA technology on genetics as we perceive the dis- 13. We all carry about 20,000 genes in our genome. So far, patents cipline today. have been issued for more than 6000 of these genes. Do you think 3. What is the chromosome theory of inheritance, and how is it that companies or individuals should be able to patent human related to Mendel’s findings? genes? Why or why not? 4. Define genotype and phenotype. Describe how they are related 14. How has the use of model organisms advanced our knowledge of and how alleles fit into your definitions. the genes that control human diseases? 5. Given the state of knowledge at the time of the Avery, MacLeod, 15. If you knew that a devastating late-onset inherited disease runs and McCarty experiment, why was it difficult for some scientists in your family (in other words, a disease that does not appear to accept that DNA is the carrier of genetic information? until later in life) and you could be tested for it at the age of 20, 6. Contrast chromosomes and genes. would you want to know whether you are a carrier? Would your 7. How is genetic information encoded in a DNA molecule? answer be likely to change when you reach age 40? 8. Describe the central dogma of molecular genetics and how it 16. Why do you think discoveries in genetics have been recognized serves as the basis of modern genetics. with so many Nobel Prizes? 9. How many different proteins, each with a unique amino acid sequence, can be constructed that have a length of five amino acids?