Introduction to Genetic Analysis Chapter 1 PDF

CHAPTER The Genetics Revolution 1 DNA (deoxyribonucleic acid) is the...

CHAPTER The Genetics Revolution 1 DNA (deoxyribonucleic acid) is the molecule that encodes genetic information. The strings of four different chemical bases in DNA store genetic information in much the same way that strings of 0’s and 1’s store information in computer code. [Sergey Nivens/ Shutterstock.] CHAPTER OU TLIN E AN D LE A R N ING OBJECTIVES 1.1 THE BIRTH OF GENETICS LO 1.1 Know the experiments by which genetics developed from Mendel to today. LO 1.2 Know the molecules involved in storage and expression of genetic information. 1.2 AFTER CRACKING THE CODE LO 1.3 Know the basic tools for genetic research including model organisms. 1.3 GENETICS TODAY LO 1.4 Give examples of how genetics has influenced our society. 1  Genetics is a form of information science. Geneticists seek to understand the rules that govern the transmission of genetic information at three levels—from parent to offspring within families, from DNA to gene action CHAPTER OBJECTIVE within and between cells, and over many generations within populations of organisms. These three foci of genetics are known as transmission genetics, molecular-developmental genetics, and population-evolutionary genetics. The three parts of this text examine these three foci of genetics. T he science of genetics was born about 120 years ago. Like begets like Since that time, genetics has profoundly changed our understanding of life, from the level of the individ- ual cell to that of a population of organisms evolving over millions of years. In 1900, William Bateson, a prominent British biologist, wrote presciently that an “exact deter- mination of the laws of heredity will probably work more change in man’s outlook on the world, and in his power over nature, than any other advance in natural knowledge that can be foreseen.” Throughout this text, you will see the realization of Bateson’s prediction. Genetics has driven a revolution in both the biological sciences and society in general. In this first chapter, we will look back briefly at the his- tory of genetics, and in doing so, we will review some of the basic concepts of genetics that were discovered over the last century. After that, we will look at a few examples of how genetic analysis is being applied to critical problems in biology, agriculture, and human health today. You will see how contemporary research in genetics integrates concepts discovered decades ago with recent technological advances. You will see that genetics today is a dynamic field of inves- tigation in which new discoveries continually advance our understanding of the biological world. FIGURE 1-1 Family groups in the gray wolf show familial resemblances for coat colors and patterning. [(Top) DLILLC/Corbis/ VCG/Getty Images; (bottom) Bev McConnell/Getty Images.] 1.1 THE BIRTH OF GENETICS LO 1.1 Know the experiments by which genetics developed from Mendel to today. the Hopi farmers hoped to harvest. Upon receiving this LO 1.2 Know the molecules involved in storage message, the gods would faithfully return them a plant that and expression of genetic information. produced kernels of the desired color. In the 1800s in Europe, horticulturalists, animal breed- Throughout recorded history, people around the world ers, and biologists also sought to explain the resemblance have understood that “like begets like.” Children resemble between parents and offspring. A commonly held view at their parents, the seed from a tree bearing flavorful fruit that time was the blending theory of inheritance, or the will in turn grow into a tree laden with flavorful fruit, and belief that inheritance worked like the mixing of fluids even members of wolf packs show familial resemblances such as paints. Red and white paints, when mixed, give (Figure 1-1). Although people were confident in these obser- pink; and so a child of one tall parent and one short par- vations, they were left to wonder as to the underlying ent could be expected to grow to a middling height. While mechanism. The Native American Hopi tribe of the south- blending theory works at times, it is also clear that there western United States understood that if they planted a red are exceptions, such as tall children born to parents of aver- kernel of maize in their fields, it would grow into a plant age height. Blending theory also provides no mechanism by that also gave red kernels. The same was true for blue, which the imagined “heredity fluids,” once mixed, could be white, or yellow kernels. So they thought of the kernel as separated—the red and white paints cannot be reconstituted a message to the gods in the Earth about the type of maize from the pink. Thus, the long-term expectation of blending 2  1.1 The Birth of Genetics 3 theory over many generations of intermating among indi- One of Mendel’s experiments viduals is that all members of the population will come to express the same average value of a trait. Clearly, this is not how nature works. There are people with a range of heights, from short to tall, and we have not all narrowed in Parents × on a single average height despite the many generations that humans have dwelled on Earth. Gregor Mendel—A monk in the garden While the merits and failings of blending theory were being Two gene debated, Gregor Mendel, an Austrian monk, was working copies to understand the rules that govern the transmission of traits from parent to offspring after hybridization among different varieties of pea plants (Figure 1-2). The setting for First-generation his work was the monastery garden in the town of Brünn, hybrid Austria (Brno, Czech Republic, today). From 1856 to 1863, Mendel cross-pollinated or intermated different varieties of the pea plant. One of his experiments involved crossing a pea variety with purple flowers to one with white flowers Self-pollination (Figure 1-3). Mendel recorded that the first hybrid gener- ation of offspring from this cross all had purple flowers, Second-generation just like one of the parents. There was no blending. Then, hybrids Mendel self-pollinated the first-generation hybrid plants and grew a second generation of offspring. Among the Eggs Sperm progeny, he saw plants with purple flowers as well as plants with white flowers. Of the 929 plants, he recorded 705 with purple flowers and 224 with white flowers (Figure 1-4). He observed that there were roughly 3 purple-flowered plants for every 1 white-flowered plant. How did Mendel explain his results? Clearly, blending theory would not work since that theory predicts a uniform group of first-generation hybrid plants with light purple flow- ers. So Mendel proposed that the factors that control traits act like particles rather than fluids and that these particles do not blend together but are passed intact from one generation to the next. Today, Mendel’s particles are known as genes. Mendel proposed that each individual pea plant has two copies of the gene that controls flower color in each of 3 purple : 1 white the cells of the plant body Gregor Mendel ( somatic cells ). However, FIGURE 1-3 The mating scheme for Mendel’s experiment involving when the plant forms sex the crossing of purple- and white-flowered varieties of pea plants. The cells, or gametes (eggs and purple and white circles signify the gene variants for purple vs. white flower color. Gametes carry one gene copy; the plants each carry two sperm), only one copy of the gene copies. The “×” signifies a cross-pollination between the purple- gene enters into these repro- and white-flowered plants. ductive cells (see Figure 1-3). A N I M ATED A RT Then, when egg and sperm unite to start a new individ- A basic plant cross ual, once again there will be two copies of the flower color gene in each cell of the plant body. and one that conditions white flowers. He proposed that Mendel had some fur- the purple allele of the flower color gene is dominant to the ther insights. He proposed white allele such that a plant with one purple allele and FIGURE 1-2 Gregor Mendel that the gene for flower one white allele would have purple flowers. Only plants with was an Austrian monk who discovered the laws of color comes in two gene two white alleles would have white flowers (see Figure 1-3). inheritance. [James King-Holmes/ variants, or alleles—one that Mendel’s two conclusions, (1) that genes behaved like par- Science Source.] conditions purple flowers ticles that do not blend together and (2) that one allele is 4 CHAPTER 1 The Genetics Revolution Mendel’s 1866 publication it, “There are people who William Bateson gave seem to be born in a van- genetics its name ishing cap. Mendel was one of them.” Mendel rediscovered As the legend goes, when the British biologist William Bateson (Figure 1-5) boarded a train bound for a confer- ence in London in 1900, he had no idea how profoundly his world would change during the brief journey. FIGURE 1-5 William Bateson, Bateson carried with him the British zoologist and a copy of Mendel’s 1866 evolutionist who introduced paper on the hybridization the term genetics for the study of inheritance and promoted of plant varieties. Bateson Mendel’s work. [SPL/Science had recently learned that Source.] biologists in Germany, the Netherlands, and Austria had each independently reproduced Mendel’s 3:1 ratio, and they each cited Mendel’s original work. Bateson needed to read Mendel’s paper. By the time FIGURE 1-4 Excerpts from Mendel’s 1866 publication, Versuche über Pflanzen-Hybriden (Experiments on Plant Hybrids). [Augustinian he stepped off the train, Bateson had a new mission in life. Abbey in Old Brno, Courtesy of the Masaryk University, Mendel Museum.] He understood that the mystery of inheritance had been solved. He soon became a relentless apostle of Mendel’s laws of inheritance. A few years later in 1905, Bateson coined the dominant to the other, enabled him to explain the lack of term genetics—the study of inheritance. The genetics revolu- blending in the first-generation hybrids and the re-appearance tion had begun. of white-flowered plants in the second-generation hybrids When Mendel’s laws of inheritance were rediscovered with a 3:1 ratio of purple- to white-flowered plants. This rev- in 1900, a flood of new thinking was unleashed. Mendel- olutionary advance in our understanding of inheritance will ism became the organizing principle for much of biology. be fully discussed in Chapter 2. There were many new questions to be asked about inheri- KEY CONCEPT Mendel concluded that (1) genes behave tance. Table 1-1 summarizes the chronology of seminal dis- like particles and do not blend together, and (2) one allele is coveries made over the coming decades and the chapters of dominant to the other. this text that cover each of these topics. Let’s look briefly at a few of the questions and their answers that transformed How did Mendel get it right when so many others the biological sciences. before him were wrong? Mendel chose a good organism Where in the cell are Mendel’s genes? The answer came in and good traits to study. The traits he studied were all con- 1910, when Thomas H. Morgan at Columbia University in trolled by single genes. Traits that are controlled by several New York demonstrated that Mendel’s genes are located on genes, as many traits are, would not have allowed him to chromosomes—he proved the chromosome theory of inher- discover the laws of inheritance so easily. Mendel was also itance. The idea was not new. Walter Sutton, who was raised a careful observer, and he kept detailed records of each of on a farm in Kansas and later served as a surgeon for the his experiments. Finally, Mendel was a creative thinker U.S. army during WWI had proposed the chromosome the- capable of reasoning well beyond the ideas of his times. ory of inheritance in 1903. Theodor Boveri, a German biol- Mendel’s particulate theory of inheritance was pub- ogist, independently proposed it at the same time. It was a lished in 1866 in the Proceedings of the Natural History compelling hypothesis, but there were no experimental data Society of Brünn (see Figure 1-4). At that time, his work to support it. This changed in 1910, when Morgan proved was read by some other biologists, but its implications the chromosome theory of inheritance using the fruit fly as and importance went unappreciated for almost 40 years. his experimental organism. In Chapter 4, you will retrace Unlike Charles Darwin, whose theory of evolution by natu- Morgan’s experiments that proved genes are on chromosomes. ral selection made him world-renowned virtually overnight, Can Mendelian genes explain the inheritance of con- when Mendel died in 1884, he was more or less unknown tinuously variable traits such as human height? While in the world of science. As biochemist Erwin Chargaff put 3:1 segregation ratios could be directly observed for simple  1.1 The Birth of Genetics 5 TABLE 1-1 Key Events in the History of Genetics Year Event Chapters 1865 Gregor Mendel showed that traits are controlled by discrete factors now known as genes. 2, 3 1903 Walter Sutton and Theodor Boveri hypothesized that chromosomes are the hereditary elements. 4 1905 William Bateson introduced the term genetics for the study of inheritance. 2 1908 G. H. Hardy and Wilhelm Weinberg proposed the Hardy–Weinberg law, the foundation for population 18 genetics. 1910 Thomas H. Morgan demonstrated that genes are located on chromosomes. 4 1913 Alfred Sturtevant made a genetic linkage map of the Drosophila X chromosome, the first genetic map. 4 1918 Ronald Fisher proposed that multiple Mendelian factors can explain continuous variation for traits, 19 founding the field of quantitative genetics. 1931 Harriet Creighton and Barbara McClintock showed that crossing over is the cause of recombination. 4, 15 1941 Edward Tatum and George Beadle proposed the one-gene–one-polypeptide hypothesis. 5 1944 Oswald Avery, Colin MacLeod, and Maclyn McCarty provided compelling evidence that DNA is the 7 genetic material in bacterial cells. 1946 Joshua Lederberg and Edward Tatum discovered bacterial conjugation. 6 1948 Barbara McClintock discovered mobile elements (transposons) that move from one place to another 16 in the genome. 1950 Erwin Chargaff showed DNA composition follows some simple rules for the relative amounts of A, C, 7 G, and T. 1952 Alfred Hershey and Martha Chase proved that DNA is the molecule that encodes genetic information. 7 1953 James Watson and Francis Crick, using data produced by Rosalind Franklin and Maurice Wilkins, 7 determined that DNA forms a double helix. 1958 Matthew Meselson and Franklin Stahl demonstrated the semiconservative nature of DNA replication. 7 1958 Jérôme Lejeune discovered that Down syndrome resulted from an extra copy of the 21st 17 chromosome. 1961 François Jacob and Jacques Monod proposed that enzyme levels in cells are controlled by feedback 11 mechanisms. 1961–1967 Marshall Nirenberg, Har Gobind Khorana, Sydney Brenner, and Francis Crick “cracked” the genetic 9 code. 1968 Motoo Kimura proposed the neutral theory of molecular evolution. 18, 20 1977 Fred Sanger, Walter Gilbert, and Allan Maxam invented methods for determining the nucleotide 10 sequences of DNA molecules. 1980 Christiane Nüsslein-Volhard and Eric F. Wieschaus defined the complex of genes that regulate body 13 plan development in Drosophila. 1989 Francis Collins and Lap-Chee Tsui discovered the gene causing cystic fibrosis. 4, 10 1995 First genome sequence of a living organism (Haemophilus influenzae) published. 14 1998 Andrew Fire and Craig Mello discover a mechanism of gene silencing by double-stranded RNA. 8, 13 1998 First genome sequence of an animal (Caenorhabditis elegans) published. 14 2001 The sequence of the human genome is first published. 14 2009 Elizabeth H. Blackburn, Carol W. Greider, and Jack W. Szostak win the Nobel prize for their discovery 7 of how chromosomes are protected by telomeres and the enzyme telomerase. 2012 John Gurdon and Shinya Yamanaka win the Nobel Prize for their discovery that just four regulatory 8, 12 genes can convert adult cells into stem cells. 6 CHAPTER 1 The Genetics Revolution Continuous variation for height 4:10 4:11 5:0 5:1 5:2 5:3 5:4 5:5 5:6 5:7 5:8 5:9 5:10 5:11 6:0 6:1 6:2 FIGURE 1-6 Students at the Connecticut Agriculture College in 1914 show a range of heights. Ronald Fisher proposed that continuously variable traits such as human height are controlled by multiple Mendelian genes. traits such as flower color, many traits show a continuous Tatum and Beadle’s breakthrough became known as the range of values in second-generation hybrids without sim- one-gene–one-enzyme hypothesis. You will see how they ple ratios such as 3:1. In 1918, Ronald Fisher, the British developed this hypothesis in Chapter 5. statistician and geneticist, resolved how Mendelian genes What is the physical nature of the gene? Are genes com- explained the inheritance of continuously variable traits posed of protein, nucleic acid, or some other substance? such as height in people (Figure 1-6). Fisher’s core idea was In 1944, Oswald Avery, Colin MacLeod, and Maclyn Mc- that continuous traits are each controlled by multiple Men- Carty offered the first compelling experimental evidence delian genes. Fisher’s insight is known as the multifactorial that genes are made of deoxyribonucleic acid (DNA). They hypothesis. In Chapter 19, we will dissect the experimental showed that DNA extracted from a virulent strain of bac- evidence for Fisher’s hypothesis. teria carried the necessary genetic information to transform a nonvirulent strain into a virulent one. Their inference was KEY CONCEPT The multifactorial hypothesis states that confirmed in 1952 by Alfred Hersey and Martha Chase. continuously variable traits are each controlled by multiple You will learn exactly how they demonstrated this in Mendelian genes. Chapter 7. How can DNA molecules store information? In the 1950s, there was something of a race among several How do genes function inside cells in a way that groups of scientists to answer this question. In 1953, James enables them to control different states for a trait such as Watson and Francis Crick, working at Cambridge Univer- flower color? In 1941, Edward Tatum and George Beadle sity in England, won that race. They determined that the proposed that genes encode enzymes. Using bread mold molecular structure of DNA was in the form of a double (Neurospora crassa) as their experimental organism, they helix—two strands of DNA wound side-by-side in a spi- demonstrated that genes encode the enzymes that perform ral. Their structure of the double helix is like a twisted lad- metabolic functions within cells (Figure 1-7). In the case der (Figure 1-8). The sides of the ladder are made of sugar of the pea plant, there is a gene that encodes an enzyme and phosphate groups. The rungs of the ladder are made of required to make the purple pigment in the cells of a flower. four bases: adenine (A), thymine (T), guanine (G), and The one-gene–one-enzyme model Gene A Gene B Gene C FIGURE 1-7 The one-gene–one-enzyme hypothesis proposed that genes encode enzymes that carry out biochemical functions within cells. Tatum and Beadle proposed this model based on the study of Enzyme A Enzyme B Enzyme C Substrate Ornithine Citrulline Arginine the synthesis of arginine (an amino acid) in the bread mold Neurospora crassa.  1.1 The Birth of Genetics 7 The structure of DNA (a) (b) 5´ O O P 3´ O O N H O H CH2 O A N H N T O O O O O P CH2 O O N H O O O CH2 P C N O O O H NG O H N O O O CH2 P O O O O O H N CH2 P T N H O O O NA O O O O P CH2 O O O H N O O CH2 P O G N H N C O O N H O O O CH2 H 3´ O O P O O 5´ FIGURE 1-8 (a) The double-helical structure of DNA, showing the sugar–phosphate backbone in blue and paired bases in brown. (b) A flattened representation of DNA showing how A always pairs with T, and G always pairs with C. Each row of dots between the bases represents a hydrogen bond. cytosine (C). The bases face the center, and each base is demonstrated that genes have regulatory elements that hydrogen bonded to the base facing it in the opposite strand. control gene expression—that is, whether a gene is turned Adenine in one strand is always paired with thymine in the on or off (Figure 1-9). The regulatory elements are specific other by a double hydrogen bond, whereas guanine is always DNA sequences to which a regulatory protein binds and paired with cytosine by a triple hydrogen bond. The bonding acts as either an activator or repressor of the expression of specificity is based on the complementary shapes and charges the gene. In Chapter 11, you will explore the logic behind of the bases. The sequence of A, T, G, and C represents the the experiments of Jacob and Monod with E. coli, and in coded information carried by the DNA molecule. You will Chapter 12, you will explore the details of gene regulation learn in Chapter 7 how this was all worked out. in eukaryotes. How is the information stored in DNA decoded to syn- KEY CONCEPT DNA is a double helix in which the nucle- thesize proteins? While the discovery of the double-helical otide bases of one strand are paired with those of the other structure of DNA was a watershed for biology, many details strand. Adenine always pairs with thymine, and guanine always were still unknown. Precisely how information was encoded pairs with cytosine. into DNA and how it was decoded to form the enzymes that Tatum and Beadle had shown to be the workhorses of How are genes regulated? Cells need mechanisms to gene action remained unknown. From 1961 through 1967, turn genes on or off in specific cell and tissue types and at teams of geneticists and chemists working in several coun- specific times during development. In 1961, François Jacob tries answered these questions when they “cracked the genetic and Jacques Monod made a conceptual breakthrough on code.” What this means is that they deduced how a string this question. Working on the genes necessary to metabo- of DNA nucleotides, each with one of four different bases lize the sugar lactose in the bacterium Escherichia coli, they (A, T, C, or G), encodes the set of 20 different amino acids 8 CHAPTER 1 The Genetics Revolution Genes have regulatory and coding regions He curiously used the word dogma, “a belief that is to be accepted without doubt,” when he intended hypothesis, “a RNA polymerase testable explanation for an observed phenomenon.” Despite Regulatory complex this awkward beginning, the phrase had an undeniable protein Direction of power and it has survived. transcription Figure 1-10b captures much of what was learned about the biochemistry of inheritance from 1905 until 1967. Let’s GGGCCC review the wealth of knowledge that this simple figure cap- Regulatory Site where the Protein coding element RNA polymerase sequence tures. At the left, you see DNA and a circular arrow repre- complex binds senting DNA replication , the process by which a copy of the DNA is produced. This process enables each of the two FIGURE 1-9 A protein-coding gene includes a regulatory DNA daughter cells that result from cell division to have a complete element (GGGCCC) to which a regulatory protein binds, the site where a group of proteins called the RNA polymerase complex binds copy of all the DNA in the parent cell. In Chapter 7, you will to initiate transcription, and a protein-coding sequence. explore the details of the structure of DNA and its replication. Another arrow connects DNA to RNA, symbolizing that are the building blocks of proteins. They also discovered how the sequence of base pairs in a gene (DNA) is copied that there is a messenger molecule made of ribonucleic acid to an RNA molecule. The process of RNA synthesis from (RNA) that carries information in the DNA in the nucleus to the a DNA template is called transcription. One class of RNA cytoplasm where proteins are synthesized. By 1967, the basic molecules made by transcription is messenger RNA , or flowchart for information transmission in cells was known. mRNA for short. mRNA is the template for protein syn- This flowchart is called the central dogma of molecular biology. thesis. In Chapter 8, you will discover how transcription is accomplished. KEY CONCEPT Genes reside on chromosomes and are The final arrow in Figure 1-10b connects mRNA and made of DNA. Genes encode proteins that conduct the basic protein. This arrow symbolizes protein synthesis, or the enzymatic work within cells. translation of the information in the specific sequence of bases in the mRNA into the sequence of amino acids that compose a protein. Proteins are the workhorses of cells, The central dogma of molecular biology comprising enzymes, structural components of the cell, In 1958, Francis Crick introduced the phrase “central and molecules for cell signaling. The process of translation dogma” to represent the flow of genetic information within takes place at the ribosomes in the cytoplasm of each cell. cells from DNA to RNA to protein, and he drew a sim- In Chapter 9, you will learn how the genetic code is writ- ple diagram to summarize these relationships (Figure 1-10a). ten in three-letter words called codons. A codon is a set of Information transfer among biological molecules (a) Replication Transcription Translation DNA RNA Protein (b) Protein DNA mRNA Ribosome Replication Transcription Translation (DNA synthesis) (RNA synthesis) (protein synthesis) FIGURE 1-10 (a) One version of Francis Crick’s sketch of the central dogma, showing informa- tion flow between biological molecules. The circular arrow represents DNA replication, the central straight arrow represents the transcription of DNA into RNA, and the right arrow the translation of RNA into protein. (b) More detailed sketch showing how the two strands of the DNA double helix A N I M ATED A RT are independently replicated, how the two strands are disassociated for transcription, and how the The central dogma messenger RNA (mRNA) is translated into protein at the ribosome.  1.2 After Cracking the Code 9 three consecutive nucleotides in the mRNA that specifies What features make a species suitable as a model organ- an amino acid in a protein. For example, CGC specifies the ism? (1) Small organisms that are easy and inexpensive to amino acid arginine, AGC specifies serine, and so forth. maintain are very convenient for research. So fruit flies Since Crick proposed the central dogma, additional are good, blue whales not so good. (2) A short generation pathways of genetic information flow have been discov- time is imperative because geneticists, like Mendel, need ered. We now know that there are classes of RNA that do to cross different strains and then study their first- and not code for proteins, instances in which mRNA is edited second-generation hybrids. The shorter the generation time, after transcription, and cases in which the information in the sooner the experiments can be completed. (3) A small RNA is copied back to DNA (see Chapters 8, 9, and 16). genome is useful. As you will learn in Chapter 16, some species have large genomes and others small genomes in KEY CONCEPT Genes are made of DNA, which is terms of the total number of DNA base pairs. Much of the transcribed to RNA molecules that serve as the template extra size of large genome species is composed of repetitive for protein synthesis. DNA elements between the genes. If a geneticist is looking for genes, these can be more easily found in organisms with smaller genomes and fewer repetitive elements. (4) Organ- 1.2 AFTER CRACKING THE CODE isms that are easy to cross or mate and that produce large numbers of offspring are best. LO 1.3 Know the basic tools for genetic research including As you read this textbook, you will encounter certain model organisms. organisms over and over. Organisms such as Escherichia coli (a bacterium), Saccharomyces cerevisiae (baker’s With the basic laws of inheritance largely worked out, the yeast), Caenorhabditis elegans (nematode or round- 1970s and beyond witnessed an era of applying genetic worm), Drosophila melanogaster (fruit fly), and Mus analysis to many questions in biology. Much effort has musculus (mice) have been used repeatedly in experiments been and continues to be invested in developing tools to and revealed much of what we know about how inheri- address these questions. Geneticists focused their research tance works. Model organisms can be found on diverse on a small number of species known as “model organisms” branches of the tree of life (see Figure 1-11), represent- that are well suited for genetic analysis. Then in the late ing bacteria, fungi, algae, plants, and invertebrate and 1990s, the first complete genome sequences were published, vertebrate animals. This diversity enables each geneticist launching the genomics era and the ability to study all the to use a model best suited to a particular question. Each genes in the genome simultaneously. model organism has a community of scientists work- ing on it who share information and resources, thereby Model organisms facilitating each other’s research. More information on each of the most commonly used model organisms can be Geneticists make special use of a small set of model organ- found in “A Brief Guide to Model Organisms” at the end isms for genetic analysis. A model organism is a species used of this book. in experimental biology with the presumption that what is Mendel’s experiments were possible because he had learned from the analysis of that species will hold true for several different varieties of pea plants, each of which other species, especially other closely related species. The phi- carried a different genetic variant for traits such as pur- losophy underlying the use of model organisms in biology ple versus white flowers, or tall versus dwarf stems. For was wryly expressed by Jacques Monod: “Anything found to each of the model species, geneticists have assembled be true of E. coli must also be true of elephants.”1 large numbers of varieties (also called strains or stocks) As genetics matured and focused on model organisms, with special genetic characters that make them useful in Mendel’s pea plants fell to the wayside, but Morgan’s fruit research. For example, there are strains of fruit flies that flies rose to prominence to become one of the most impor- have trait variants such as red versus white eyes. Similarly, tant model organisms for genetic research. New species were there are strains of mice that are prone to develop specific added to the list. An inconspicuous little plant that grows as forms of cancer or other diseases such as diabetes. Genetic a weed called Arabidopsis thaliana became the model plant strains enable geneticists to study how genes influence species, and a minute roundworm called Caenorhabditis ele- physiology, development, and disease. The different gans that lives in compost heaps became a star of genetic strains of each model organism are available to research- analysis in developmental biology (Figure 1-11). ers through stock centers that maintain and distribute the KEY CONCEPT Genetic discoveries made in a model organ- strains. ism are often true of related species and may even apply to all KEY CONCEPT Model organisms have features that make forms of life. them well-suited for genetic studies, such as small size, small genome, large numbers of offspring, and short generation time. Geneticists working with the same model organism share 1 F. Jacob and J. Monod, Cold Spring Harbor Quant. Symp. Biol. 26, stocks and information with one another. 1963, 393. 10 CHAPTER 1 The Genetics Revolution Model organisms are dispersed across the tree of life Fruit fly Drosophila Nematode melanogaster Caenorhabditis elegans Yeast Saccharomyces cerevisiae Mouse Mus musculus Mouse-eared cress Arabidopsis thaliana Mycoplasma gentalium Bacillus subtilis Helicobacter pylori E. coli Eubacteria FIGURE 1-11 The tree shows evolutionary relationships among the major groups of organisms: Bacteria, Archaea, and Eukaryota (plants, fungi, and animals). [(Clockwise, from top, center) Sinclair Stammers/Science Source; SCIMAT/Science Source; Darwin Dale/Science Source; Biophoto Associates/ Science Source; imageBROKER/Superstock; blickwinkel/Alamy.] Tools for genetic analysis or other enzymes, DNA can also be “labeled” or “tagged” Geneticists and biochemists have created an incredible with a fluorescent dye or radioactive element so that the DNA array of tools for characterizing and manipulating DNA, can be detected using a fluorescence or radiation detector. RNA, and proteins. Many of these tools are described in Second, geneticists have developed methods to clone DNA Chapter 10 or in other chapters relevant to a specific tool. molecules. Here, cloning refers to making many copies (clones) There are a few themes to mention here. of a DNA molecule. The common way of doing this involves First, geneticists have harnessed the cell’s own enzymatic isolating a relatively small DNA molecule (up to a few thou- machinery for copying, pasting, cutting, and transcribing sand base pairs in length) from an organism of interest. The DNA, enabling researchers to perform these reactions inside DNA molecule might be an entire gene or a portion of a gene. test tubes. The enzymes that perform each of these func- The molecule is inserted into a host organism (often E. coli) tions in living cells have been purified and are available to where it is replicated many times by the host’s DNA poly- researchers: DNA polymerases can make a copy of a single merase. Having many copies of a gene is important for a vast DNA strand by synthesizing a matching strand with the com- array of experiments used to characterize and manipulate it. plementary sequence of A’s, C’s, G’s, and T’s. Nucleases can Third, geneticists have developed methods to insert foreign cut DNA molecules in specific locations or degrade an entire DNA molecules into the genomes of many species, including DNA molecule into single nucleotides. Ligases can join two those of all the model organisms (Figure 1-12). This process DNA molecules together end-to-end. Using DNA polymerase is called transformation, and it is possible, for instance, to  1.2 After Cracking the Code 11 Genetically modified transform genes from one cloned DNA of a gene can be tagged with a fluorescent dye tobacco species into the genome and then hybridized to chromosomes fixed on a microscope of another. The recipi- slide, revealing the chromosome on which the gene is located ent species then becomes (Figure 1-13b). a ge ne t ic a l ly mo d i f ie d Fifth, geneticists and biochemists have developed mul- organism (GMO). In the last tiple methods for determining the exact sequence of all the few years, geneticists have A’s, C’s, G’s, and T’s in a DNA molecule. These methods developed an exciting new are collectively called DNA sequencing, and they have method called CRISPR/Cas9 allowed geneticists to read the language of life. Recently, that facilitates editing the cost-effective, high-through-put methods to sequence both genes of an organism and very short (100 bp) and very long (10,000 bp) DNA mole- is expected to revolutionize cules were developed, enabling sequencing of the complete not just laboratory genetics, genomes of thousands of individuals of a single species but also medicine and agri- such as humans (see Chapter 14). culture (see Chapter 10). Finally, over the last 20 years, researchers have created Fourth, geneticists have molecular and computational tools for analyzing the entire FIGURE 1-12 This genetically modified tobacco plant has a developed a large set of genome of an organism. These efforts gave birth to the field gene from the firefly inserted methods based on hybridiz- of genomics—the study of the structure and function of entire into its genome, giving it the ing DNA molecules to one genomes (see Chapter 14). Geneticists and genomicists have capability to emit light. [Republished another (or to RNA mol- assembled mind-boggling amounts of information on model with permission of the American ecules). The two comple- organisms and their genomes, including the complete DNA Association for the Advancement of Science, from D.W. Ow et al., mentary strands of DNA in sequence of their genomes, lists of all their genes, catalogs “Transient and Stable Expression the double helix are bound of variants in these genes, data on the cell and tissue types in of the Firefly Luciferase Gene in together by hydrogen bonds, which each gene is expressed, and much more. To get an idea Plant Cells and Transgenic Plants” either G ≡ C or A = T. These of what is available, try browsing Fly Base (http://flybase.org/), Science 234, 4778: (1986) bonds can be broken by heat the genomics Web site for the fruit fly (see also Appendix B). pp. 856–859, Figure 5. Permission conveyed through Copyright (denatured) in an aqueous solution to give two sin- KEY CONCEPT Geneticists developed tools to replicate, Clearance Center, Inc.] gle-stranded DNA molecules cut, label, and degrade DNA as well as use it as a template to be transcribed into RNA. These tools allow the assembly of the (Figure 1-13a). When the solution is cooled under controlled DNA sequence of whole genomes. Computational tools allow conditions, DNA molecules with complementary strands will biological questions to be answered by the analysis of genome preferentially hybridize with one another. DNA hybridization sequences and associated information. methods have enabled many discoveries. For example, the Strands of nucleic acids hybridize to complementary sequences (a) 5′ 3′ (b) 5′ 3′ 5′ 3′ Heat Cool Denature Anneal 5′ 3′ 5′ 3′ 3′ 5′ FIGURE 1-13 (a) The two strands of the DNA double helix can be dissociated by heat in aqueous solutions. Upon cooling under controlled conditions, strands reassociate, or hybridize, with their complement. (b) A cloned copy of the human gene for muscle glycogen phosphorylase was tagged with a yellow fluorescent dye. The fluorescent-tagged DNA was then denatured and allowed to hybridize to the chromosomes in a single cell. The fluorescent-tagged clone hybridized to the loca- tion on chromosome 11 (yellow fluorescent regions) where the gene is located. [(b) Republished with permission of the American Association for the Advancement of Science, from P Lichter, CJ Tang, K Call, G Hermanson, GA Evans, D Housman, DC Ward, “High-resolution mapping of human chromosome 11 by in situ hybridization with cosmid clones” Science 05 Jan 1990: Vol. 247, Issue 4938, pp. 64–69, Figure 1B. Permission conveyed through Copyright Clearance Center, Inc.] 12 CHAPTER 1 The Genetics Revolution 1.3 GENETICS TODAY should convey a dual message—the science of genetics has profoundly changed our understanding of life, but it is LO 1.4 Give examples of how genetics has influenced our also a youthful field in the midst of a dynamic phase of its society. development. In an interview in 2008, geneticist Leonid Kruglyak From classical genetics to medical remarked, genomics “You have this clear, tangible phenomenon in Meet patient VI-1 (Figure 1-14a). Her name is Louise Benge, which children resemble their parents. Despite what and as a young woman, she developed a crippling illness. students get told in elementary-school science, we Starting in her early 20s, she began to experience excruciat- just don’t know how that works.” ing pain in her legs after walking as little as a city block. At B. Maher, Nature 456:18, 6 Nov 2008. first, she ignored the pain, then spoke with her primary care Although Kruglyak’s remark might seem disparaging to physician, and later visited specialists. She was given a bat- the progress made in the understanding of inheritance over tery of tests and X rays, and these revealed the problem—her the last 100 years, this was certainly not his intention. Rather, arteries from her aorta on down to her legs were calcified, his remark highlights that despite the paradigm-shifting dis- clogged with calcium phosphate deposits (Figure 1-14b). It coveries of the nineteenth and twentieth centuries, enigmas was a disease for which her doctors had no name and no abound in genetics and the need for new thinking and new therapy. She had a disease, but not a diagnosis. There was technologies remains. Mendel, Morgan, McClintock, Wat- only one thing left to do; her primary care physician referred son, Crick, and many others (see Table 1-1) delimited the Benge to the Undiagnosed Diseases Program (UDP) at the foundation of the laws of inheritance, but most of the details National Institutes of Health in Bethesda, Maryland. that rest atop that foundation remain obscure. The six feet The UDP is a group of MDs and scientists that has of DNA in the single cell of a human zygote encodes the connections with specialists throughout the National Insti- information needed to transform that cell into an adult, but tutes of Health. This is the team that is asked to tackle the exactly how this works is not understood. most challenging cases. Working with Benge, the UDP team In this section, we will review some recent advances in subjected her to a vast array of tests, and soon they found genetics—discoveries of enough general interest that they the underlying defect that caused her disease. Benge had a were featured in the popular press. Reading about these very low level of an enzyme called CD73. This enzyme is discoveries will both reveal the power of genetics to answer involved in signaling between cells, and specifically it sends critical questions about life and highlight how this knowl- a signal that blocks calcification. Now the UDP doctors edge can be applied to addressing problems in society. This could give Benge a diagnosis. They named her disease “arte- textbook and the course of study in which you are engaged rial calcification due to deficiency of CD73,” or ACDC. Louise Benge has an undiagnosed disease (a) (b) → FIGURE 1-14 (a) Louise Benge developed an undiagnosed disease as a young woman. (b) An X ray revealed that Louise Benge’s disease condition caused calcification of the arteries in her legs. [(a) Jeannine Mjoseth, NHGRI/www.genome.gov; (b) National Human Genome Research Institute (NHGRI).]  1.3 Genetics Today 13 What intrigued the UDP team about Benge’s case was copies would be defective. Each of Benge’s siblings would that she was not alone in having this disease. Benge had two also need to have inherited two mutant copies from their brothers and two sisters, and all of them had arterial calci- parents to explain the fact that they have ACDC. In Chap- fication. Remarkably, however, Benge’s parents were unaf- ter 2, you will learn how to calculate the probability of this fected. Moreover, Benge and her siblings all had children, and actually happening. none of these children had arterial calcification. This pattern With this hint from the family history, the UDP team of inheritance suggested that the underlying cause might be now knew where to look in the genome for the mutant genetic. Specifically, it suggested that Benge and all of her sib- gene. They needed to look for a segment on one of the lings inherited two defective copies of either CD73 or a gene chromosomes for which the copy that Benge inherited from that influences CD73 expression—one from their mother her mother is identical to the copy she inherited from her and one from their father. A person with one good copy and father. Moreover, each of Benge’s siblings must also have one defective copy can be normal, but if both of a person’s two copies of this segment identical to Benge’s. Such regions copies are defective, then they lack the function that the gene are very rare in people unless their parents are related, as in provides. The situation is just like Mendel’s white-flowered the case of Benge since her parents are third cousins. Gener- pea plants. Since the functional allele is dominant to the dys- ally, a segment of a chromosome that is just a few hundred functional allele, ACDC, like white flowers, appears only if base pairs long will have several differences in the sequence an individual carries two defective alleles. of A’s, C’s, G’s, and T’s between the copy we inherited from The UDP team delved further into Benge’s family his- our mother and the one we inherited from our father. These tory and learned that Benge’s parents were third cousins differences are known as single nucleotide polymorphisms, (Figure 1-15). This revelation fit well with the idea that the or SNPs for short (see Box 1-1). cause was a defective gene. When a husband and wife are The UDP team used a genomic technology, called a DNA close relatives such as third cousins, there is an increased microarray (see Chapter 18), that allowed them to study one chance that they will both have inherited the same version million base-pair positions across the genome. At each of of a defective gene from their common ancestor and that these base-pair positions along the chromosomes, the team they will both pass on this defective gene to their children. could see where Benge’s two chromosomal segments were Children with one copy of a defective gene are often nor- identical, and whether all of Benge’s siblings also carried mal, but a child who inherits a defective copy from both two identical copies in this segment. The UDP team found parents is likely to have a genetic disorder. exactly the type of chromosome segment for which they were In Figure 1-15, we can see how this works. Benge’s looking, and furthermore, they discovered that the gene that mother and father (individuals V-1 and V-2 in the figure) encodes the CD73 enzyme is located in this segment. This have the same great-great-grandparents (I-1 and I-2). If result suggested that Benge and her siblings all had two iden- one of these great-great-grandparents had a mutant gene tical copies of the same defective CD73-encoding gene. The for CD73, then it could have been passed down over the team seemed to have found the needle in a haystack; how- generations to both Benge’s mother and father (follow the ever, there was one last experiment to perform. red arrows). After that, if Benge received the mutant copy The team needed to identify the specific defect in the from both her mother and her father, then both of her defective CD73 gene that Benge and her siblings had Tracing a disease gene through a family tree I ? ? 1 2 II III FIGURE 1-15 Family tree or pedigree showing the inheritance of the mutant gene causing arterial calcification due to deficiency of CD73 (ACDC). Squares are males, and circles are females. Horizontal lines connecting a male and female are matings. Vertical IV lines connect a mating pair to its offspring. Roman numerals designate generations; Arabic numerals designate individuals within generations. Half-filled squares or circles indicate an individ- V ual carrying one copy of the mutant gene. Filled squares or circles 1 2 indicate an individual with two copies of the mutant gene and who have the ACDC disease. Either individual I-1 or individual I-2 must VI have carried the mutant gene, but which one carried it is uncer- 1 2 3 4 5 tain as indicated by the question marks. The blue arrow indicates Louise Benge. The red arrows show the path of the mutant gene VII through the generations. [Data from C. St. Hilaire et al., New England Journal of Medicine 364, 2011, 432–442.] 14 CHAPTER 1 The Genetics Revolution BOX 1-1 Single Nucleotide Polymorphisms Genetic variation is any difference between two copies Single nucleotide polymorphisms of the same gene or DNA molecule. The simplest form of genetic variation one might observe at a single nucleotide Strand 1 site is a difference in the nucleotide base present, whether G A adenine, cytosine, guanine, or thymine. These types A T C A Copy 1 C C T C of variants are called single nucleotide polymorphisms T G G G A T G C (SNPs), and they are the most common type of variation in most, if not all, organisms. The figure shows two copies of Strand 2 a DNA molecule from the same region of a chromosome. SNP Notice that the bases are the same in the two molecules except where one molecule has a CG pair and the other a Strand 1 TA pair. If we read strand 1 of the two molecules, then the G top molecule has a “G” and the lower molecule an “A” at A A T C A Copy 2 C T T C the SNP site. T G G A A T G C Strand 2 inherited. After determining the DNA sequence for the of inheritance. The genealogies of some British families sug- CD73 gene from Benge and her siblings, the team found gested that new mutations for the blood-clotting disorder the defect in the gene—“the smoking gun.” The defective hemophilia tended to arise in men more frequently than in gene encoded only a short, or truncated, protein—it did women. Taken together, these two observations suggested not encode the complete sequence of amino acids. One of that the risk of an inherited disorder for a child is greater the DNA codons with letters TCG that encodes the amino as the parents age and also that fathers are more likely than acid serine was mutated to TAG, which signals the end of mothers to contribute new mutations to their children. the protein. The protein made from Benge’s version of the Advances in genomics and DNA sequencing technology CD73 gene was truncated, so it could not signal cells in the (see Chapter 14) allowed new analyses proving that Wein- arteries to keep the calcification pathway turned off. berg’s and Haldane’s suspicions were correct and provid- Louise Benge’s journey from first experiencing pain in ing a very detailed picture of the origin of new mutations her legs to learning that she had a new disease called ACDC within families. Here is how it was accomplished. A team of was a long one. The diagnosis of her disease was a triumph geneticists in Iceland studied 78 “trios”—a family group of made possible by the integration of classic transmission a mother, a father, and their child. genetics and genomics. Knowing the defect underlying the disease ACDC allowed the doctors to try a medication that Simple trio they would never have considered before they knew that the cause was a defective CD73 enzyme. The medication in question is called etidronate, and it can substitute for CD73 The researchers determined the complete genome sequence in signaling cells to keep the calcification pathway turned of each individual with DNA isolated from their blood cells, off. Clinical trials with etidronate began in 2012 and are compiling genome sequences from a total of 219 individuals. scheduled for completion in 2020. With these genome sequences in hand, the research- ers could comb through the data for new or de novo KEY CONCEPT The integration of classical genetics and mutations—unique DNA variants that exist in a child but in genomic technologies allows the causes of inherited diseases neither of its parents. Their focus was on point mutations, to be readily identified and appropriate therapies applied. changes of one letter in the DNA code to another—for example, a change of an adenosine (A) to a guanine (G) (Figure 1-16). A point mutation creates a SNP. The logic of the discovery process used by the Icelandic Investigating mutation and disease risk geneticists is outlined in Figure 1-16, which shows a seg- Shortly after the rediscovery of Mendel’s work, the German ment of DNA for each member of a trio. Each individual physician Wilhelm Weinberg reported that there appeared has two copies of the segment. Notice that copy M1 in the to be a higher incidence of short-limbed dwarfism (achon- mother has a SNP (green letter) that distinguishes it from droplasia) among children born last in German families copy M2. Similarly, there are two SNPs (purple letters) that than among those born first. A few decades later, British distinguish the father’s two copies of this segment. Compar- geneticist J. B. S. Haldane observed another unusual pattern ing the child to the parents, we see that the child inherited  1.3 Genetics Today 15 Tracing the origin of a new point mutation Mother Father Copy M1 C AGCAGA T TGCTGC T T TGT A TGAG Copy F1 C AGC TGA T TGCTGC T T TGT AGGAG Copy M2 CAGC TGA T TGCTGC T T TGT A TGAG Copy F2 CAA C TGA T TGCTGC T T TGT A TGAG Child Copy M1 C AGCAGA T TGCTGC T T TGT A TGAG Copy F2 CAA C TGA T TGCT TC T T TGT A TGAG FIGURE 1-16 A short segment of DNA from a specific location in the genome is depicted using the nucleotide base letters of just one strand of the DNA duplex. Each individual has two copies of the DNA segment. In the mother, these are labeled M1 and M2; in the father, F1 and F2. The child inherited copy M1 from its mother and F2 from its father. The version of F2 in the child carries a new point mutation (red, arrow). Single nucleotide polymorphisms (SNPs) that distinguish the different copies are shown in green (mother) and purple (father). copy M1 from its mother and copy F2 from its father. Look of mutation rises with the mother’s age when controlling more closely at the child’s two copies of the segment, and for the age of the father, the team found no evidence that it you will notice a unique variant (red letter) that occurs in did. Older mothers did not pass on more new point muta- the child but in neither of its parents. This is a de novo tions to their offspring than younger ones. (Older moth- point mutation. It this case, it is a mutation from a guanine ers are known to produce more chromosomal aberrations (G) to a thymine (T). We can see that the mutation arose in than younger mothers, such as an extra copy of the 21st the father because it is on the F2 copy of the segment. chromosome that causes Down syndrome; see Chapter 17.) Where and exactly when did the new mutation depicted Next, they examined the relationship between mutation in Figure 1-16 arise? Most of our bodies are composed of and the age of the father when controlling for the age of somatic cells that make up everything from our brain to the mother. Here, they found a powerful relationship. Older our blood. However, we also have a special lineage of cells fathers produce more new point mutations than young ones called the germline that divide to produce eggs in women (Figure 1-17). In fact, for each year of increase in his age, and sperm in men. New mutations that arise in somatic a father will pass on two additional new mutations to his cells as they divide during the growth and development of children. A 20-year-old father will pass on about 25 new our bodies are not passed on to our offspring. However, a mutations to each of his children, but a 40-year-old father new mutation that occurs in the germline can be transmit- will pass on about 65 new mutations. Weinberg’s observa- ted to the offspring. The mutation depicted in Figure 1-16 tion made 100 years earlier was confirmed. arose in the germline of the father. Why does the age of the father matter, while that of the With the genome sequence data for the trios, the Ice- mother seems to have no effect on the frequency of new landic geneticists made some startling discoveries. First, point mutations? The answer lies in the different ways by among the 78 children in the study, they observed a total which men and women form gametes. In women, as in the of 4933 new point mutations. Each child carried about females of other mammals, the process of making eggs takes 63 unique mutations that did not exist in its parents. Most place largely before a woman is born. Thus, when a woman of these occurred in parts of the genome where they have is born, she possesses in her ovaries a set of egg precursor only a small chance to pose a health risk, but 62 of the cells that will mature into egg cells without further rounds of 4933 mutations caused potentially damaging changes to DNA replication. For a woman, from the point when she was the genes such that they altered the amino acid sequence conceived until the formation of the egg cells in her ovaries, of the protein encoded. Second, among the mutations that there are about 23 rounds of cell division with DNA replica- could be assigned a parent of origin, there were on average tion and an opportunity for a copying error or mutation. All 55 from the father for every 14 from the mother. The chil- 23 of these rounds of chromosome replication occur before dren were inheriting nearly four times as many new muta- a woman is born, so there are no additional rounds after her tions from their fathers as their mothers. The Icelandic team birth and no chance for additional mutations as she ages. had confirmed Haldane’s prediction made 90 years earlier. Thus, older mothers contribute no more new point muta- The genome sequences also allowed the team to test tions to their children than younger mothers. Weinberg’s prediction that the frequency of mutation rises Sperm production is altogether different. The cell divi- with the age of the parents. For each trio, the researchers sions that produce sperm continue throughout a man’s knew the ages of the mother and the father at the time of life, and there are many more rounds of cell division in conception. When they investigated whether the frequency sperm formation than in egg formation. Sperm produced 16 CHAPTER 1 The Genetics Revolution FIGURE 1-17 Plot of the number of new The number of new point mutations increases with father’s age point mutations in each child (y-axis) by the age of the child’s father (x-axis). Each dot represents one of the 78 children studied. The diagonal line indicates the rate of increase in new mutations with the father’s Number of new mutations observed 100 age. [Data from A. Kong et al., Nature 488, 2012, 471–475.] 80 60 40 15 20 25 30 35 40 45 Age of father at conception of child (years) by 20-year-old men will have replicated their DNA about When rice gets its feet a little too wet 150 times since the man’s conception, compared to only Among the cereal crops, rice is unique. Whereas wheat, 23 DNA replications for the eggs produced by 20-year-old barley, maize, and the other grain crops grow solely in women. By the time a man is age 40, his sperm will have a dry fields, rice is commonly grown in flooded fields called history that involves over 25 times as many rounds of DNA paddies (Figure 1-18). The ability of rice to grow in flooded replication as for eggs in a woman of the same age. Thus, fields offers it an advantage: rice can survive modest flood- there is much greater risk of new point mutations occurring ing (up to 25 cm of standing water) in the paddies, but most during these extra rounds of cell division and DNA replica- weeds cannot. So rice farmers can use flooding to control tion with the increase in the age of the father. the weeds in their field while their rice thrives. There is one final twist to the remarkable project per- The strategy works well where farmers have irrigation formed by the Icelandic geneticists. The 78 trios that they stud- systems to control the water levels in their paddies and ied were chosen because the children in most of the trios had heavy rains do not exceed their capacity to control these inherited disorders. These included 44 children with autism levels. If the water in the paddies gets too deep (greater spectrum disorder and 21 with schizophrenia. For all these than 50 cm) for a prolonged period, then the rice plants, children, there were no other cases of these disorders among like the weeds, can suffer or even die. their relatives, suggesting that their condition was due to a new Paddy agriculture, as practiced in the lowlands of India, mutation. As anticipated, the researchers observed a correlation Southeast Asia, and West Africa, relies on natural rainfall, between the father’s age and disease risk—older fathers were rather than irrigation, to flood the fields. This circumstance more likely to have children with autism and schizophrenia. poses a risk. When the rains are heavy, water depth in the Studies such as this can have important implications paddies can exceed 50 cm and completely submerge the for individuals and society. Some men who intend to delay plants, causing rice plants to either suffer a loss in yield or parenting until later in life might choose to freeze samples simply die. Of the 60 million hectares of rain-fed lowland of their sperm while still young. This study also informs paddies, one-third experience damaging floods that reduce us that changes in society can impact the number of new yield on a regular basis. Since this loss is incurred mostly mutations that enter the human gene pool. If men choose to by the poorest farmers, it can lead to malnourishment and delay fatherhood for postsecondary education or establish- even starvation. ing their careers, there will be an associated increase in the In the early 1990s, David Mackill, a plant geneticist and number of new mutations among their children. It is com- breeder at the International Rice Research Institute, had an mon knowledge that infertility rises with age for women— idea about how to improve rice so that it could tolerate as is often stated, a woman’s “biological clock” is ticking being submerged in flood waters. He identified a remark- once she is past puberty. This work by the Icelandic geneti- able variety of rice called FR13A that could survive sub- cists informs us that a clock is ticking for men as well. mergence and even thrive after the plants remained fully submerged in deep water for up to two weeks. Unfortu- KEY CONCEPT Mutation is a random process that occurs nately, FR13A had a low yield and the quality of its grain during DNA replication. was marginal. So Mackill set out to transfer FR13A’s  1.3 Genetics Today 17 Rice growing in a flooded field or paddy The next question was, how does switching on SUB1 enable FR13A to survive complete submergence? To answer this question, let’s review how ordinary rice plants respond to submergence. When a plant is completely submerged, oxy- gen levels in its cells drop, and the concentration of ethylene, a plant hormone, in the cells increases. Ethylene signals the plant to escape submergence by elongating its leaves and stems to keep its “head” above water. This escape strategy works fine as long as the water is not too deep. If the flood waters are too deep, then the plant cannot grow enough to escape. As a plant in such deeply flooded circumstances grows, it uses up all its energy reserves (carbohydrates), becomes spindly and weak, and eventually dies. How does the FR13A variety manage to survive submer- gence while many other types of rice cannot? FR13A has a different strategy that could be called sit tight, and SUB1 FIGURE 1-18 Rice is grown in fields with standing water called paddies. Rice is adapted to tolerate modest levels of standing water, acts as the