Classical Genetics

Genetics, the study of ways in which biological information is passed from one generation to the next, was pioneered by an Austrian monk named Gregor Mendel (1822–1884). Perhaps more than any other prominent scientist, Mendel closely matches the popular image of the lonely genius conducting exacting research in isolation. Working at the monastery in Brno, in what is now the Czech Republic, Mendel began to ask the kinds of questions we have been posing: Why do offspring resemble parents? And why do offspring differ from parents?

Mendel attempted to answer these questions, as any good scientist should—that is, by observing nature, doing experiments, and seeing what there was to see. In a series of studies with pea plants in his monastery garden, he delineated the basic laws that govern the inheritance of physical characteristics.

The technique that Mendel used is simple to describe, although it was difficult and tedious to carry out: He cross-pollinated different varieties of peas. For example, he would fertilize the flowers of true breeding tall pea plants—plants that always produced tall offspring—with the pollen from short ones, and then observe the characteristics of the “children” and “grandchildren,” as shown in Figure 23-1. The offspring of two different strains, such as tall and short pea plants, are called hybrids.

When Mendel made these observations, he found that there were remarkable regularities in the characteristics of the offspring. All offspring from the first generation of a tall–short cross were tall. If these offspring were bred with each other, however, the results were quite different. On average, three-fourths of second-generation offspring were tall, whereas one-fourth reverted to being short. Thus, in hybridization, shortness disappears for one generation, only to reappear in the next. Mendel observed the same kind of behavior in half-a-dozen other pea plant traits: seed pod shape, flower color, and so on (Figure 23-2).

Mendel invented the “unit of inheritance,” what we now call the gene, to explain his findings. He had no idea what a gene might be, or even whether it had a real physical existence. Today, as we shall see shortly, the gene can be identified as part of a long molecule of DNA. For Mendel, however, the existence of DNA was unknown, and he deduced the presence of genes purely from mathematical analysis of how traits of his plants were inherited. In what ways were Mendel's experiments with peas similar to Galileo's experiments with falling bodies?

In the simplest version of Mendelian or classical genetics, we assume that every offspring receives two genes for every characteristic—one from the father and one from the mother. In the experiment with pea plants, for example, every offspring in every generation received a gene for height (either tall or short) from its mother (the plant that provided an egg) and another gene for height from its father (the plant that provided the pollen). Mendel concluded that pairs of genes determined every characteristic he observed and that the offspring may receive a different gene from the father than from the mother. So, if two genes are present, which characteristic is actually seen in the offspring? In the language of modern geneticists, we phrase the question by asking: Which gene is “expressed”?

Returning to our example of the pea plants, we recall that Mendel produced plants with both a gene for tallness and a gene for shortness in the first generation. The fact that all of these first-generation plants were tall means that, in all cases, the gene for tallness was expressed. Mendel stated this fact by saying that the gene for tallness is dominant. By this he meant that if an offspring receives a “tall gene” from one parent and a “short gene” from the other, that offspring will be tall. In this situation, the short gene is said to be recessive. The gene is present in the offspring, but it does not determine the offspring's physical characteristics; it is not expressed. That gene, however, can be passed along to subsequent generations. You should note that, in spite of the name, “dominant” is not the same as “good” or “strong” in the world of genes. Many fatal genetic diseases are passed from generation to generation by dominant genes.

Mendel's experiment can be understood in very simple terms. In the first generation, every hybrid receives a tall gene and a short gene. Because the tall gene is dominant, all of the first generation of hybrid plants will be tall. In the next generation, there are four possible gene combinations, as shown in Table 23-1. Each plant in the second generation can receive either a tall or a short gene from each of its parents. On average, the distribution of genes will be random so that we can argue as follows: In roughly one-fourth of the cases, the offspring will receive a tall gene from its mother and a tall gene from its father. In another one-fourth of the cases, the offspring will receive a short gene from its mother and a short gene from its father. In the remaining half of these cases, the offspring will receive a tall gene from its father and a short gene from its mother, or vice versa. (Note that in the table, a plant with Tt will have the same characteristics as a plant with tT—it makes no difference which parent donates a gene.)

Consequently, in the second generation approximately three out of every four offspring will have at least one gene for tallness, and only one in four will have two genes for shortness. Given the fact that tallness is a dominant characteristic, this distribution means that three of four offspring in the second generation will be tall and only one will be short. This situation is precisely what Mendel observed.The Rules of Classical Genetics

Mendel's research can be summarized by three rules that frame classical genetics.

Rule 1. Physical characteristics or traits are passed from parents to offspring by some unknown mechanism (we call it a gene).

Rule 2. Each offspring has two genes for each trait, one gene from each parent.

Rule 3. Some genes are dominant and some are recessive. When present together, the trait of a dominant gene will be expressed in preference to the trait of a recessive gene.

The rules of classical genetics were deduced during the early twentieth century. Careful records were kept on many kinds of organisms, from humans to cattle to agricultural plants, and large lists of dominant and recessive genes were compiled. In human beings, for example, dark hair and eye color are dominant over light, the ability to roll your tongue is dominant over inability, and hairy toe knuckles are dominant over hairless.

Qualitative versus Quantitative Genetics

In one sense, the qualitative aspects of Mendelian genetics have been understood for many centuries. Early human societies knew, for example, that if you saved the largest potatoes and planted them in the spring, the resulting crop would be better than if you just planted potatoes at random (Figure 23-3). They also knew that if you had a bull that gained weight rapidly and produced lots of meat, you should breed that bull to as many cows as possible so that some of the offspring would share the characteristics of the father.

But Mendel's careful statistical analysis of pea plant traits carried genetics beyond the qualitative level. By discovering the distinctive 3:1 and 9:3:3:1 ratios of traits in second-generation plants, Mendel was able to propose a predictive model of genetics—a model that recognized the equal importance of both parents, and the distinction between dominant and recessive traits. When Mendel's rather obscure publications were “discovered” at about the turn of the century, they provided a model that allowed breeders to approach their work in a far more controlled and directed manner.

The traits of prize bulls and racehorses, for example, are carefully documented, as are the pedigrees of their offspring. The success of plant and animal breeders in controlling the flow of genes from one generation to the next is attested to by the appearance of cattle such as Black Angus (which are little more than a rectangular block of beef on very short legs) and the many varieties of vegetables and fruits that stock supermarket shelves.Of equal importance, the laws of Mendelian genetics can now be used to trace cases of hereditary or genetic disease, such as the many cases of families with cystic fibrosis, a disease that affects approximately one in every 2,000 Caucasian children in North America. Individuals with cystic fibrosis suffer from thick mucus deposits that obstruct the lungs, as well as other abnormalities of the body's chemistry. When both parents carry the recessive gene for cystic fibrosis, their children have about a one-in-four chance of acquiring the disease.

Although we have chosen examples in which one physical characteristic is correlated to one gene, most cases of inheritance are not this simple. Human height and skin color, for example, are affected by the action of several genes, and nutrition as well as genetics can influence height. Thus, although the principles of classical genetics have widespread validity, the way that they work out in practice may be quite complex.

Science in the Making

Mendel Lost and Found

Gregor Mendel conducted his famous research over an intense eight-year span, during which he performed some 28,000 individual experiments. He published his results in 1866 in the proceedings of the local natural history society, and he sent copies of his paper to 133 other scientific societies and dozens of other scientists. He also planned to continue this line of research using other organisms, but his appointment as abbot of the monastery led to many new responsibilities and eventual abandonment of his scientific efforts. As so often happens in science, without Mendel's own follow-up experiments and active participation in the scientific community, his ideas were quickly forgotten.

A generation later, in the spring of 1900, Mendel's work was finally rediscovered when three European botanists, Karl Correns (1864–1933) of Germany, Erich von Tschermak (1871–1962) of Austria, and Hugo de Vries (1848–1935) of Holland, independently deduced Mendel's laws and subsequently found his earlier publication. Only then, a dozen years after his death, was Mendel recognized as a scientific pioneer.

23.2 DNA and the Birth of Molecular Genetics

The key to understanding Mendel's genetic principles is molecular genetics, which is the study of the mechanism that passes genetic information from parents to offspring at the molecular level. In Chapter 22 we saw that cellular functions, the basic mechanisms of all life, depend on chemical interactions between molecules. Chromosomes, the distinctive elongated structures that appear to divide just prior to cell division, became an obvious focus for genetic study. Could these structures carry information and pass it from one generation to the next? Studies of cell division by meiosis pointed strongly in that direction. Recall that meiosis produces gametes—sex cells with half the usual number of chromosomes. Gametes from two parents are subsequently joined during sexual reproduction to yield a full complement of chromosomes.

By the mid-twentieth century, biochemists analyzed chromosomes and showed that they are made primarily of DNA, deoxyribonucleic acid. The discovery of the nature and function of nucleic acids has fundamentally transformed the study of biological systems in the past three decades. Nucleic acids, so called because they were originally found in the nucleus of cells, include DNA and RNA, the molecules that carry and interpret the genetic code. These chemicals govern both the inheritance of physical traits by offspring and the basic chemical operation of the cell. These extraordinary molecules conform to the twin principles of modularity and geometry that are followed by all other organic materials (see Chapter 22).Nucleotides: The Building Blocks of Nucleic Acids

On the one hand, proteins (chains of amino acids) and carbohydrates (clusters of sugar molecules) can form large structures from a single kind of building block. Nucleic acids, on the other hand, are assembled from subunits that are themselves made from three different kinds of smaller molecules. The assemblage of three molecules is called a nucleotide, and nucleic acids are made by putting nucleotides together in a long chain.

The first of the smaller molecules that go into an individual nucleotide is a sugar. The sugar in DNA is deoxyribose (thus giving DNA its complicated name, deoxyribonucleic acid), while in RNA (ribonucleic acid) the sugar is ribose. Ribose is a common sugar containing five carbon atoms. Deoxyribose, as the name implies, is like ribose but is missing one oxygen atom (Figure 23-4).

The second small molecule of the nucleotide is the phosphate ion, which includes one phosphorus atom surrounded by four atoms of oxygen (we met the phosphate group as a key component of ATP in Chapter 22).

Finally, each nucleotide incorporates one of four different kinds of molecules in DNA that are called bases. The four different base molecules are often abbreviated by a single letter: A for adenine, G for guanine, C for cytosine, and T for thymine.

Each nucleotide combines the three basic building blocks: a sugar, a phosphate, and a base (Figure 23-5). These three molecules bond together, with the sugar molecule in the middle. Think of a nucleotide as something like a prefabricated wall in a house. Both DNA and RNA are made by linking nucleotides together in a specific way.

DNA Structure

We can start putting DNA together by assembling a long strand of nucleotides. In this strand, the alternating phosphate and sugar molecules form a long chain, and the base molecules hang off the side. The whole thing looks like a half-ladder that has been sawn vertically through the rungs.

DNA consists of two such strands of nucleotides joined together to form a complete “ladder.” The bases sticking out to the side provide the natural points for joining the two single strands. As you can see from Figure 23-6, however, the distinctive shapes of the four bases ensure that only certain pairs of bases can form hydrogen bonds. Adenine, for example, can form bonds with thymine but not with any of the other bases or with itself. Similarly, cytosine can form a bond with guanine but not with itself, thymine, or adenine. One way to look at it is to note that adenine and thymine have two places where they can form bonds, whereas guanine and cytosine have three.

As a consequence, only four possible rungs can exist in a DNA ladder. They are:

AT

TA

CG

GC

With the bonding of these base pairs, the complete DNA molecule is formed into a ladder-like double strand. Because of the details of the shape of the bases, each rung is twisted slightly with respect to the one before it. The net result is that this ladder comes to resemble a spiral staircase—a helical shape that gives DNA its common nickname, the double helix.

A quick review: as we shall see, genes are short segments of a DNA double helix. Separate segments of DNA wrapped around a protein core are called chromosomes, with each chromosome containing many genes. The sum of all DNA on all the chromosomes in an individual cell, called the genome, constitutes the entire set of genetic instructions for that organism. Every cell in an individual organism contains the same complement of DNA, with the exception of the sex cells.

RNA Structure

RNA is built in a manner similar to DNA with three important differences. First, RNA is only half the ladder; that is, it consists of only one string of nucleotides put together. Second, the sugar in the RNA nucleotide is ribose instead of deoxyribose. And third, the base thymine is replaced by a different base, uracil, abbreviated U. The shape of uracil is such that, like thymine, it will bond to the base adenine. As we shall see, the ability of uracil to bond to adenine plays an important role in regulating chemical reactions in the cell. Several different kinds of RNA operate in the cell at any given time. All of them, however, have the same basic structure.

The Replication of DNA

In Chapter 21, we described the processes by which cells divide. Prior to both mitosis and meiosis, DNA in the chromosomes is copied. Thus, DNA replication is one of the first steps in passing genetic information from one generation to the next.

DNA replication is possible because the geometry of the base pairs allows only certain kinds of bindings; that is, adenine (A) binds only to thymine (T), and cytosine (C) binds only to guanine (G). No other pairings are allowed. When a cell is about to divide, special enzymes move along the DNA double helix, breaking the hydrogen bonds that link the bases—in effect, breaking the “rungs of the ladder,” as shown in Figure 23-7. As a result, the two split arms of the DNA ladder have exposed bases.

Consider an adenine (A) base that is no longer locked into its partner on the other side of the double helix. In the fluid around the DNA are many nucleotides, some of which contain an unattached thymine (T). With the aid of another enzyme, this thymine will bind to the exposed adenine in the original DNA strand. In the same way, an exposed cytosine (C) will bind to a nucleotide containing guanine (G) from the fluid in the nucleus. No other type of nucleotide can bind to that particular site.

The net result of these preferential bindings along a single strand of exposed DNA is that the missing strand is reconstructed, base by base. The same thing happens in mirror image to the other half of the exposed DNA strand. Thus, once the DNA is unraveled, each strand replicates its missing partner. The end product is two double-stranded DNA molecules, each of which is identical to the original molecule (Figure 23-8).

As we saw in Chapter 21, when a cell divides by means of mitosis, the genetic information contained in the DNA of one cell is passed on to its daughters. Thus, each daughter cell will have chromosomes identical to those of the parent. In meiosis, in contrast, each daughter cell has only one chromosome, which differs from either of the pair of chromosomes in the original cell through shuffling of genetic material. When a sperm and an egg come together during fertilization, the resulting cell once again has a full set of chromosomes, but now one chromosome in each pair comes from the father, the other from the mother.

The simple chemistry of the base pairs provides a mechanism for reproducing DNA. This feature of DNA molecular structure accounts for one of the striking facts about life—offspring do share many traits of their parents. Ultimately, chemical binding of base pairs results in the inheritance of parental traits.23.3 The Genetic Code

DNA carries all our genetic information; this molecule is, in effect, the book of life. But how is the book read? How are the almost endless strings of DNA nucleotides translated into flesh and blood? That is the role of RNA.

Transcription of DNA

In addition to replicating itself so that cell division can take place, DNA also supplies the information that runs the chemistry within each individual cell. This process depends on the fact that all cells are governed by protein enzymes that run chemical reactions (see Chapter 22). Thus, the question of how cell chemistry is regulated boils down to how the information in DNA can be used to produce proteins. If we understand this step, then we will understand how DNA governs the chemical functioning of every cell in our body.

DNA is a very large molecule. In eukaryotic cells, it is found outside the nucleus only in mitochondria and chloroplasts. Thus, the first question we have to ask is how information in the DNA gets out into the cell at large. The answer to this question involves a process called transcription, which uses the other nucleic acid, RNA.

When it is time to fabricate a new protein to act as an enzyme in a cell, other enzymes “unzip” a section of DNA, as shown in Figure 23-9. Nucleotides of RNA that are always floating in the nuclear material are then hooked, with the aid of enzymes, onto the appropriate bases by a process exactly analogous to that which occurs in the replication of DNA. Each of the exposed bases on the “unzipped” strand of DNA binds to its appropriate nucleotide—A to U, C to G, and so forth. (Remember that in RNA, the base uracil, U, substitutes for the thymine in DNA.) In this way, a short strand of RNA is created that carries information from the original exposed strand of DNA. Think of the RNA as being the “negative” of the true picture, which is the DNA.

Because it is relatively short and not connected to anything else, the RNA strand can move out through tiny pores in the wall of the nucleus and into the cell at large. Thus, the function of this kind of RNA is to carry the information that was contained in the central DNA molecule out into the region of the cell where chemical reactions are going on. Because it carries a message, this kind of RNA (one of three important types in every cell) is called messenger RNA, or mRNA for short.

The Synthesis of Proteins

The exact sequence of base pairs on messenger RNA carries a coded message that contains chemical instructions. Once the mRNA arrives at the place in the cell where proteins are to be synthesized, it encounters a second type of RNA—a molecule called transfer RNA, or tRNA for short. The job of tRNA is to read that coded message. Transfer RNA, whose shape is shown in Figures 23-10 and 23-11, has a shape at one end that attracts 1 of the 20 amino acids found in living things (see Chapter 22). At the other end is a small loop of molecules with three exposed bases on it. One of four different bases can be found in each of the places on the top loop. In other words, there are four possible choices for the first base in tRNA, and for each of these four possible choices for the second base. This means that there are 16 (4 × 4) possible combinations for the first two bases in tRNA, and for each of these 16 there are four possible choices for the third base. In the end, then, there are 64 (4 × 4 × 4) different possible kinds of tRNA molecules.The sequence of bases along the mRNA is, as we have seen, a transcription of the information contained in the sequence of bases along the original DNA. Messenger RNA in effect carries a coded message, spelled out in four letters: A, U, C, and G. Each group of three exposed bases on the mRNA chain is like a word—a sequence of three letters that will bind to one, and only one, of the sets of bases on 1 of the 64 tRNA molecules. If a segment along the mRNA reads G-C-C, for example, then the tRNA molecule that has C-G-G as its unpaired bases will bond to that particular spot as shown in Figure 23-11.

The set of three bases on the mRNA, called a codon, determines which of the possible tRNA molecules will attach at that point. Each codon on the mRNA determines a single amino acid, and the string of codons determines the sequence of amino acids—what we have called the primary structure of the protein that is being assembled. This connection between the codons and the amino acid they select is called the genetic code, as detailed in Figure 23-12. All living things share this code.

As the tRNA molecules attach themselves along the mRNA, a string of amino acids in a specific order—a protein—is assembled as shown in Figure 23-13. Once its amino acid has been incorporated into the protein, a tRNA molecule moves away to be replenished with another amino acid and used again.

The protein synthesis takes place on ribosomes, which are large, irregularly shapedorganelles made of proteins and yet another kind of RNA, called ribosomal RNA, or rRNA. As shown in Figure 23-13, the process of synthesis is somewhat more complex than the simple discussion we have given here. Ribosomes align the messenger RNA and transfer RNA during protein assembly. Thus three different kinds of RNA—transfer, messenger, and ribosomal—are involved in the synthesis of a single protein.

As a net effect of this rather complex molecular manufacturing process, the information encoded in the DNA molecule has been expressed as a particular sequence of amino acids that determines the identity of the appropriate protein enzyme. Thus, a specific stretch of DNA located on one chromosome produces the enzyme that runs a particular chemical reaction in the cell. This stretch of DNA is what we have called a gene. That chemical might have an influence on skin color, hair texture, or any of the other traits that we recognize.

One of the central rules of modern biology, often referred to as the “central dogma of molecular biology,” is: One gene codes for one protein.

That is, one stretch of DNA will code for one mRNA molecule, which will code for the sequence of amino acids in one protein, which will drive one chemical reaction in the cell (Figure 23-14).

It was once believed that all genetic processes follow this rule. Today we understand that, although genes in prokaryotes are usually found on one continuous stretch of DNA, in eukaryotes like human beings the geometry of genes is often more complicated. A gene on human DNA does not always consist of a single continuous stretch of DNA; rather, the coding sections of the DNA of a single gene are often separated from each other by stretches of noncoding DNA. The parts of the DNA that code for the protein are called exons, whereas the noncoding sections that are interspersed between them are called introns. The cellular machinery that transcribes the gene is able to cut out the introns and assemble the protein only from exons. In the assembly process, however, the exons can be put together in different ways, so that a single gene can code for more than one protein. In humans, for example, a single stretch of DNA may contribute to three or more different proteins.

But the great truth of modern biology is this: more than a century ago, Mendel postulated the existence of a gene without knowing what it was. Today molecular biologists can tell you exactly where many specific genes lie along a stretch of DNA, as well as the sequence of base pairs along them.

All living systems employ the genetic mechanism we have just described. The transfer of genetic information by DNA and the production of proteins by RNA is a process shared by every cell on Earth. Each species, and each individual within a species, has a slightly different message written on its DNA. The identity of every cell, as well as the organism of which the cell is a part, is determined by the chemical reactions that take place there. The enzymes determine the chemical reactions, and the enzymes are coded for in the DNA. Thus, DNA is truly the molecule that contains the code of life.

What is perhaps most remarkable about this process is that all living things use essentially the same code to translate between the messages carried in the genes of DNA, the messages carried in RNA, and the string of amino acids in proteins. This relationship explains why biologists speak of “the genetic code” when they refer specifically to the relationship between a triplet of base pairs on the mRNA and the corresponding amino acid in the protein. The basic “word” of the molecular world, then, is the triplet of bases along DNA—the codon. Each codon eventually codes to one amino acid in a string of proteins.

The fact that all living organisms, from single-celled yeast to human beings, use precisely the same biochemical apparatus and precisely the same technique for making proteins and running their chemistry is one of the great unifying ideas in the science of biology. Indeed, one of the great principles of science is: The formation of a protein requires three kinds of RNA. (a) A strand of messenger RNA fits into a groove in a ribosome (an organelle formed from proteins and ribosomal RNA). (b) The ribosome attracts the appropriate transfer RNA, which carries with it an amino acid (shown in blue). (c) A second tRNA attaches to the ribosome, and the two adjacent amino acids are linked (d–f). The ribosome begins to shift along the mRNA, attracting new tRNA molecules and adding amino acids to the chain. Once the amino acids and tRNA are disconnected, the tRNA floats off to find another amino acid (g–h). The completed protein is assembled and released by the ribosome, and all the components are available to start the process over again.

Figure 23-14 A schematic diagram of protein production from DNA. (a) One stretch of DNA codes for one mRNA molecule. (b) One messenger RNA molecule attaches to a ribosome. (c) Transfer RNA molecules match an amino acid to each codon on the messenger RNA. (d) Amino acids link together to make one protein, which will drive one chemical reaction in the cell.

All living things on Earth use the same genetic code.

This finding in no way limits the tremendous variety and diversity one can find in living things. Just as many different books can be written using the 26 letters of the English alphabet, so too can many different life forms be constructed using the four “letters” in the genetic code.

Mutations and DNA Repair

If DNA were copied faithfully from one generation to the next, no living thing could be much different from its ancestors. But mistakes do happen, and many agents in nature can alter and even damage the DNA molecule. Numerous chemicals (particularly those that cause oxidation reactions in cells), nuclear radiation, X-rays, and ultraviolet light (which also produces oxidizing chemicals) are all examples of such agents. If the DNA of a parent's egg or sperm is altered, then the alteration will be faithfully copied by the process we have just described. The offspring will inherit the change, just as they inherit all other genetic information from the parents. Such a change in the DNA of the parent is called a mutation. As we shall see in Chapter 25, mutations have played a very important role in the development of life on Earth.

Recently, scientists have begun to realize that DNA is damaged at a far higher rate than had previously been thought. Careful chemical analyses indicate that damage to DNA in humans goes on at the rate of about 10,000 “hits” per cell per day. Fortunately, the body has developed repair mechanisms that take care of almost all of this damage as soon as it happens. The study of DNA repair, and the hope that it may help us deal with diseases such as cancer, represents a major frontier in science today and will be discussed more fully in Chapter 24.

Why Are Genes Expressed?

Every cell in your body except the reproductive cells contains an identical set of chromosomes —the exact same set of DNA molecules—yet your cells are not all alike. In fact, chemical reactions critical to one set of cells—those that produce insulin in your pancreas, for example—play no role whatsoever elsewhere. The genetic coding for making insulin is contained in every cell in your body but turned on only in a few. How do the cells in the pancreas “know” that they are supposed to activate the particular gene for insulin, whereas the cells in the brain know they are not supposed to?

The mystery of DNA's operation runs even deeper than this. It now appears that only about 5% of all DNA in human beings is actually taken up by the genes. The other 95% used to be called “junk DNA” because nobody understood why it was there. Scientists are increasingly coming to believe, however, that at least some of the rest of the DNA contains instructions for turning genes on and off. The study of gene control is a frontier field, and we understand very little about how it works. We do know, however, that genes are activated at certain times in the growth of plants or animals, and the triggers for this activation appear to be enzymes or other chemical agents.

Many scientists also think that the failure of these instructions leads to diseases such as cancer. If a cell is dividing and the mechanism that tells it when it's time to stop is faulty, the cell may continue to multiply and produce a tumor. Damage to the control mechanisms in a cell thus may be much more serious than damage to the genes themselves.

23.4 Viruses

If you have ever had influenza (“the flu”) or a common cold, you've experienced the consequences of viruses. Viruses aren't alive in the sense that bacteria and other single-celled organisms are. Unlike the life forms we discussed in Chapter 20, viruses do not metabolize and are not capable of reproduction on their own. Rather, they rely on the genetic mechanisms of cells to reproduce.

A virus consists of nothing more than a short length of RNA or DNA wrapped in a protein coating (Figure 23-15). The protein is shaped so that it fits cell receptors and is taken into a cell. Once inside the cell, a variety of events may occur, depending on the exact nature of the virus. The viral DNA may replicate itself, producing its own mRNA, or viral RNA may serve directly as messenger RNA. Thus, the virus takes over the cell's machinery, using the cell's enzymes and tRNA to produce more viruses like itself, eventually killing the cell.

Note that a “computer virus” operates in the same way. This kind of virus is a set of instructions taken into a computer that highjacks the computer's machinery to its own ends.

Alternatively, as in the HIV (human immunodeficiency virus) that causes AIDS, the virus contains an RNA sequence that can be transcribed back into DNA along with some enzymes that insert the DNA into the cell's own DNA. Once that stretch of DNA is inserted, it acts just like any other gene and co-opts the cell into making more viruses. No matter what the mechanisms, however, the result is the same: the cell eventually dies.

HIV turns out to be an unusually complex virus (Figure 23-16). It has two coats of proteins: the outer coat contains molecules that fit receptors in cells in the human immune systems known as T cells, whereas the inner coat encloses the RNA that will be translated into DNA by attached enzymes. The net effect of the virus's action is to destroy cells that are essential to the operation of the immune system, making the infected person vulnerable to many deadly diseases. We will discuss methods that have been developed for managing AIDS in the next chapter. Viruses can have a wide variety of shapes and sizes. This diagram of a bacterial virus shows the protein coat containing DNA at the head. The tail fibers at the bottom attach the virus to the cell wall. DNA is then injected into the cell through the cylindrical core. (b) An electron microscope photograph of herpes viruses, enlarged more than 10,000 times, reveals the regular protein coating that surrounds a strand of DNA.

Viral Epidemics

There is an old joke about someone who goes to a doctor with a cold and is told to take a shower and stay outside in the cold with wet hair and without a coat.

“But if I do that, I'll get pneumonia,” the patient protests.

“Of course,” says the doctor, “but I can cure pneumonia.”

The medical profession has enjoyed a great deal of success in dealing with diseases such as pneumonia that are caused by invading bacteria. Antibiotics often work by blocking particular enzymes in the bacteria. Because these enzymes don't operate in human cells, antibiotics can destroy the bacteria without harming the human whose body they are invading.

In contrast, viruses with their simple structure of a protein coat surrounding a piece of genetic material, are able to co-opt most of the host cell's machinery while antibiotics do not affect them. This difference is why viral diseases such as the common cold cannot be treated as effectively with commonly available drugs as bacterial infections. The most effective countermeasure for viral diseases has been vaccination, which stimulates the human immune system to produce antibodies that neutralize the virus (Figure 23-17). These antibodies are molecules that have a precise shape that binds to the virus and prevents them from attaching to cells. Poliomyelitis, smallpox, and yellow fever have all been dealt with in this way, and new vaccines against such threats as ebola and new strains of flu are constantly in development.

Viruses not only hide inside cells; many of them also have the ability to change very rapidly, producing new forms as quickly as we find vaccines against them. The copying of DNA in cell division is subject to the cell's “proofreading” mechanisms so that daughter cells are the same as those of the parents. However, some viruses like HIV have no such proofreading, and consequently they mutate at a rate up to a million times faster than normal eukaryotic cells. The influenza virus adopts a different strategy. If two influenza viruses invade the same host, they have the ability to swap sections of their nucleic acids, producing a new strain in the process. This rapid rate of mutation in influenza viruses is the main reason that Americans are urged to get new flu shots each year. The new vaccine attempts to counteract whatever virus has developed since last year's shot.

As news about AIDS and possible epidemics of SARS, bird flu, ebola, and other diseases should remind us, viral diseases remain a very real threat to the human race. Several features of modern life make human beings particularly susceptible to viral attack. For one thing, we now tend to live together in cities, providing a large host population for new viruses. We also travel a great deal so that a virus that develops in one part of the world will quickly spread. Finally, humans are coming into more contact with isolated wilderness areas and therefore into contact with whatever viruses are already living on hosts in those areas. One example is the virus responsible for AIDS, which is believed to have arisen from a virus affecting monkeys in remote African forests. A hunter cutting his finger while skinning an infected monkey, for instance, could have introduced the virus to the human population.23.5 The Human Genome

In the summer of 2000, the first phase of one of the most ambitious scientific projects in history was completed. Called the Human Genome Project, the project set a goal that was nothing less than a complete description of all the base pairs in human DNA—all three billion pairs on all 23 chromosomes.

In human beings, as in other eukaryotes, the DNA does not occur as one long, continuous molecule but instead is cut up into bundles called chromosomes. In a chromosome, a stretch of DNA is wrapped around a core of protein molecules. A human being receives 23 different chromosomes from each parent, and each gene has a specific location on a specific chromosome.

Different organisms have different numbers of chromosomes. Humans have a total of 23 pairs, for example, whereas goldfish have 47 pairs and cabbages have 9. There is no connection between the number of chromosomes and the complexity of the organism. It is best to think of chromosomes as the “packaging” into which the DNA is put.

Studying human DNA is particularly important in part because many diseases arise from mutations on specific genes. As we shall see in the next chapter, for example, a common form of cystic fibrosis results from a mutation on a specific gene on chromosome 7. In recent years, scientists have been able to pinpoint the causes of diseases such as sickle-cell anemia, some forms of arthritis, and familial tendencies to develop cancer on specific chromosomes.

DNA sequencing is the process of determining, base pair by base pair, the exact order of bases along a DNA molecule. The net result of a sequencing operation is a string of letters (ATTGCGCATT…, and so on), a sequence that tells us how the DNA is put together in that particular stretch (Figure 23-18). The entire sequence of base pairs in an organism's DNA is called the genome of that organism. For reference, the relationships among DNA, genes, chromosomes, and genomes are summarized in Table 23-3.

Many people are surprised to learn that a key ongoing goal of the Human Genome Project is to determine the complete genomes of hundreds of other species, including the mouse, the fruit fly, yeast, and numerous microbes. Our ability to read DNA has even advanced to the point, as we shall see in the next chapter, that the genome of extinct species such as Neanderthal Man have been sequenced. In addition, we shall see that reading the sequence of living species can help us unravel complex genealogies.

More importantly, it turns out that many life forms, even relatively primitive ones, have many of the same genes and thus reveal many of the same genetic mechanisms that occur in humans. One result of this sort of knowledge is that a gene sequence can be used to deduce the sequence of amino acids in a protein. This information, in turn, may give some insight into the function of that protein in the organism and prove useful in developing treatments for various diseases.

Keep watching the news for announcements of the latest progress in this mammoth undertaking.

Two important goals of the Human Genome Project are DNA mapping and DNA sequencing. A genetic map shows the location and sequence of genes along a chromosome. It can be used to identify the genes for a specific trait. Scientists working on the Human Genome Project created physical maps that describe the chemical characteristics of the DNA molecule at any given point. The physical maps were used for DNA sequencing, which determined the exact sequence of base pairs along a DNA molecule.

Science in the Making

Connecting Genes and DNA

In 1911, an undergraduate student and a professor were talking at Columbia University. The professor was Thomas Hunt Morgan, who was studying the genetics of fruit flies in his laboratory. Like Mendel's pea plants, fruit flies are ideal organisms for this sort of work because they produce new generations in a matter of weeks. (Morgan, incidentally, was the great-grandson of Francis Scott Key, the man who wrote “The Star Spangled Banner”). The student was Alfred Sturtevant, a young man who went on to have a distinguished scientific career.

The two were discussing the fact that in their experiments, certain characteristics of the flies seemed to be inherited in groups—if one appeared in an offspring, the others were likely to appear as well. They were also finding, however, that occasionally this linkage was broken and that the frequency of the breaking of the link varied from one pair of genes to the next.

During the conversation, Sturtevant realized that if the genes were laid out in a linear array on the chromosomes, then the process of gene exchange that occurs during meiosis would be more likely to separate genes that lay far apart from each other than genes that are close together. In fact, the process of gene exchange would be like cutting up a highway map. Nearby towns would tend to be on the same piece of paper when the cutting was finished, whereas distant towns would be separated more often. Using this insight and the data on how often linkages were broken, Sturtevant came into the lab the next day with the first genetic map of a chromosome.

Work in the Columbia “fly room” thus led to one of the most important basic tenets of modern genetics—that genes are laid out in a linear sequence on chromosomes. During the coming decades, with support from the Carnegie Institution, this lab remained at the center of genetic research. Morgan received the Nobel Prize in 1933 and, in a telling gesture, shared the prize money with Sturtevant and another former student in order to help the two men pay their childrens' college tuition bills.

Science by the Numbers

The Human Book of Life

In Chapter 10 we saw that information can be quantified in units of the “bit”—a simple statement about “yes or no” or “on or off.” We can use this notion to calculate the amount of information in the human genome.

Each site along the DNA molecule can be occupied by one of four bases. This information can be represented by two bits. We could, for example, set up a code as follows:

A: on on

T: on off

C: off on

G: off off

Using this code, we could go down the molecule specifying two bits of information at each nucleotide, and this would tell us the sequenceTechnology

New Ways to Sequence

When the Human Genome Project was starting, scientists estimated that it would take decades and cost billions of dollars. Even well into the project, the official estimate was that it wouldn't be completed until 2005 and would cost $3 billion (about $1 per base pair).

This situation was changed drastically when molecular biologist J. Craig Venter, who is now head of the Venter Institute, developed a new way of combining computers with automatic DNA sequencing machines (Figure 23-20;). As a result of his work, the Genome Project finished in 2000, 5 years ahead of schedule, with the cost of sequencing being only about 10 cents per base pair (and the price has now dropped to a few cents per base pair).

Venter's novel technique is called shotgun, and here's how it works: Long stretches of DNA are broken up into many small pieces. These pieces are fed into an army of sequencing machines, each of which “reads” only a short segment—a few hundred base pairs of the original. By identifying overlapping segments from among the thousands of short DNA strands, powerful computers are able to reconstruct the entire DNA sequence.

It is important to realize that in this technique, the contributions of computers are just as important as those of the sequencers. This is why scientists often speak of the Genome Project as an example of the bioinformatics revolution.The Ongoing Process of Science

Epigenetics

From the time of Mendel on, scientists studying the way traits are passed from one generation to another concentrated on genes. Today we understand that genes are stretches of base pairs along a DNA molecule, and our understanding of genetic change involves changes in the sequence of those pairs. Recent research, however, has shown that there is more to the story of genetic inheritance than this—that there are ways to influence inheritance that do not involve genes. These new modes of influence go under the name of epigenetics (literally “outside the genes”).

It has long been known that a mother's behavior during pregnancy—smoking or drinking, for example—can influence the long-term health of her child. What is new, however, is the recognition that these sorts of effects can be passed on to that child's children. Experiments with laboratory mice have established that this process does not occur by changing the genes themselves, but by attaching markers to the DNA that influence whether or not a gene can be turned on. A common process that induces this kind of change is called methylation because it involves a simple methyl molecule (a carbon atom with three hydrogen atoms). This molecule attaches itself to a spot on the DNA chain and prevents the normal process of gene expression from starting. For some reason we do not yet understand, these tags survive the normal cleaning up of markers in the DNA of sperm and egg and are inherited. We know that these effects can be passed to several generations of mice and, in the case of a short-lived flatworm, to 30 generations.

Bottom line: your great grandmother's behavior may be influencing your DNA.Return to the Integrated Question

Why do offspring resemble their parents?

In the science of biology, the term offspring refers to new organisms that are produced by the process of reproduction.

Offspring inherit traits from their parents. This fact is the basis of selective breeding, which has been used by humans for millennia to improve crops and domestic animal stocks.

The modern science of genetics studies the phenomena of inheritance and began with the work of Gregor Mendel in 1865.

Mendel sought to understand the process of inheritance and the transmission of characteristics from parent to offspring.

In 1915, Thomas Hunt Morgan postulated the chromosome theory of inheritance. These early works became the foundation of classical or Mendelian genetics.

Genetics and the laws of inheritance for sexual reproduction follow a few simple rules:

Physical characteristics or traits are passed from parents to offspring by some unknown mechanism (we call it a gene).

Each offspring has two genes for each trait, one gene from each parent.

Some genes are dominant and some are recessive. When present together, the trait of a dominant gene will be expressed in preference to the trait of a recessive gene.

Genes play a large role in the appearance and behavior of all organisms.

Nevertheless, the environment in which an organism lives has a large influence on its ultimate development.

This idea is the basis of the “nature versus nurture” debate. In reality, both nature (i.e., genetic inheritance) and nurture (i.e., the totality of the environment of an organism) play complementary roles in the maturation and development of all characteristics.

A more correct formulation of the “nature versus nurture” debate: Genes interact with environment across time.

Summary

Genetics, the study of the way in which biological information is carried from one generation to the next, is a field as old as the selective breeding of animals and the selection of seeds for crops. Gregor Mendel attempted to quantify aspects of this process by cross-pollinating purebred varieties of pea plants to produce hybrids. He discovered that all first-generation hybrids appeared the same, with the traits of just one parent plant, but the second generation displayed characteristics of both parents. Typically, three-fourths of the members of the second generation display one trait, one-fourth the other. Mendel explained his observations by developing laws of classical genetics: (1) traits are passed from parent to offspring by “units of inheritance” (we call them genes); (2) each parent contributes one gene for each trait; and (3) some genes are dominant and will be expressed, whereas others are recessive and will appear only if no dominant gene is present.

Modern molecular genetics seeks to understand the molecular basis for Mendel's observations. The key to understanding genetics lies in the unique structure of the nucleic acids, including DNA, with its double helix, ladder-like sequence of base pairs, and the closely related single-stranded RNA. The four different DNA bases, A, T, C, and G, which always come in the pairs AT or CG, act like letters of a coded message—the message of life. Because of its structure, DNA can replicate itself and store the information needed to make proteins.

Every cell has a set of chromosomes with the complete DNA blueprint in its nucleus. The process of copying DNA before cell division is called replication and involves splitting apart the two sides of the DNA double helix, thus exposing the complementary base pairs. Each exposed base binds to its complement, and so two complete DNA strands form where before there was only one.

The coded DNA message is read by RNA, a process called transcription. Messenger RNA, a single-stranded molecule, copies the sequence for one gene and carries it out of the nucleus to the part of the cell where proteins are made. Transfer RNA matches sequences of three base pairs to corresponding amino acids; thus an RNA sequence translates into a string of amino acids—a protein. The correspondence between base-pair sequences and amino acids is called the genetic code, which is shared by every living organism.

Although the DNA message is resilient to most damage, errors in the coded sequence can occur and cause mutations. Conversely, viruses cause sickness by usurping a cell's chemical factories with foreign genetic instructions.

Segments of DNA are wrapped around a protein core to form chromosomes. The complete description of an organism's genetic code is called its genome. Scientists determine a genome by first mapping the positions of every gene on every chromosome and then sequencing the exact order of base pairs on every gene. The Human Genome Project has produced the 3-billion-base-pair sequence of the human genome, as well as genomes for many other organisms.

Key Terms

genetics

true breeding

hybrid

gene

classical genetics

dominant

recessive

molecular genetics

nucleic acids

DNA

RNA

double helix

messenger RNA (mRNA)

transfer RNA (tRNA)

genetic code

mutation

virus

Human Genome Project

DNA sequencing

genome