Gene

Considering the central role that genes play in the understanding of biology, it is surprising that no single, simple definition of a gene exists. This is partly because genes are under multiple evolutionary constraints, and partly because the concept of a gene has both structural and functional aspects that do not always align perfectly. A modern description of a gene must consider not only its structure, as a length of DNA, but also its function, as a unit of heredity in transmission from one generation to the next and in development as a carrier of coded information of the sequence of a protein or RNA molecule. In addition, the description should recognize the multiple roles a single gene can play in different tissues during various stages of development and over the course of evolution.

In the table on page 118, some different sorts of geneticists are listed along with the aspects of genes on which they focus and what kinds of phenomena they investigate. In order to understand someone who is discussing genes, it is critical for the listener or reader to know sufficient context such that s/he can ferret out which of the possible interpretations of "gene" in this list is most likely implied.

Units of Heredity

The modern conception of genes begins with the work of Gregor Mendel (1822–1884), who showed that inheritance involved discrete factors passed from parent to offspring. (While Mendel is given credit as the originator of modern genetics, the word "gene" was not coined until well after his death.) In this view, genes are those elements responsible for the "phenotype," the set of observable traits that make up the organism. In the original Mendelian conception, genes came in pairs, as did possible phenotypes . Classic examples include round versus wrinkled seeds in peas, or presence or absence of hairs on the middle section of the fingers in humans.

WEISMANN, AUGUST (1834–1914)

German biologist who kept alive English naturalist Charles Darwin's theory of natural selection as the mechanism for evolution, when most biologists were looking for other mechanisms. Weismann also predicted the existence of deoxyribonucleic acid (DNA), arguing that parents pass traits, such as eye color, to their children by means of molecules of some kind.

The competing school of thought for the first thirty years of the twentieth century was Darwinism, which considered characters with a continuous distribution such as speed, strength, skin color, height, weight, number of progeny , etc., for which no simple paired set of elements could account. By 1930, these seemingly incompatible views had been combined in the "neo-Darwinian synthesis," which incorporated features of both sides of the debate. This involved a transformation of the "one gene, one trait"

relationship to a recognition that single inheritable genes could influence many different observable traits (called pleiotropy), and a single definable trait could be influenced by many different genes called polygenes.

Pleiotropy is a one-to-many genetic phenomenon. If a human has two copies of the gene for hemoglobin S, then with high probability the individual is likely to develop a broad constellation of symptoms that constitute sickle cell disease. Complications of swelled heart, ulcerated skin, spleen failure, and shortness of breath are all associated with this single gene.

On the other hand, polygenic inheritance, epistasis , gene interaction, operons, and regulatory circuits all involve a many-to-one relationship between genotype and phenotype. Wheat color provides a good example of polygenic inheritance, the contribution of more than one gene to a single trait. When a very dark red, completely homozygous individual is crossed with a white, completely homozygous individual, all of their progeny are phenotypically red. When these red progeny are self-crossed, their offspring include individuals that are very dark red, dark red, red, light red, and white, in a ratio of 1:4:6:4:1. The inference drawn by geneticists is that two independently assorting genes are interacting to determine color, and that each gene has two alleles , one that contributes red color and the other that does not. Hence, the genotypes range from four contributing alleles (making very dark red) to zero (making white). Involvement of more genes can give even more complex and more continuous distributions.

It is important to realize that in none of these cases is any information provided about the physical nature of the gene. In classical genetics, a gene is a unit of heredity, and understanding inheritance patterns does not require knowledge of gene structure.

However, without an understanding of structure, it is tempting to think of genes as being "for" the trait they influence, in the sense that a hammer is "for" pounding nails or a CD player is "for" listening to music. However, the whole notion of "for" is an unacceptable concept to most research biologists. "For" connotes a determinism that is inconsistent with our understanding of the complexities of cellular processes. There is no gene for intelligence, although many genes influence intelligence through their actions within individual cells. Intelligence, like any other complex trait, arises as the result of many genes interacting.

Genes Are Carried on Chromosomes

Long before the discovery that genes were made of DNA, geneticists realized that hereditary factors—genes—were carried on chromosomes . Unlike genes themselves, chromosomes can be easily seen under the microscope, and their movements can be followed during the processes of mitosis and meiosis . Beginning around 1910, Thomas Morgan and colleagues showed that the patterns of Mendelian inheritance could be correlated with the patterns of movement and recombination of the chromosomes. Morgan's group showed that one of the central events of meiosis is crossing over, in which genes trade places between maternal and paternal chromosomes. In this way, Morgan and colleagues developed the chromosomal theory of inheritance and gave a physical reality to the abstract concept of the gene.

CHASE, MARTHA (1927–)

American biologist who, with Alfred Hershey, used a friend's blender to show that genes are made of deoxyribonucleic acid (DNA). In their ingenious experiment, Chase and Hershey labeled virus proteins with one radioactive label and virus DNA with another label. When the viruses then infected bacteria, Hershey and Chase found DNA, not protein, inside the bacteria.

From this point, much work was devoted to discovering the physical nature of the gene. Throughout the next several decades, a series of experiments showed that genes were made of DNA (deoxyribonucleic acid), and finally that the double-helical structure of DNA accounted for the faithful replication and inheritance of genes.

Genes Encode Enzymes and Other Proteins

Parallel to the growing understanding of the structure of the gene came discoveries about how genes affect the phenotype. From patients who suffered from Mendelian diseases and from experiments on bread mold, early researchers inferred that mutant genes were frequently associated with disfunctional enzymes that could not catalyze particular metabolic steps. Thus, they concluded that enzymes perform the actual functions in a cell that lead to phenotype. These observations led to the first definition of a gene that combined structure and function, stated as "one gene, one enzyme." In this formulation, a gene was thought to be enough DNA to bring about the production of one enzyme. This view had to be modified slightly with the realization that many enzymes are composed of several subunits, called polypeptides , whose corresponding DNA sequences (genes) may be on entirely different chromosomes. In addition, not all proteins are enzymes; there are structural proteins, transcription factors , and other types. This led to the reformulation "one gene, one polypeptide."

Information Sequences that Code for Production of RNA

The discovery of the structure of DNA led quickly to an unraveling of the means by which it controls protein production. RNA was discovered to be an intermediate between DNA and protein, and this led Francis Crick to formulate the "central dogma of molecular genetics":

DNA → RNA → Protein

The sequence of DNA subunits, called nucleotides , was found to correspond to the sequence of amino acids in the resulting protein. This led to the explicit formulation of a gene as a coded instruction.

Three major aspects of DNA as a code—a sequence of symbols that carry information—are widely employed. First, molecular biologists describe genes as messages that can be decoded or translated. The letters in the DNA alphabet (A, C, G, T) are transcribed into an RNA alphabet (A, C, G, U), which in turn is translated at the ribosome into a protein alphabet (twenty amino acids). A word in DNA or RNA is a sequence of three nucleotides that corresponds to a particular amino acid. Thus, translating the messenger RNA word AUG via the standard genetic code yield the amino acid methionine.

In this conception, the gene is a DNA molecule with instructions written within it. The analogy to words, books, and libraries has been drawn repeatedly, because it offers a way to understand the hierarchy of information contained in the genome .

TONEGAWA, SUSUMU (1939– )

Japanese molecular biologist and immunologist who won the 1987 Nobel Prize in physiology for discovering how the immune system makes billions of unique antibodies to fight disease and other unwanted intruders of the human body. Tonegawa showed that white blood cells mix and match a few genes to make billions of combinations that are then translated into billions of unique antibodies.

Further work showed that not all DNA sequences are ultimately translated into protein. Some are used only for production of RNA molecules, including transfer RNA (tRNA) and ribosomal RNA (rRNA). This led to yet another formulation of the gene definition, as the code for an RNA molecule. This encompasses tRNA, rRNA, and the mRNA that ultimately is used to make proteins.

Genes Have Complex Structures

A surprising fact about gene structure was revealed in 1977 with the discovery of intron. Introns are segments of DNA within the gene that are not ultimately translated into protein. The introns alternate with exons, segments that are translated. The entire gene is first transcribed to make RNA, but then the intronic sections are removed, and the RNA exons are spliced together to form mature mRNA. The transcribed DNA of a gene is also flanked by nontranslated and nontranscribed regions that are essential to its function. These include the promoter region, a section of "upstream" DNA that binds RNA polymerase, the enzyme that forms the RNA copy. In Figure 1, an overly simplified version of a genetic message is presented. Other DNA segments called enhancers also regulate gene transcription, and these may be located upstream, downstream, within the gene, or far from it.

Genes Have Complex Functions

Further complexity arose with the discovery of alternative splicing and multiple promoters. In many eukaryotic genes, the exons can be combined in different ways to make closely related but slightly different proteins, called isoforms. There can be multiple promoters, some within the gene, that begin transcription at different sites within the gene. Such an example is illustrated in Figure 2. The dystrophin gene codes for a muscle protein that, when absent, causes Duchenne muscular dystrophy. Other isoforms of dystrophin are expressed in white blood cells, neurons , and the Schwann cells that wrap neurons with insulation.

Thus, it is difficult to speak of "the" dystrophin gene because the alternative splicing of noncontiguous pieces of RNA produces a variety of different proteins. Isoforms help generate the differences between tissues, and are thus partly responsible for the complexity of the fully differentiated organism. Similarly, the vast variety of antibodies we produce are coded for a much smaller number of exons, shuffled and expressed in a combinatorial fashion.

With these complications, defining a gene becomes yet more complicated. While it would be possible to describe the set of dystrophin isoforms as arising from an equal-numbered set of genes, most biologists find that unnecessarily complex. Instead, the gene is defined as a DNA sequence that is transcribed as a single unit, and one that encodes one set of closely related polypeptides or RNA molecules. Thus there is one dystrophin gene, which at varies times in various tissues codes for each of the known dystrophin isoforms. This has been summarized as "one gene, many polypeptides."

Genes Act in Evolution, Heredity, and Development

Finally, some fruitful connections can be made by looking at genes in three different contexts and from three different points of view. First, developmental biologists focus on the action of genes at different times and places over the life history of an individual from conception to death. Over time, a particular gene will be expressed or silenced depending on stage of development and the tissue it is in. Second, geneticists focus on transmission of information, assortment and recombination of markers, and reproduction within families and populations within one species. Over time, a particular gene will be copied and transmitted to offspring and may accumulate mutations in the process. Third, evolutionary biologists focus on history, mutation, variability, and gene duplication. Over time in different species, as mutation and natural selection have their effects, there is divergence of each duplicate's structure and function.

These perspectives can be understood by displaying multiple views as graphs called trees. In Figures 3 and 4, the general form of the tree, representing the transfer of genes from one biological ancestor to descendents, can be identical, yet the diagrams illustrate a passage of genes with a variety of spatial, temporal, and biological changes in different contexts.

A gene is a unit of both structure and function, whose exact meaning and boundaries are defined by the scientist in relation to the experiment he or she is doing. Despite an inability to define a gene precisely, the concept of gene has been a fruitful one for a century. In fact, these ambiguities have helped scientists to develop a concept of "gene" that has attained a robustness. This dynamic richness of meaning has contributed to the endurance of "the gene" in biologists' vocabulary. All of these meanings will have value as we face genetic problems in the future and try to establish wise policy in using our knowledge of genes.

see also Gene Therapy; Genetic Analysis; Genetic Code; Genetic Control of Development; Genetic Diseases; History of Biology: Inheritance; Mendel, Gregor; Protein Synthesis

John R. Jungck

Bibliography

Condit, Celeste Michelle. The Meanings of the Gene: Public Debates About Human Heredity. Madison, WI: The University of Wisconsin Press, 2000.

Dawkins, Richard. The Selfish Gene. Oxford: Oxford University Press, 1989.

Fowler, C., and P. Mooney. The Threatened Gene: Food, Politics, and the Loss of Genetic Diversity. Cambridge: Lutterworth Press, 1990.

Jones, Steve. The Language of Genes: Solving the Mysteries of Our Genetic Past, Present and Future. New York: Anchor Books, 1993.

Jungck, John R., and John N. Calley. "Genotype as Phenotype: How Genetic Engineering Has Changed Our Fundamental Concepts of Biology." American Biology Teacher 46 (1984): 357, 405.

Mulligan, R.C. "The Basic Science of Gene Therapy." Science 60 (1993): 926–932.

Olby, Robert. Origins of Mendelism, 2nd edition. Chicago: University of Chicago Press, 1985.

Singer, Maxine, and Paul Berg. Genes and Genomes. Mill Valley, CA: University Science Books, 1991.

Wallace, Bruce. The Search for the Gene. Ithaca, NY: Cornell University Press, 1992.

Gene

A gene is the fundamental physical and functional unit of heredity. Whether in a microorganism or in a human cell, a gene is an individual element of an organism's genome and determines a trait or characteristic by regulating biochemical structure or metabolic process.

Genes are segments of nucleic acid, consisting of a specific sequence and number of the chemical units of nucleic acids, the nucleotides. In most organisms, the nucleic acid is DNA (deoxyribonucleic acid ), although in retroviruses , the genetic material is composed of ribonucleic acid (RNA ). Some genes in a cell are active more or less all the time, which means they are continuously transcribed and provide a constant supply of their protein product. These "housekeeping" genes are always needed for basic cellular reactions. Others may be rendered active or inactive depending on the needs and functions of the organism under particular conditions. The signal that masks or unmasks a gene can come from outside the cell, for example, from a steroid hormone or a nutrient, or it can come from within the cell itself because of the activity of other genes. In both cases, regulatory substances can bind to the specific DNA sequences of the target genes to control the synthesis of transcripts.

In a paper published in 1865, Gregor Mendel (1823–1884), advanced a theory of inheritance dependent on material elements that segregate independently from each other in sex cells. Before Mendel's findings, inherited traits were thought to be passed on through a blending of the mother and father's characteristics, much like a blending of two liquids. The term "gene" was coined later by the Danish botanist Wilhelm Johannsen (1857–1927), to replace the variety of terms used up until then to describe hereditary factors. His definition of the gene led him to distinguish between genotype (an organism's genetic makeup) and phenotype (an organism's appearance). Before the chemical and physical nature of genes were discovered they were defined on the basis of phenotypic expression and algebraic symbols were used to record their distribution and segregation. Because sexually reproducing, eukaryotic organisms possess two copies of an inherited factor (or gene), one acquired from each parent, the genotype of an individual for a particular trait is expressed by a pair of letters or symbols. Each of the alternative forms of a gene is also known as alleles. Dominant and recessive alleles are denoted by the use of higher and lower case letters. It can be predicted mathematically, for example, that a single allele pair will always segregate to give a genotype ratio 1AA:2Aa:1aa, and the phenotype ratio 2A:1aa (where A represents both AA and Aa since these cannot be distinguished phenotypically if dominance is complete).

The molecular structure and activity of genes can be modified by mutations and the smallest mutational unit is now known to be a single pair of nucleotides, also known as a muton. To indicate that a gene is functionally normal it is assigned a plus (+) sign, whereas a damaged or mutated gene is indicated by a minus (–) sign. A wild-type Escherichia coli able to synthesize its own arginine would thus, be symbolized as arg ⁺ and strains that have lost this ability by mutation of one of the genes for arginine utilization would be arg ^–. Such strains, known as arginine auxotrophs, would not be able to grow without a supplement of arginine. At this level of definition, the plus or minus actually refer to an operon rather than a single gene, and finer genetic analysis can be used to reveal the exact location of the mutated gene.

The use of mutations in studying genes is well illustrated in a traditional genetic test called the "cis–trans test" which also gave the gene the alternative name, cistron. This is a complementation test that can be used to determine whether two different mutations (m¹ and m²) occur in the same functional unit, i.e., within the same gene or cistron. It demonstrates well how genes can be defined phenomenologically and has been performed successfully in microorganisms such as yeasts. It works on the principle that pairs of homologous chromosomes containing similar genes can complement their action. Two types of heterozygotes of the test organism are prepared. Heterozygotes are organisms having different alleles in the two homologous chromosomes each of which was inherited from one parent. One heterozygote contains the mutations under investigation within the same chromosome, that is in the cis— configuration, which is symbolically designated ++/m¹m² (m¹ and m² are the two mutations under investigation and the symbol "+" indicates the same position on the homologous chromosome in the unmutated, wild type state). The second mutant is constructed to contain the mutations in such a way that one appears on each of the homologous chromosomes. This is called the trans— configuration and is designated, for example, by 2+/+m¹. If two recessive mutations are present in the same cistron, the heterozygous trans— configuration displays the mutant phenotype, whereas the cis— configuration displays the normal, wild type, phenotype. This is because in the cis— configuration, there is one completely functional, unmutated, cistron (++) within the system which masks the two mutations on the other chromosome and allows for the expression of the wild type phenotype. If one or both mutations are dominant, and the cis– and trans– heterozygotes are phenotypically different, then both mutations must be present in the same cistron. Conversely, if the cis– and trans– heterozygotes are phenotypically identical, this is taken as evidence that the mutations are present in different cistrons.

In 1910, the American geneticist Thomas Hunt Morgan (1866–1945) began to uncover the relationship between genes and chromosomes. He discovered that genes were located on chromosomes and that they were arranged linearly and associated in linkage groups, all the genes on one chromosome being linked. For example the genes on the X and Y chromosomes are said to be sex-linked because the X and Y chromosomes determine the sex of the organisms, in humans X determining femaleness and Y determining maleness. Nonhomologous chromosomes possess different linkage groups, whereas homologous chromosomes have identical linkage groups in identical sequences. The distance between two genes of the same linkage group is the sum of the distances between all the intervening genes and a schematic representation of the linear arrangement of linked genes, with their relative distances of separation, is known as a genetic map. In the construction of such maps the frequency of recombination during crossing over is used as an index of the distance between two linked genes.

Advances in molecular genetics have allowed analysis of the structure and biochemistry of genes in detail. They are no longer the nebulous units described by Mendel purely in terms of their visible expression (phenotypic expression). It is now possible to understand their molecular structure and function in considerable detail. The biological role of genes is to carry, encode, or control information on the composition of proteins. The proteins, together with their timing of expression and amount of production are possibly the most important determinants of the structure and physiology of organisms. Each structural gene is responsible for one specific protein or part of a protein and codes for a single polypeptide chain via messenger RNA (mRNA). Some genes code specifically for transfer RNA (tRNA) or ribosomal RNA (rRNA) and some are merely sequences, which are recognized by regulatory proteins. The latter are termed regulator genes. In higher organisms, or eukaryotes , genes are organized in such a way that at one end, there is a region to which various regulatory proteins can bind, for example RNA polymerase during transcription , and at the opposite end, there are sequences encoding the termination of transcription. In between lies the protein encoding sequence. In the genes of many eukaryotes this sequence may be interrupted by intervening non-coding sequence segments called introns, which can range in number from one to many. Transcription of eukaryotic DNA produces pre–mRNA containing complementary sequences of both introns and the information carrying sections of the gene called exons. The pre–mRNA then undergoes post–transcriptional modification or processing in which the introns are excised and exons are spliced together, leaving the complete coding transcript of connected exons ready to code directly for the protein. When the central dogma of genetics was first established, a "one gene–one enzyme" hypothesis was proposed, but today it is more accurate to restate this as a one to one correspondence between a gene and the polypeptide for which it codes. This is because a number of proteins are now known to be constituted of multiple polypeptide subunits coded for by different genes.

See also Bacterial artificial chromosome (BAC); Chromosomes, eukaryotic; Chromosomes, prokaryotic; DNA (Deoxyribonucleic acid); Evolution and evolutionary mechanisms; Gene amplification; Genetic code; Genetic mapping; Genotype and phenotype; Immunogenetics; Microbial genetics; Molecular biology, central dogma of; Molecular biology and molecular genetics

Gene

Resources

A gene is the fundamental physical and functional unit of heredity. Whether in a microorganism or in a human cell, a gene is an individual element of an organism’s genome and determines a trait or characteristic by regulating biochemical structure or metabolic process.

Genes are segments of nucleic acid, consisting of a specific sequence and number of the chemical units of nucleic acids, the nucleotides. In most organisms, the nucleic acid is DNA (deoxyribonucleic acid), though in retroviruses, the genetic material is composed of ribonucleic acid (RNA). Some genes in a cell are active more or less all the time, which means they are continuously transcribed and provide a constant supply of their protein product. These “housekeeping” genes are always needed for basic cellular reactions. Others may be rendered active or inactive depending on the needs and functions of the organism under particular conditions. The signal that masks or unmasks a gene can come from outside the cell, for example, from a steroid hormone or a nutrient, or it can come from within the cell itself because of the activity of other genes. In both cases, regulatory substances can bind to the specific

DNA sequences of the target genes to control the synthesis of transcripts.

In a paper published in 1865, Gregor Mendel (1823–1884), advanced a theory of inheritance dependent on material elements that segregate independently from each other in sex cells. Before Mendel’s findings, inherited traits were thought to be passed on through a blending of the mother and father’s characteristics, much like a blending of two liquids. The term “gene” was coined later by the Danish botanist Wilhelm Johannsen (1857-1927), to replace the variety of terms used up until then to describe hereditary factors. His definition of the gene led him to distinguish between genotype (an organism’s genetic makeup) and pheno-type (an organism’s appearance). Before the chemical and physical nature of genes were discovered they were defined on the basis of phenotypic expression and algebraic symbols were used to record their distribution and segregation. Because sexually reproducing, eukaryotic organisms possess two copies of an inherited factor (or gene), one acquired from each parent, the genotype of an individual for a particular trait is expressed by a pair of letters or symbols. Each of the alternative forms of a gene is also known as alleles. Dominant and recessive alleles are denoted by the use of higher and lower case letters. It can be predicted mathematically, for example, that a single allele pair will always segregate to give a genotype ratio 1AA:2Aa:1aa, and the phenotype ratio 2A:1aa (where A represents both AA and Aa since these cannot be distinguished phenotypically if dominance is complete).

The molecular structure and activity of genes can be modified by mutations and the smallest mutational unit is now known to be a single pair of nucleotides, also known as a muton. To indicate that a gene is functionally normal it is assigned a plus (+) sign, whereas a damaged or mutated gene is indicated by a minus (−) sign. A wild-type Escherichia coli able to synthesize its own arginine would thus, be symbolized as arg+ and strains that have lost this ability by mutation of one of the genes for arginine utilization would be arg~. Such strains, known as arginine auxotrophs, would not be able to grow without a supplement of arginine. At this level of definition, the plus or minus actually refer to an operon rather than a single gene, and finer genetic analysis can be used to reveal the exact location of the mutated gene.

The use of mutations in studying genes is well illustrated in a traditional genetic test called the “cistrans test” which also gave the gene the alternative name, cistron. This is a complementation test that can be used to determine whether two different mutations (m and m ) occur in the same functional unit, i.e., within the same gene or cistron. It demonstrates well how genes can be defined phenomenologically and has been performed successfully in microorganisms such as yeasts. It works on the principle that pairs of homologous chromosomes containing similar genes can complement their action. Two types of heterozygotes of the test organism are prepared. Heterozygotes are organisms having different alleles in the two homologous chromosomes each of which was inherited from one parent. One heterozygote contains the mutations under investigation within the same chromosome, that is in the cis — configuration, which is symbolically designated ++/m m (m and m are the two mutations under investigation and the symbol “+” indicates the same position on the homologous chromosome in the unmutated, wild type state). The second mutant is constructed to contain the mutations in such a way that one appears on each of the homologous chromosomes. This is called the trans — configuration and is designated, for example, by +/+m . If two recessive mutations are present in the same cistron, the heterozygous trans — configuration displays the mutant phenotype, whereas the cis — configuration displays the normal, wild type, phenotype. This is because in the cis — configuration, there is one completely functional, unmutated, cistron (++) within the system which masks the two mutations on the other chromosome and allows for the expression of the wild type phenotype. If one or both mutations are dominant, and the cis— and trans— heterozygotes are phe-notypically different, then both mutations must be present in the same cistron. Conversely, if the cis— and trans— heterozygotes are phenotypically identical, this is taken as evidence that the mutations are present in different cistrons.

In 1910, the American geneticist Thomas Hunt Morgan (1866-1945) began to uncover the relationship between genes and chromosomes. He discovered that genes were located on chromosomes and that they were arranged linearly and associated in linkage groups, all the genes on one chromosome being linked. For example the genes on the X and Y chromosomes are said to be sex-linked because the X and Y chromosomes determine the sex of the organisms, in humans X determining femaleness and Y determining maleness. Nonhomologous chromosomes possess different linkage groups, whereas homologous chromosomes have identical linkage groups in identical sequences. The distance between two genes of the same linkage group is the sum of the distances between all the intervening genes and a schematic representation of the linear arrangement of linked genes, with their relative distances of separation, is known as a genetic map. In the construction of such maps the frequency of recombination during crossing over is used as an index of the distance between two linked genes.

Resources

BOOKS

Chiu, Lisa Seachrist and Judith A. Seachrist. When a Gene Makes You Smell Like a Fish and Other Amazing Tales about the Genes in Your Body. New York: Oxford University Press, USA, 2006.

Dawkins, Richard. The Selfish Gene. 3rd ed. Oxford: Oxford University Press, 2006.

Lewin, Benjamin. Essential Genes. New York: Prentice Hall, 2005.

PERIODICALS

The International Human Genome Mapping Consortium. “A Physical Map of the Human Genome.” Nature 409, 934–941 (2001).

International Human Genome Sequencing Consortium. “Initial Sequencing and Analysis of the Human Genome.” Nature 409, 860–921 (2001).

OTHER

National Institutes of Health. “Guide to the Human Genome.” <http://www.ncbi.nlm.nih.gov/genome/guide/human/> (accessed October 30, 2006).

Bryan R. Cobb

Gene

Genes are functional units of DNA that contain the instructions for making proteins or RNA. Genes also act as units of heredity, transferring the same instructions from parent to offspring. The nature, structure, and regulation of genes has been a central topic of scientific research for more than 100 years.

History of the Gene and Structure of DNA

Genes were first defined as units of hereditary transmission. The name "gene" was coined by Wilhelm Johannsen in 1909, although the concept of a discrete unit governing inherited characteristics goes back at least to Gregor Mendel in 1861. The work of Thomas Hunt Morgan and his colleagues established that genes were located on chromosomes, and in the mid-1940s Oswald Avery demonstrated that genes were composed of DNA (deoxyribonucleic acid). Since that time, some types of viruses have been discovered that use ribonucleic acid (RNA) instead of DNA, but here we shall concentrate on DNA genes. The discovery of the structure of DNA in 1953 by James Watson and Francis Crick set the stage for the next fifty years of research into gene structure, function, and regulation.

DNA is a linear molecule composed of subunits called nucleotides . Each nucleotide is made of a sugar and phosphate group, plus a chemical base, of which there are four types: adenine, thymine, guanine, and cytosine (A, T, G, C). Nucleotides are typically referred to by the name of their base. DNA exists as a pair of strands, wound around one another into a double helix, with the bases directed into the center. The structure and charges of the bases dictate that A on one strand can match only up with T on the other, and C only with G. This complementarity provides the basis for faithful replication of the entire DNA molecule.

Genes Code for Protein and RNA

While all genes are made of DNA, not all stretches of DNA act as genes. Indeed, in eukaryotic organisms, most of the DNA does not function as genes, meaning it is not the code for making proteins or RNA. Some DNA outside of genes has a structural role, some are remnants of old genes that now are functionless, and much of it appears to be "junk," inserted and copied by viruslike sequences. Within a gene, usually only one side of the double helix actually codes for product; the other side is silent. Which side of the helix acts as code varies from gene to gene.

Almost all genes code for proteins. Proteins are strings of amino acids , and the sequence of nucleotides in the gene dictates the sequence of amino acids in the protein. Proteins perform almost all the functions in cells, and can be grouped into four major classes: they act as enzymes that control the rate of chemical reactions in the cell; they form structural components of organelles, membranes, and other cell components; they receive and transmit signals between and within cells; or they act as regulators of genes by latching onto DNA, thereby increasing or decreasing the rate at which the gene is used, or "expressed."

Genes vary in length. The largest human gene is 2.5 million base pairs in length, and codes for the muscle protein named dystrophin, which is more than 3,500 amino acids long. Eukaryotic genes generally produce proteins of about 150 to 3,000 amino acids in length. Some genes are relatively small, as in prokaryotes , which produce proteins of 50 to 300 amino acids. Most eukaryotic protein-coding genes are present in only two copies per genome, occurring in the same position on homologous chromosomes, one of which is received from each parent. If the two copies differ slightly they are called alleles. Changes in nucleotide sequences are termed mutations or polymorphisms, depending on their effect.

Some genes code not for protein but for RNA molecules that have their own functions within the cell. These include the transfer RNAs, ribosomal RNAs, and a variety of other smaller RNAs with roles in the nucleus. RNA-coding genes are usually present in multiple copies per eukaryotic genome.

Gene Expression

Expression of protein-coding genes begins with the process of transcription . During transcription, the helix is unwound, and an enzyme (RNA polymerase) binds to the DNA. It then moves along the DNA, and beginning slightly "downstream" at the so-called initiation site, it copies one of the strands to form a molecule of RNA. Transcription ceases when the polymerase reaches a special DNA sequence called the termination site, usually a region high in G-Cs followed by A-Ts.

In prokaryotes, this RNA product is ready to use for protein synthesis, and is called messenger RNA (mRNA). After the mRNA of a gene is formed, it is used by the cell in protein synthesis (translation ) at the ribosomes.

Thus, the prokaryotic gene consists of an RNA binding site (called the "promoter"), a transcription initiation site, the coding region, and a termination signal. The initiation site should not be confused with the start signal for protein synthesis, nor the termination site with the stop signal in protein synthesis. Each of the translation signals is within the coding region, or "open reading frame," of the gene.

Eukaryotic Genes

In eukaryotic cells, genes are more complex. It was discovered in 1977 that eukaryotic genes are functionally separated into coding segments called exons, which are interrupted by noncoding sequences of DNA called introns. The entire region between the initiation and termination sites is transcribed, including the introns, to form the primary transcript. This must then be processed by special enzymes that cut out the introns and splice together the exons to form an mRNA. The mRNA is then exported from the nucleus for translation.

The existence of introns allows for the creation of multiple proteins from one gene, by the use or exclusion of different exons. Such alternative splicing gives rise to protein "isoforms," highly similar but slightly different proteins, with functions that vary as well. Isoforms are typically tissue-specific. For example, the muscle enzyme creatine kinase exists in one form in the heart, and another form in the skeletal muscles (such as the biceps), which have different ends formed through use of different exons. Even though it codes for two or more proteins, most scientists call such a DNA sequence a single gene.

Eukaryotic genes also contain a sequence close to the termination site called the polyadenylation signal. After transcription, this sequence prompts a special enzyme, called poly-A polymerase, to cut the RNA chain and begin adding multiple adenine nucleotides, as many as 250, to the primary transcript. This poly-A tail helps transport the RNA out of the nucleus, stabilizes it in the cytoplasm , and promotes efficient transcription at the ribosome.

Thus, the eukaryotic gene consists of an RNA binding site (promoter), a transcription initiation site, the coding region including exons and introns, the polyadenylation signal, and a termination site.

Genes for RNAs are transcribed in the same way, but the RNA formed is not translated into protein. Details vary among different types, but most RNA-coding genes do not contain introns. Transcripts of the ribosomal RNA genes must be cut apart to form a number of smaller functional RNA molecules.

Controlling Gene Expression

The complexity of any living cell is due to the well-orchestrated interactions of its proteins. Just as an orchestra cannot have every instrument play at once, a cell cannot have all its proteins function at once. One method of regulating protein function is to control when the protein is made, which is to say when the gene is expressed. Prokaryotic genes are usually controlled by operon systems, relatively simple systems that tie expression directly to metabolic activity in the cell. Eukaryotic genes are controlled by more complex regulatory systems that respond to hormones, growth factors, internal conditions, and many other influences.

To ensure that each gene is expressed when, and only when, it is needed, each eukaryotic gene has several control regions, termed the promoter and enhancer regions. These do not code for amino acids but are critical for proper gene expression. Mutations in these regions often change the rate at which a gene is expressed, or the factors in the cell or the environment to which it responds.

The promoter region is a sequence of 20 to 200 nucleotides "upstream" of the coding region to which the RNA polymerase enzyme binds, permitting it to begin transcribing the DNA. Promoters differ in size and sequence in prokaryotic and eukaryotic genes. Promoters attract RNA polymerase by first binding a variety of other proteins, called transcription factors . In some eukaryotic genes, promoter sites also occur within the coding region, allowing alternative transcripts with fewer exons.

Enhancers, also called activation sites, are located either nearby or far away from the promoter. Because DNA is looped and coiled, however, these sites are actually physically close to the gene's promoter even when distant on the DNA strand. Enhancers are gene-specific, and attract a variety of transcription factors. All of these work together to increase the rate of transcription by increasing the likelihood of RNA polymerase binding. Controlling the availability of these proteins is an important factor in regulating expression of the gene.

see also Chromosome, Eukaryotic; Chromosome, Prokaryotic; Crick, Francis; DNA; Evolution of Genes; Gene Expression: Overview of Control; Gene Families; Genetic Code; Mendel, Gregor; Morgan, Thomas Hunt; Muscular Dystrophy; Mutation; Nature of the Gene, History; Nucleotide; Operon; Proteins; RNA Polymerases; RNA Processing; Transcription; Transcription Factors; Watson, James.

Elof Carlson

Bibliography

Alberts, Bruce, et al. Molecular Biology of the Cell, 4th ed. New York: Garland Science,2002.

Carlson, Elof. The Gene: A Critical History. Philadelphia, PA: Saunders Publishing,1966.

Muller, H. J. "The Development of the Gene Theory." In Genetics in the Twentieth Century, L. C. Dunn, ed. New York: Macmillan, 1951.

Olby, Robert. The Path to the Double Helix. Seattle, WA: University of Washington Press, 1974.

Gene

A gene is the fundamental physical and functional unit of heredity. It is an individual element of an organism's genome and determines a trait or characteristic by regulating biochemical structure or metabolic process.

Genes are segments of nucleic acid, consisting of a specific sequence and number of the chemical units of nucleic acids, the nucleotides. In most organisms the nucleic acid is deoxyribonucleic acid (DNA ) although in retroviruses the genetic material is composed of ribonucleic acid (RNA ). Some genes in a cell are active more or less all the time, which means that they are continuously transcribed and provide a constant supply of their protein product. These are the "housekeeping" genes that are always needed for basic cellular reactions. Others may be rendered active or inactive depending on the needs and functions of the organism under particular conditions. The signal that masks or unmasks a gene can come from outside the cell, for example, from a steroid hormone or a nutrient, or it can come from within the cell itself as a result of the activity of other genes. In both cases, regulatory substances can bind to the specific DNA sequences of the target genes to control the synthesis of transcripts.

In a paper published in 1865, Gregor Mendel (1823–1884) advanced a theory of inheritance dependent on material elements that segregate independently from each other in sex cells. Before Mendel's findings, inherited traits were thought to be passed on through a blending of the mother and father's characteristics, much like a blending of two liquids. The term "gene" was coined later by the Danish botanist Wilhelm Johannsen (1857–1927), to replace the variety of terms used up until then to describe hereditary factors. His definition of the gene led him to distinguish between genotype (an organism's genetic makeup) and phenotype (an organism's appearance). Before the chemical and physical nature of genes were discovered they were defined on the basis of phenotypic expression and algebraic symbols were used to record their distribution and segregation. Because sexually reproducing, eukaryotic organisms possess two copies of an inherited factor (or gene), one acquired from each parent, the genotype of an individual for a particular trait is expressed by a pair of letters or symbols. Each of the alternative forms of a gene is also known as alleles. Dominant and recessive alleles are denoted by the use of higher and lower case letters. It can be predicted mathematically, for example, that a single allele pair will always segregate to give a genotype ratio 1AA:2Aa:1aa, and the phenotype ratio 2A:1aa (where A represents both AA and Aa since these cannot be distinguished phenotypically if dominance is complete).

The molecular structure and activity of genes can be modified by mutations and the smallest mutational unit is now known to be a single pair of nucleotides, also known as a muton. To indicate that a gene is functionally normal it is assigned a plus (+) sign, whereas a damaged or mutated gene is indicated by a minus (–) sign. A wild type Escherichia coli able to synthesize its own arginine would thus be symbolized as arg+ and strains that have lost this ability by mutation of one of the genes for arginine utilization would be arg-. Such strains, known as arginine auxotrophs, would not be able to grow without a supplement of arginine. At this level of definition, the plus or minus actually refer to an operon rather than a single gene and finer genetic analysis can be used to reveal the exact location of the mutated gene.

The use of mutations in studying genes is well illustrated in a traditional genetic test called the "cistrans test" which also gave the gene the alternative name, cistron. This is a complementation test that can be used to determine whether two different mutations (m1 and m2) occur in the same functional unit, i.e., within the same gene or cistron. It demonstrates well how genes can be defined phenomenologically and has been performed successfully in microrganisms such as yeasts. It works on the principle that pairs of homologous chromosomes containing similar genes can complement their action. Two types of heterozygotes of the test organism are prepared. Heterozygotes are organisms with different alleles in the two homologous chromosomes each of which was inherited from one parent. One heterozygote contains the mutations under investigation within the same chromosome , that is in the cis-configuration, which is symbolically designated ++/m1m2 (m1 and m2 are the two mutations under investigation and the symbol "+" indicates the same position on the homologous chromosome in the unmutated, wild type state). The second mutant is constructed to contain the mutations in such a way that one appears on each of the homologous chromosomes. This is called the trans-configuration and is designated, for example, by m2+/+m1. If two recessive mutations are present in the same cistron, the heterozygous trans-configuration displays the mutant phenotype, whereas the cis-configuration displays the normal, wild type, phenotype. This is because in the cis-configuration, there is one completely functional, unmutated, cistron (++) within the system which masks the two mutations on the other chromosome and allows for the expression of the wild type phenotype. If one or both mutations are dominant, and the cis- and trans-heterozygotes are phenotypically different, then both mutations must be present in the same cistron. Conversely, if the cis- and trans-heterozygotes are phenotypically identical, this is taken as evidence that the mutations are present in different cistrons.

In 1910, the American geneticist Thomas Hunt Morgan (1866–1945) began to uncover the relationship between genes and chromosomes. He discovered that genes were located on chromosomes and that they were arranged linearly and associated in linkage groups, with all the genes on one chromosome being linked. For example, the genes on the X and Y chromosomes are said to be sex-linked because the X and Y chromosomes determine the sex of the organisms (in humans X determining femaleness and Y determining maleness). Non-homologous chromosomes possess different linkage groups whereas homologous chromosomes have identical linkage groups in identical sequences. The distance between two genes of the same linkage group is the sum of the distances between all the intervening genes. A schematic representation of the linear arrangement of linked genes, with their relative distances of separation, is known as a genetic map. In the construction of such maps the frequency of recombination during crossing over is used as an index of the distance between two linked genes.

Advances in molecular genetics have allowed analysis of the structure and biochemistry of genes in greater detail. They are no longer the nebulous units described by Mendel purely in terms of their visible expression (phenotypic expression). It is now possible to understand their molecular structure and function in considerable detail. The biological role of genes is to carry, encode, or control information on the composition of proteins. The proteins, together with their timing of expression and amount of production, are possibly the most important determinants of the structure and physiology of organisms. Each structural gene is responsible for one specific protein or part of a protein and codes for a single polypeptide chain via messenger RNA (mRNA). Some genes code specifically for transfer RNA (tRNA) or ribosomal RNA (rRNA) and some are merely sequences that are recognized by regulatory proteins. The latter are termed regulator genes. In higher organisms, or eukaryotes, genes are organized in such a way that at one end there is a region to which various regulatory proteins can bind, for example, RNA polymerase during transcription, and at the opposite end there are sequences encoding the termination of transcription. In between lies the protein encoding sequence. In the genes of many eukaryotes this sequence may be interrupted by intervening non-coding sequence segments called introns, which can range in number from one to many. Transcription of eukaryotic DNA produces pre-mRNA containing complementary sequences of both introns and the information carrying sections of the gene called exons. The pre-mRNA then undergoes post-transcriptional modification or processing in which the introns are excised and exons are spliced together, leaving the complete coding transcript of connected exons ready to code directly for the protein. When the central dogma of genetics was first established, a "one gene-one enzyme" hypothesis was proposed, but today it is more accurate to restate this as a one-to-one correspondence between a gene and the polypeptide for which it codes. This is because a number of proteins are now known to be constituted of multiple polypeptide subunits coded by different genes.

Judyth Sassoon, ARCS, PhD