gene

A hereditary unit consisting of a sequence of DNA that occupies a specific location on a chromosome and determines a particular characteristic in an organism. Genes undergo mutation when their DNA sequence changes.

[German Gen, from gen-, begetting, in Greek words (such as genos, race, offspring).]

The basic unit in inheritance. There is no general agreement as to the exact usage of the term, since several criteria that have been used for its definition have been shown not to be equivalent.

The facts of mendelian inheritance indicate the presence of discrete hereditary units that replicate at each cell division, producing remarkably exact copies of themselves, and that in some highly specific way determine the characteristics of the individuals that bear them. The evidence also shows that each of these units may at times mutate to give a new equally stable unit (called an allele), which has more or less similar but not identical effects on the characters of its bearers. These hereditary units are the genes, and the criteria for the recognition that certain genes are alleles have been that they (1) arise from one another by a single mutation, (2) have similar effects on the characters of the organism, and (3) occupy the same locus in the chromosome. It has long been known that there were a few cases where these criteria did not give consistent results, but these were explained by special hypotheses in the individual cases. However, such cases have been found to be so numerous that they appear to be the rule rather than the exception. See also Allele; Gene action; Mendelism; Mutation; Recombination (genetics).

The term gene, or cistron, may be used to indicate a unit of function. The term is used to designate an area in a chromosome made up of subunits present in an unbroken unit to give their characteristic effect. See also Chromosome.

Every gene consists of a linear sequence of bases in a nucleic acid molecule. Genes are specified by the sequence of bases in DNA in prokaryotic, archaeal, and eukaryotic cells, and in DNA or ribonucleic acid (RNA) in prokaryotic or eukaryotic viruses. The ultimate expressions of gene function are the formation of structural and regulatory RNA molecules and proteins. These macromolecules carry out the biochemical reactions and provide the structural elements that make up cells. See also Deoxyribonucleic acid (DNA); Nucleic acid; Ribonucleic acid (RNA); Virus.

One goal of molecular biology is to understand the function, expression, and regulation of a gene in terms of its DNA or RNA sequence. The genetic information in genes that encode proteins is first transcribed from one strand of DNA into a complementary messenger RNA (mRNA) molecule by the action of the RNA polymerase enzyme. Many kinds of eukaryotic and a limited number of prokaryotic mRNA molecules are further processed by splicing, which removes intervening sequences called introns. In some eukaryotic mRNA molecules, certain bases are also changed posttranscriptionally by a process called RNA editing. The genetic code in the resulting mRNA molecules is translated into proteins with specific amino acid sequences by the action of the translation apparatus, consisting of transfer RNA (tRNA) molecules, ribosomes, and many other proteins. The genetic code in an mRNA molecule is the correspondence of three contiguous (triplet) bases, called a codon, to the common amino acids and translation stop signals; the bases are adenine (A), uracil (U), guanine (G), and cytosine (C). There are 61 codons that specify the 20 common amino acids, and 3 codons that lead to translation stopping. See also Genetic code; Intron.

In many cases, the genes that mediate a specific cellular or viral function can be isolated. The recombinant DNA methods used to isolate a gene vary widely depending on the experimental system, and genes from RNA genomes must be converted into a corresponding DNA molecule by biochemical manipulation using the enzyme reverse transcriptase. The isolation of the gene is referred to as cloning, and allows large quantities of DNA corresponding to a gene of interest to be isolated and manipulated.

After the gene is isolated, the sequence of the nucleotide bases can be determined. The goal of the large-scale Human Genome Project is to sequence all the genes of several model organisms and humans. The sequence of the region containing the gene can reveal numerous features. If a gene is thought to encode a protein molecule, the genetic code can be applied to the sequence of bases determined from the cloned DNA. The application of the genetic code is done automatically by computer programs, which can identify the sequence of contiguous amino acids of the protein molecule encoded by the gene. If the function of a gene is unknown, comparisons of its nucleic acid or predicted amino acid sequence with the contents of huge international databases can often identify genes or proteins with analogous or related functions. These databases contain all the known sequences from many prokaryotic, archaeal, and eukaryotic organisms. Putative regulatory and transcript-processing sites can also be identified by computer. These putative sites, called consensus sequences, have been shown to play roles in the regulation and expression of groups of prokaryotic, archaeal, or eukaryotic genes. However, computer predictions are just a guide and not a substitute for analyzing expression and regulation by direct experimentation. See also Genetic engineering; Human Genome Project; Molecular biology.

A gene is part of a DNA molecule within the nucleus of all cells. Each gene codes for a particular protein. Thus a gene is a unit of the inheritable characteristics of the organism. Humans have tens of thousands of different genes; these determine the phenotype of the individual.

— Alan W. Cuthbert

See cell; gene therapy; genetic testing; genetics, human.

In the early 1860s, Gregor Mendel developed the concept of the gene to help explain results obtained while crossbreeding strains of garden peas. He identified physical characteristics (phenotypes), such as plant height and seed color, that could be passed on, unchanged, from one generation to the next. The hereditary factor that predicted the phenotype was termed a "gene." Mendel hypothesized that genes were inherited in pairs, one from the male and one from the female parent. Plants that bred true (homozygotes) had inherited identical genes from their parents, whereas plants that did not breed true (hybrids, or heterozygotes) inherited alternative copies of the genes (alleles) from one parent that were similar, but not identical, to those from the other parent.

Some of these alleles had a greater effect on the phenotypes of hybrids than others. For example, if a single copy of a given allele was sufficient to produce the same phenotype seen in homozygous organisms, that gene was termed a "dominant." Conversely, if the allele could only be detected in the minority of the offspring of hybrid parents that were homozygous for that "weaker" allele, the gene was termed a "recessive." Based on these observations, Mendel formulated a series of laws that are the basis of what we now term "Mendelian" inheritance patterns.

The "law of unit inheritance" holds that factors retain their identity from generation to generation and do not blend in the hybrid. The "law of segregation" states that two members (alleles) of a single pair of genes are never found in the same mature sperm or ovum (gamete) but always separate out (segregate). Finally, the "law of independent assortment" holds that members of different pairs of genes (nonalleles) are sorted out (assort) independently to different gametes.

Almost a century later, in 1953, Watson and Crick solved the structure of the DNA molecule and helped explain how this genetic information could be encoded in a polymer, deoxyribonucleic acid (DNA), which was found in the nucleus of the cell. They demonstrated that DNA is a double-stranded polymer consisting of two linear arrays of diverse purine (adenine [A] and guanine [G]) and pyrimidine (thymine [T] and cytosine [C]) bases. Each purine or pyrimidine on one strand pairs with a complementary base (A:T and G:C) on the other strand. Each strand is thus complementary to the other. The two antiparallel polynucleotide strands are gently twisted to form what is termed a "double helix."

In humans, the nucleus of each somatic cell contains twenty-three pairs of chromosomes, which are formed by tightly coiled DNA strands. Twenty-two pairs of the chromosome pairs are found in the cells of both men and women. These chromosomes are termed "autosomes," and they are numbered by size from 1 (the largest) to 22 (the smallest). The twenty-third pair of chromosomes determine the sex of the individual, and these two chromosomes are thus termed the "sex chromosomes." Women have a pair of X chromosomes, whereas men have a single X chromosome, which they inherit from their mother, and a single Y chromosome, which they inherit from their father. The Y chromosome is dominant for maleness.

During "mitosis," the DNA double strand is unwound and split apart. Each individual strand is then duplicated. By making copies of each DNA strand, a parental cell can transmit a complete set of genetic information into each of its two daughter cells.

Gametes result from "meiosis," which differs from mitosis in two ways. First, allelic chromosomes are paired prior to their duplication. Second, there are two sets of divisions before the final product, the gamete, is created. In the first set of divisions after DNA duplication, allelic chromosomes, rather than chromatids, segregate into the daughter cells. In the second set of divisions, the chromatids separate and segregate into the gamete. Thus, one and only one copy of each allelic pair is contributed to the gamete. In this way, a "diploid" germ cell gives rise to a "haploid" sperm or egg that contains an assortment of one of each of the twenty-three pairs of allelic chromosomes in the parental cell. During fertilization, a sperm and an egg unite to create a zygote with a newly constituted complete set of forty-six chromosomes. These fundamental properties of DNA and cell division are the basis of Mendel's laws of unit inheritance, segregation, and independent assortment.

The central dogma of molecular genetics holds that each gene encodes one polypeptide, forming a monomeric protein. The portion of the gene that specifies the polypeptide sequence is termed "coding" DNA. Each human cell contains approximately 3.9 × 10⁹ base pairs of DNA per haploid genome, which is enough to encode about 1 million polypeptides of average length. However, there are approximately 35,000 structural genes—possibly in the range of 30,000—in humans; thus more than 90 percent of DNA does not encode peptide sequences. The DNA that does not code for protein, termed "noncoding" DNA, is often involved in the regulation of gene expression. Noncoding DNA can also play a structural role. Structural functions include providing structural stability for the chromosome (e.g., matrix-associated regions, or MARs), providing the specialized sequences that define the ends of the chromosome (telomeres), and providing a site to which the cellular cytoskeleton can be attached in order to allow the movement of chromosomes during meiosis and mitosis (centromeres). Approximately 10 percent of cellular DNA consists of a repetitive sequence that has been randomly inserted throughout the genome. Although the function of this repetitive DNA is unknown, its presence has proven useful for gene mapping studies.

Genetic information proceeds in a stepwise fashion from the sequence of a gene to the synthesis of a polypeptide. Located near the coding sequence of the gene are sequences, called DNA control regions, that identify the transcription start site (promoters), mark the tissue in which it will be expressed (enhancers), and control the use of batteries of genes during ontogeny (locus control regions). The regions of DNA that specify the sequence of a polypeptide chain, or structural genes, are organized into discrete units (exons) that are separated by noncoding sequences (introns). The first step in synthesizing a new protein occurs in the nucleus, where the sequence of the coding DNA is copied (transcribed) into ribonucleic acid (RNA), a less stable nucleic acid that can be rapidly degraded. The ends of the RNA are modified to help stabilize the final product and the introns are removed, or spliced out, generating messenger ribonucleic acid (mRNA). The mRNA is transported from the nucleus to the cytoplasm, where it is translated by ribosomes into polypeptide strands.

Ribosomes read the sequence of the mRNA in sequential groups of three, or triplets, termed a codon. There are sixty-four different combinations (e.g., AAA, TTT, CAC), all but three of which specify a specific amino acid. Each codon specifies a single amino acid, but amino acids can be encoded by more than one codon, thus there is considerable degeneracy in the code. Translation begins when the mRNA is bound to the ribosome. Transfer RNA (tRNA), an adapter molecule, contains a complementary triplet anticodon at one end, and an amino acid bound to the other end. The tRNA anticodon binds to the mRNA codon and helps stabilize the interaction with the ribosome. Each ribosome has two sites where the tRNA can bind. Binding of the downstream tRNA, which contains sequence complementary to the next three nucleotide codon on the RNA, brings its amino acid next to the end of the growing polypeptide strand. Formation of a peptide bond allows the ribosome to shift down the mRNA, providing a site for the next amino acid and its adapter to bind. Step by step, the protein is allowed to grow until the mRNA brings one of the three remaining codons into the ribosome. These codons do not have tRNA partners, and they function to terminate translation and allow the release from the ribosome of the mRNA and its protein product.

Many genes are composed of a series of structural or functional domains, with each exon specifying part or all of the sequence of a single structural domain. Each domain can endow the protein with a different property. For example, a protein may have one or more extracellular domains that allow it to bind to a specific soluble ligand, a transmembrane domain that allows it to be anchored in the cell membrane, and one or more intracellular domains that allow it to signal inside the cell. These types of proteins are the product of mixing and matching different types of domains during evolution, a process that is facilitated by the exon/intron structure of the gene. By changing the extracellular domains while maintaining the rest of the molecule relatively intact, for example, a similar signal can be elicited by the binding of several different types of ligands. Conversely, the presence or absence of a transmembrane domain can allow the protein to be tethered to the cell or to exist as a soluble factor. The function of an unknown protein can often be guessed by analyzing its complement of domains.

At first glance, the linking of genes in chromosomal units and their transmission as a unit to daughter cells would seem to violate Mendel's laws of independent assortment and segregation, because effectively one might expect genes to be inherited as part of only 23 sets of genes. However, when allelic chromosomes are brought into close juxtaposition during the process of meiosis, breaks occur in the chromosomes and allow bridges, or chiasmata, to form between homologous portions of the chromosomes. This crossing over of DNA strands allows allelic chromosomes to recombine, forming patchwork or chimeric chromosomes that contain portions of each of the parental chromosomes. Although recombination can occur anywhere in the chromosome, only a limited number of chiasmata form during each meiosis. Two genes that are on opposite ends of the chromosome may thus behave as if they were on different chromosomes, whereas recombination is less likely between genes that are very close to each other in their primary sequence. The increased frequency of the joint inheritance of two genes that are closely physically linked on a chromosome is termed "linkage disequilibrium."

Distances between genes on a chromosome are quantified by either their physical distance from each other in millions of base pairs (megabases), or by their genetic distance, as measured by the frequency of recombination between the two genes per generation. One percent of genetic recombination is termed a "centimorgan," after the geneticist Thomas Hunt Morgan, whose studies of the common fruitfly, Drosophila, in the first half of the twentieth century helped elucidate the properties of recombination. As a rough guide, one centimorgan covers approximately one megabase of DNA. However, the relationship between linear and genetic distance is not absolute. The frequency of recombination, and thus the genetic distance between genes in specific regions of the genome, may differ depending on the sequence or the nonhistone proteins that cover the DNA. Recombination frequencies in selected regions of the genome may differ in male and female gametes, implying that segments of chromosomes can be handled differently by spermatogonia and oocytes. This disparity in how DNA is treated by male and female gametes can lead to differences in the function of alleles, depending on whether they have been inherited from the mother or the father, a process termed "imprinting."

A "mutation" is defined as a stable, heritable alteration in the DNA sequence that can be passed from a parental cell to at least one its daughters. From the standpoint of evolution, mutations are required to generate the genetic diversity that is needed to permit species to adapt to a changing environment. The normal rate of mutation is approximately one base pair change per generation per 10⁷ base pairs; thus, on average, each child differs from its parent by approximately 390 base pairs as a result of mutations in the gametes. Mutations in the nonreproductive cells of the body are termed "somatic" mutations. Although by definition these alterations are not transmitted to the gametes, the mutations are passed on to the daughter cells of the mutated parent. Somatic mutations in oncogenes, for example, foster the development of many cancers.

Mutations can involve an entire human genome, as in triploidy, in which a third copy of the entire chromosomal complement occurs. Mutations may involve all or part of a single chromosome, including duplications, deletions, and translocations of a portion of one chromosome to another. At the other extreme, a mutation can be minute and involve a small deletion or insertion, or a replacement of only a single base pair (point mutation). Deletions or insertions that occur in a coding region can alter the reading frame distal to the mutation (frameshift mutations). Frameshift mutations frequently alter the protein sequence and can lead to premature peptide termination by generating a stop codon, one of the three triplet sequences that does not encode an amino acid. Point mutations in coding regions may be of three types: (1) a nonsense mutation (about 4% of base substitutions in coding regions), in which the base change generates one of the three termination codons; (2) a missense, or replacement, mutation (about 73% of base substitutions in coding regions), in which the base change results in substitution of one amino acid for another; and (3) a synonymous, or silent, mutation (about 23% of random base substitutions in coding regions), in which the base replacement does not lead to a change in the amino acid but only to a different codon for the same amino acid. Even synonymous mutations can have deleterious affects, however. A change in the coding sequence of a given gene may alter splicing patterns or diminish mRNA stability, reducing protein production.

The consequences of a single-point mutation to the function of a given protein can vary greatly. Enzymes, for example, exhibit a hierarchy of resistance to mutation. Portions of the hydrophilic exterior may serve primarily to allow the protein to be soluble in an aqueous solution, hence changes in the amino acid sequence that preserve hydropathicity may have little or no effect on the function of the protein. The hydrophobic core provides structural stability for the molecule, and amino acid changes may result in an unstable protein product that is temperature sensitive (e.g., falling apart at high temperature). Finally, the catalytic site is exquisitely sensitive, and a single mutation may completely abolish function.

Large deletions may interrupt a coding region and cause an absence of one or more closely linked protein products. If the deletion removes a bridge between two coding regions, the result may be a fusion or hybrid protein containing the initial sequence of one protein and the terminal portion of the other. Such deletions can also result from unequal crossing-over between homologous genes. Finally, alterations of the DNA in the surrounding regions may lead to changes in RNA splicing, transcriptional efficiency, or control of tissue expression.

The Human Genome Project began in 1990 with the goals of developing genetic and physical maps and determining the complete DNA sequence of the human genome. The ultimate goal is to use this mapping and sequence information to isolate and study the structure and function of genes that can contribute to the development of disease. Knowledge of the genetic basis of susceptibility for specific diseases is likely to aid in disease prevention as well as therapy. Associated with these benefits, however, is the risk of discrimination against healthy at-risk individuals that may never develop a disorder. Thus, in addition to learning how to use this new knowledge, we must gain the wisdom to use genetic information appropriately.

(SEE ALSO: Genetic Disorders; Genetics and Health; Human Genome Project; Medical Genetics)

Bibliography

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Sybenga, J. (1999). "What Makes Homologous Chromosomes Find Each Other in Meiosis? A Review and an Hypothesis." Chromosoma 108(4):209–219.

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— HARRY W. SCHROEDER, JR.

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.

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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.

—Elof Carlson

For more information on gene, visit Britannica.com.

The ‘unit of inheritance’ that controls the passing of a hereditary characteristic from parent to offspring, by controlling the structure of proteins or other genetic material. The term was introduced by W. L. Johannsen in 1909 as an abbreviation of ‘pangene’. It is interesting as having been consciously intended as a purely functional notion: ‘completely free from any hypothesis; it expresses only the evident fact that, in any case, many characteristics of the organism are specified in the gametes by means of special conditions, foundations and determiners…’ Genes are now identified with lengths of DNA or RNA. Simplistic forms of biological determinism suppose that arbitrary characteristics of an organism (e.g. poverty, criminality) are genetically specified.

The basic unit of inheritance by which hereditary characteristics are passed from parents to offspring. It is generally considered that one gene contains the information responsible for the synthesis of one polypeptide chain. See also genetic endowment.

A gene is a specific sequence of DNA that contains the molecular recipe for a polypeptide. A polypeptide is a subunit of a protein.

A portion of a DNA molecule that serves as the basic unit of heredity. Genes control the characteristics that an offspring will have by transmitting information in the sequence of nucleotides on short sections of DNA.

The unit of heredity most simply defined as a specific segment of DNA, usually in the order of 1000 nucleotides, that specifies a single polypeptide. Many phenotypic characteristics are determined by a single gene, while others are multigenic. Genes are specifically located in linear order along the single DNA molecule that makes up each chromosome. All eukaryotic cells contain a diploid (2n) set of chromosomes so that two copies of each gene, one derived from each parent, are present in each cell; the two copies often specify a different phenotype, i.e. the polypeptide will have a somewhat different amino acid composition. These alternative forms of gene, both within and between individuals, are called alleles. Genes determine the physical (structural genes), the biochemical (enzymes), physiological and behavioral characteristics of an animal.
The formation of gametes (sperm, ova) involves a process of meiosis, which allows crossing over between four pairs of chromosomes, two derived from each parent, which means that new forms of a particular chromosome are created. Gamete formation also results in cells (gametes) with a haploid (n) set of chromosomes that in fertilization creates a new individual, which is a recombinant of 2n chromosomes, half derived by way of the ovum from the mother and half via the spermatozoa from the father.
Changes in the nucleotide sequence of a gene, either by substitution of a different nucleotide or by deletion or insertion of other nucleotides, constitute mutations which add to the diversity of animal species by creating different alleles and can be used as a basis for genetic selection of different phenotypes. Some mutations, be they a single base change in a single gene or a major deletion, are lethal.

• g. action — the way in which genes exert their effects on tissues or processes, e.g. by being dominant or recessive, or partially so, being absent, being sex-linked, being involved in chromosomal aberrations.
• allelic g's — different forms of a particular gene usually situated at the same position (locus) in a pair of chromosomes.
• g. amplification — see gene duplication (below).
• g. bank — the collection of DNA sequences in a given genome. Called also gene library.
• barring g. — responsible for the barred pattern on the feathers of Barred Plymouth Rock birds.
• g. box — see box (4).
• g. clone — see clone.
• g. cluster — a group of related genes derived from a common ancestral gene, located closely together on the same chromosome. Called also multigene family.
• complementary g's — two independent pairs of nonallelic genes, neither of which is functional without the other.
• g. conversion — a non-reciprocal exchange of DNA elements during meiosis which results in a functional rearrangement of chromosomal DNA.
• dhfr g. — dihydrofolate reductase gene; an enzyme required to maintain cellular concentrations of H₂ folate for nucleotide biosynthesis, and which has been used as a ‘selective marker’; cells lacking the enzyme only survive in media containing thymidine, glycine and purines; mutant cells (dhfr) transfected with DNA that is dhfr′ can be selectively grown in medium lacking these elements.
• diversity (D) g. — genes located in diversity (D) segment; contribute to the hypervariable region of immunoglobulins.
• dominant g. — one that produces an effect (the phenotype) in the organism regardless of the state of the corresponding allele. Examples of traits determined by dominant genes are short hair in cats and black coat color in dogs.
• g. duplication — as a result of non-homologous recombination, a chromosome carries two or more copies of a gene.
• g. expression — see expression (3).
• g. frequency — the proportion of the substances or animals in the group which carry a particular gene.
• holandric g's — genes located on the Y chromosome and appearing only in male offspring.
• immune response (Ir) g's — genes of the major histocompatibility complex (MHC) that govern the immune response to individual immunogens.
• jumping g. — see mobile dna.
• g. knockout — replacement of a normal gene with a mutant allele, as in gene knockout mice.
• lethal g. — one whose presence brings about the death of the organism or permits survival only under certain conditions.
• g. library — see gene bank (above).
• g. locus — see locus.
• mutant g. — one that has undergone a detectable mutation.
• non-protein encoding g. — the final products of some genes are RNA molecules rather than proteins.
• overlapping g's — when more than one mRNA is transcribed from the same DNA sequence; the mRNAs may be in the same reading frame but of different size or they may be in different reading frames.
• g. pool — total of all genes possessed by all members of the population which are capable of reproducing during their lifetime.
• g. probe — see probe (2).
• recessive g. — one that produces an effect in the organism only when it is transmitted by both parents, i.e. only when the individual is homozygous.
• regulator g., repressor g. — one that synthesizes repressor, a substance which, through interaction with the operator gene, switches off the activity of the structural genes associated with it in the operon.
• reporter g. — one that produces products which can be measured and therefore used as an indicator of whether a DNA construct has successfully been transferred.
• sex-linked g. — one that is carried on a sex chromosome, especially an X chromosome.
• g. splicing — see splicing.
• structural g. — nucleotide sequences coding for proteins.
• g. therapy — the insertion of functional genes into cells of the host in order to alter its phenotype, usually used to treat an inherited defect.
• g. transcription — see transcription.
• g. transfer — see recombination.
• tumor suppressor g's — a class of genes that encode proteins that normally suppress cell division that when mutated allow cells to continue unrestricted cell division and may result in a tumor.

The monk Gregor Mendel is now famous for explaining the laws of heredity, including the roles of dominant and recessive genes and the different mathematical consequences arising from the two types of genes when sexual organisms reproduce. He worked with garden peas and looked for such traits as tall versus short or smooth seed versus wrinkled. By mating peas with different traits, he discovered such rules as, when two organisms each has one gene for a recessive trait and they are mated, approximately one-quarter of the offspring will exhibit the recessive trait. In fact, Mendel worked backward from the ratios of traits in offspring to determine the rules of inheritance.

Mendel performed his famous experiments at about the same time that Charles Darwin was explaining evolution. Darwin was already a popular author, and his ideas were soon known around the world. Mendel, however, had trouble getting published. He first sent his work to a prominent biologist who, as it happened, did not like mathematics. The biologist sent the paper back to Mendel with negative comments. In 1865 and 1869 Mendel's work was published -- by the local natural history society. After this Mendel was promoted to abbot, which kept him busy at the same time that it allowed him to grow fat. He gave up both gardening and science.

Darwin never got the chance to learn of Mendel's work, which is unfortunate, since Mendel's laws neatly fill a major gap in Darwin's theory. Darwin knew that variation occurred, but he did not know how it was inherited. Mendel's laws described the mechanism by which many traits pass from generation to generation.

In 1900, however, an astonishing coincidence put Mendel's work into the scientific mainstream. Three different biologists working in three different countries -- Hugo de Vries in the Netherlands, Karl Correns in Germany, and Erich Tschermak von Seysenegg in Austria -- worked out Mendel's laws for themselves. Each searched the scientific literature for prior discoveries of these laws and each somehow found the obscure papers from over 30 years before. When they published their work, they each unselfishly credited Mendel. The concept of a gene finally entered the mainstream of science.

Tutor's tip: You must have the skinny "gene" (part of a cell which determines hereditary traits) to wear tight "jeans" (pants mad of a kind of cotton cloth) well.

For a non-technical introduction to the topic, see Introduction to genetics.

For other uses, see Gene (disambiguation).

This stylistic diagram shows a gene in relation to the double helix structure of DNA and to a chromosome (right). The chromosome is X-shaped because it is dividing. Introns are regions often found in eukaryote genes that are removed in the splicing process (after the DNA is transcribed into RNA): Only the exons encode the protein. This diagram labels a region of only 50 or so bases as a gene. In reality, most genes are hundreds of times larger.

A gene is the basic unit of heredity in a living organism. All living things depend on genes. Genes hold the information to build and maintain their cells and pass genetic traits to offspring. A modern working definition of a gene is "a locatable region of genomic sequence, corresponding to a unit of inheritance, which is associated with regulatory regions, transcribed regions, and or other functional sequence regions ".^[1][2] Incorrect colloquial usage of the term gene may actually refer to an allele: a gene is the basic instruction, a sequence of DNA, while an allele is one variant of that instruction.

The notion of a gene^[3] is evolving with the science of genetics, which began when Gregor Mendel noticed that biological variations are inherited from parent organisms as specific, discrete traits. The biological entity responsible for defining traits was termed a gene, but the biological basis for inheritance remained unknown until DNA was identified as the genetic material in the 1940s. All organisms have many genes corresponding to many different biological traits, some of which are immediately visible, such as eye color or number of limbs, and some of which are not, such as blood type or increased risk for specific diseases, or the thousands of basic biochemical processes that comprise life.

In cells, a gene is a portion of DNA that contains both "coding" sequences that determine what the gene does, and "non-coding" sequences that determine when the gene is active (expressed). When a gene is active, the coding and non-coding sequences are copied in a process called transcription, producing an RNA copy of the gene's information. This piece of RNA can then direct the synthesis of proteins via the genetic code. In other cases, the RNA is used directly, for example as part of the ribosome.

The molecules resulting from gene expression, whether RNA or protein, are known as gene products, and are responsible for the development and functioning of all living things. The physical development and phenotype of organisms can be thought of as a product of genes interacting with each other and with the environment.^[4] A concise definition of a gene, taking into account complex patterns of regulation and transcription, genic conservation and non-coding RNA genes, has been proposed by Gerstein et al.:^[5] "A gene is a union of genomic sequences encoding a coherent set of potentially overlapping functional products".

Contents 1 History 2 Mendelian inheritance and classical genetics 3 Physical definitions 3.1 RNA genes and genomes 3.2 Functional structure of a gene 3.3 Chromosomes 4 Gene expression 4.1 Genetic code 4.2 Transcription 4.3 Translation 5 DNA replication and inheritance 5.1 Molecular inheritance 5.2 Mutation 6 Genome 6.1 Chromosomal organization 6.2 Number of genes 6.3 Genetic and genomic nomenclature 7 Evolutionary concept of a gene 8 Gene targeting and implications 9 Changing concept 10 See also 11 References 12 Further reading 13 External links

History

Main article: History of genetics

The existence of genes was first suggested by Gregor Mendel (1822–1884), who, in the 1860s, studied inheritance in peaplants (Pisum sativum) and hypothesized a factor that conveys traits from parent to offspring. He spent over 10 years of his life on one experiment. Although he did not use the term gene, he explained his results in terms of inherited characteristics. Mendel was also the first to hypothesize independent assortment, the distinction between dominant and recessive traits, the distinction between a heterozygote and homozygote, and the difference between what would later be described as genotype (the genetic material of an organism) and phenotype (the visible traits of that organism). Mendel's concept was given a name by Hugo de Vries in 1889, who, at that time probably unaware of Mendel's work, in his book Intracellular Pangenesis coined the term "pangen" for "the smallest particle [representing] one hereditary characteristic".^[6] Wilhelm Johannsen abbreviated this term to "gene" ("gen" in Danish and German) two decades later.

In the early 1900s, Mendel's work received renewed attention from scientists. In 1910, Thomas Hunt Morgan showed that genes reside on specific chromosomes. He later showed that genes occupy specific locations on the chromosome. With this knowledge, Morgan and his students began the first chromosomal map of the fruit fly Drosophila. In 1928, Frederick Griffith showed that genes could be transferred. In what is now known as Griffith's experiment, injections into a mouse of a deadly strain of bacteria that had been heat-killed transferred genetic information to a safe strain of the same bacteria, killing the mouse.

In 1941, George Wells Beadle and Edward Lawrie Tatum showed that mutations in genes caused errors in specific steps in metabolic pathways. This showed that specific genes code for specific proteins, leading to the "one gene, one enzyme" hypothesis.^[7] Oswald Avery, Colin Munro MacLeod, and Maclyn McCarty showed in 1944 that DNA holds the gene's information.^[8] In 1953, James D. Watson and Francis Crick demonstrated the molecular structure of DNA. Together, these discoveries established the central dogma of molecular biology, which states that proteins are translated from RNA which is transcribed from DNA. This dogma has since been shown to have exceptions, such as reverse transcription in retroviruses.

In 1972, Walter Fiers and his team at the Laboratory of Molecular Biology of the University of Ghent (Ghent, Belgium) were the first to determine the sequence of a gene: the gene for Bacteriophage MS2 coat protein.^[9] Richard J. Roberts and Phillip Sharp discovered in 1977 that genes can be split into segments. This leads to the idea that one gene can make several proteins. Recently (as of 2003–2006), biological results let the notion of gene appear more slippery. In particular, genes do not seem to sit side by side on DNA like discrete beads. Instead, regions of the DNA producing distinct proteins may overlap, so that the idea emerges that "genes are one long continuum".^[1]

Mendelian inheritance and classical genetics

Main articles: Mendelian inheritance and Classical genetics

Darwin used the term Gemmule to describe a microscopic unit of inheritance, and what would later become known as Chromosomes had been observed separating out during cell division by Wilhelm Hofmeister as early as 1848. The idea that chromosomes are the carriers of inheritance was expressed in 1883 by Wilhelm Roux. The modern conception of the gene originated with work by Gregor Mendel, a 19th-century Augustinian monk who systematically studied heredity in pea plants. Mendel's work was the first to illustrate particulate inheritance, or the theory that inherited traits are passed from one generation to the next in discrete units that interact in well-defined ways. Danish botanist Wilhelm Johannsen coined the word "gene" in 1909 to describe these fundamental physical and functional units of heredity,^[10] while the related word genetics was first used by William Bateson in 1905.^[7] The word was derived from Hugo de Vries' 1889 term pangen for the same concept,^[6] itself a derivative of the word pangenesis coined by Darwin (1868).^[11] The word pangenesis is made from the Greek words pan (a prefix meaning "whole", "encompassing") and genesis ("birth") or genos ("origin").

Crossing between two pea plants heterozygous for purple (B, dominant) and white (b, recessive) blossoms

According to the theory of Mendelian inheritance, variations in phenotype—the observable physical and behavioral characteristics of an organism—are due to variations in genotype, or the organism's particular set of genes, each of which specifies a particular trait. Different forms of a gene, which may give rise to different phenotypes, are known as alleles. Organisms such as the pea plants Mendel worked on, along with many plants and animals, have two alleles for each trait, one inherited from each parent. Alleles may be dominant or recessive; dominant alleles give rise to their corresponding phenotypes when paired with any other allele for the same trait, whereas recessive alleles give rise to their corresponding phenotype only when paired with another copy of the same allele. For example, if the allele specifying tall stems in pea plants is dominant over the allele specifying short stems, then pea plants that inherit one tall allele from one parent and one short allele from the other parent will also have tall stems. Mendel's work found that alleles assort independently in the production of gametes, or germ cells, ensuring variation in the next generation.

Prior to Mendel's work, the dominant theory of heredity was one of blending inheritance, which proposes that the traits of the parents blend or mix in a smooth, continuous gradient in the offspring. Although Mendel's work was largely unrecognized after its first publication in 1866, it was rediscovered in 1900 by three European scientists, Hugo de Vries, Carl Correns, and Erich von Tschermak, who had reached similar conclusions from their own research. However, these scientists were not yet aware of the identity of the 'discrete units' on which genetic material resides.

A series of subsequent discoveries led to the realization decades later that chromosomes within cells are the carriers of genetic material, and that they are made of DNA (deoxyribonucleic acid), a polymeric molecule found in all cells on which the 'discrete units' of Mendelian inheritance are encoded. The modern study of genetics at the level of DNA is known as molecular genetics and the synthesis of molecular genetics with traditional Darwinian evolution is known as the modern evolutionary synthesis.

Physical definitions

The chemical structure of a four-base fragment of a DNA double helix.

The vast majority of living organisms encode their genes in long strands of DNA. DNA consists of a chain made from four types of nucleotide subunits: adenine, cytosine, guanine, and thymine. Each nucleotide subunit consists of three components: a phosphate group, a deoxyribose sugar ring, and a nucleobase. Thus, nucleotides in DNA or RNA are typically called 'bases'; as a consequence, they are commonly referred to simply by their purine or pyrimidine original base components adenine, cytosine, guanine, thymine. Adenine and guanine are purines, and cytosine and thymine are pyrimidines. The most common form of DNA in a cell is in a double helix structure, in which two individual DNA strands twist around each other in a right-handed spiral. In this structure, the base pairing rules specify that guanine pairs with cytosine and adenine pairs with thymine (each pair contains one purine and one pyrimidine). The base pairing between guanine and cytosine forms three hydrogen bonds, whereas the base pairing between adenine and thymine forms two hydrogen bonds. The two strands in a double helix must therefore be complementary, that is, their bases must align such that the adenines of one strand are paired with the thymines of the other strand, and so on.

Due to the chemical composition of the pentose residues of the bases, DNA strands have directionality. One end of a DNA polymer contains an exposed hydroxyl group on the deoxyribose; this is known as the 3' end of the molecule. The other end contains an exposed phosphate group; this is the 5' end. The directionality of DNA is vitally important to many cellular processes, since double helices are necessarily directional (a strand running 5'-3' pairs with a complementary strand running 3'-5'), and processes such as DNA replication occur in only one direction. All nucleic acid synthesis in a cell occurs in the 5'-3' direction, because new monomers are added via a dehydration reaction that uses the exposed 3' hydroxyl as a nucleophile.

The expression of genes encoded in DNA begins by transcribing the gene into RNA, a second type of nucleic acid that is very similar to DNA, but whose monomers contain the sugar ribose rather than deoxyribose. RNA also contains the base uracil in place of thymine. RNA molecules are less stable than DNA and are typically single-stranded. Genes that encode proteins are composed of a series of three-nucleotide sequences called codons, which serve as the words in the genetic language. The genetic code specifies the correspondence during protein translation between codons and amino acids. The genetic code is nearly the same for all known organisms.

RNA genes and genomes

In some cases, RNA is an intermediate product in the process of manufacturing proteins from genes. However, for other gene sequences, the RNA molecules are the actual functional products. For example, RNAs known as ribozymes are capable of enzymatic function, and miRNAs have a regulatory role. The DNA sequences from which such RNAs are transcribed are known as RNA genes.

Some viruses store their entire genomes in the form of RNA, and contain no DNA at all. Because they use RNA to store genes, their cellular hosts may synthesize their proteins as soon as they are infected and without the delay in waiting for transcription. On the other hand, RNA retroviruses, such as HIV, require the reverse transcription of their genome from RNA into DNA before their proteins can be synthesized. In 2006, French researchers came across a puzzling example of RNA-mediated inheritance in mouse. Mice with a loss-of-function mutation in the gene Kit have white tails. Offspring of these mutants can have white tails despite having only normal Kit genes. The research team traced this effect back to mutated Kit RNA.^[12] While RNA is common as genetic storage material in viruses, in mammals in particular RNA inheritance has been observed very rarely.

Functional structure of a gene

Diagram of the "typical" eukaryotic protein-coding gene. Promoters and enhancers determine what portions of the DNA will be transcribed into the precursor mRNA (pre-mRNA). The pre-mRNA is then spliced into messenger RNA (mRNA) which is later translated into protein.

All genes have regulatory regions in addition to regions that explicitly code for a protein or RNA product. A regulatory region shared by almost all genes is known as the promoter, which provides a position that is recognized by the transcription machinery when a gene is about to be transcribed and expressed. A gene can have more than one promoter, resulting in RNAs that differ in how far they extend in the 5' end.^[13] Although promoter regions have a consensus sequence that is the most common sequence at this position, some genes have "strong" promoters that bind the transcription machinery well, and others have "weak" promoters that bind poorly. These weak promoters usually permit a lower rate of transcription than the strong promoters, because the transcription machinery binds to them and initiates transcription less frequently. Other possible regulatory regions include enhancers, which can compensate for a weak promoter. Most regulatory regions are "upstream"—that is, before or toward the 5' end of the transcription initiation site. Eukaryotic promoter regions are much more complex and difficult to identify than prokaryotic promoters.

Many prokaryotic genes are organized into operons, or groups of genes whose products have related functions and which are transcribed as a unit. By contrast, eukaryotic genes are transcribed only one at a time, but may include long stretches of DNA called introns which are transcribed but never translated into protein (they are spliced out before translation). Splicing can also occur in prokaryotic genes, but is less common than in eukaryotes.^[14]

Chromosomes

The total complement of genes in an organism or cell is known as its genome, which may be stored on one or more chromosomes; the region of the chromosome at which a particular gene is located is called its locus. A chromosome consists of a single, very long DNA helix on which thousands of genes are encoded. Prokaryotes - bacteria and archaea - typically store their genomes on a single large, circular chromosome, sometimes supplemented by additional small circles of DNA called plasmids, which usually encode only a few genes and are easily transferable between individuals. For example, the genes for antibiotic resistance are usually encoded on bacterial plasmids and can be passed between individual cells, even those of different species, via horizontal gene transfer. Although some simple eukaryotes also possess plasmids with small numbers of genes, the majority of eukaryotic genes are stored on multiple linear chromosomes, which are packed within the nucleus in complex with storage proteins called histones. The manner in which DNA is stored on the histone, as well as chemical modifications of the histone itself, are regulatory mechanisms governing whether a particular region of DNA is accessible for gene expression. The ends of eukaryotic chromosomes are capped by long stretches of repetitive sequences called telomeres, which do not code for any gene product but are present to prevent degradation of coding and regulatory regions during DNA replication. The length of the telomeres tends to decrease each time the genome is replicated in preparation for cell division; the loss of telomeres has been proposed as an explanation for cellular senescence, or the loss of the ability to divide, and by extension for the aging process in organisms.^[15]

Whereas the chromosomes of prokaryotes are relatively gene-dense, those of eukaryotes often contain so-called "junk DNA", or regions of DNA that serve no obvious function. Simple single-celled eukaryotes have relatively small amounts of such DNA, whereas the genomes of complex multicellular organisms, including humans, contain an absolute majority of DNA without an identified function.^[16] However it now appears that, although protein-coding DNA makes up barely 2% of the human genome, about 80% of the bases in the genome may be being expressed, so the term "junk DNA" may be a misnomer.^[2]

Gene expression

Main article: Gene expression

In all organisms, there are two major steps separating a protein-coding gene from its protein: First, the DNA on which the gene resides must be transcribed from DNA to messenger RNA (mRNA); and, second, it must be translated from mRNA to protein. RNA-coding genes must still go through the first step, but are not translated into protein. The process of producing a biologically functional molecule of either RNA or protein is called gene expression, and the resulting molecule itself is called a gene product.

Genetic code

Main article: Genetic code

Schematic diagram of a single-stranded RNA molecule illustrating the position of three-base codons.

The genetic code is the set of rules by which a gene is translated into a functional protein. Each gene consists of a specific sequence of nucleotides encoded in a DNA (or sometimes RNA) strand; a correspondence between nucleotides, the basic building blocks of genetic material, and amino acids, the basic building blocks of proteins, must be established for genes to be successfully translated into functional proteins. Sets of three nucleotides, known as codons, each correspond to a specific amino acid or to a signal; three codons are known as "stop codons" and, instead of specifying a new amino acid, alert the translation machinery that the end of the gene has been reached. There are 64 possible codons (four possible nucleotides at each of three positions, hence 4³ possible codons) and only 20 standard amino acids; hence the code is redundant and multiple codons can specify the same amino acid. The correspondence between codons and amino acids is nearly universal among all known living organisms.

Transcription

The process of genetic transcription produces a single-stranded RNA molecule known as messenger RNA, whose nucleotide sequence is complementary to the DNA from which it was transcribed. The DNA strand whose sequence matches that of the RNA is known as the coding strand and the strand from which the RNA was synthesized is the template strand. Transcription is performed by an enzyme called an RNA polymerase, which reads the template strand in the 3' to 5' direction and synthesizes the RNA from 5' to 3'. To initiate transcription, the polymerase first recognizes and binds a promoter region of the gene. Thus a major mechanism of gene regulation is the blocking or sequestering of the promoter region, either by tight binding by repressor molecules that physically block the polymerase, or by organizing the DNA so that the promoter region is not accessible.

In prokaryotes, transcription occurs in the cytoplasm; for very long transcripts, translation may begin at the 5' end of the RNA while the 3' end is still being transcribed. In eukaryotes, transcription necessarily occurs in the nucleus, where the cell's DNA is sequestered; the RNA molecule produced by the polymerase is known as the primary transcript and must undergo post-transcriptional modifications before being exported to the cytoplasm for translation. The splicing of introns present within the transcribed region is a modification unique to eukaryotes; alternative splicing mechanisms can result in mature transcripts from the same gene having different sequences and thus coding for different proteins. This is a major form of regulation in eukaryotic cells.

Translation

Translation is the process by which a mature mRNA molecule is used as a template for synthesizing a new protein. Translation is carried out by ribosomes, large complexes of RNA and protein responsible for carrying out the chemical reactions to add new amino acids to a growing polypeptide chain by the formation of peptide bonds. The genetic code is read three nucleotides at a time, in units called codons, via interactions with specialized RNA molecules called transfer RNA (tRNA). Each tRNA has three unpaired bases known as the anticodon that are complementary to the codon it reads; the tRNA is also covalently attached to the amino acid specified by the complementary codon. When the tRNA binds to its complementary codon in an mRNA strand, the ribosome ligates its amino acid cargo to the new polypeptide chain, which is synthesized from amino terminus to carboxyl terminus. During and after its synthesis, the new protein must fold to its active three-dimensional structure before it can carry out its cellular function.

DNA replication and inheritance

The growth, development, and reproduction of organisms relies on cell division, or the process by which a single cell divides into two usually identical daughter cells. This requires first making a duplicate copy of every gene in the genome in a process called DNA replication. The copies are made by specialized enzymes known as DNA polymerases, which "read" one strand of the double-helical DNA, known as the template strand, and synthesize a new complementary strand. Because the DNA double helix is held together by base pairing, the sequence of one strand completely specifies the sequence of its complement; hence only one strand needs to be read by the enzyme to produce a faithful copy. The process of DNA replication is semiconservative; that is, the copy of the genome inherited by each daughter cell contains one original and one newly synthesized strand of DNA.^[17]

After DNA replication is complete, the cell must physically separate the two copies of the genome and divide into two distinct membrane-bound cells. In prokaryotes - bacteria and archaea - this usually occurs via a relatively simple process called binary fission, in which each circular genome attaches to the cell membrane and is separated into the daughter cells as the membrane invaginates to split the cytoplasm into two membrane-bound portions. Binary fission is extremely fast compared to the rates of cell division in eukaryotes. Eukaryotic cell division is a more complex process known as the cell cycle; DNA replication occurs during a phase of this cycle known as S phase, whereas the process of segregating chromosomes and splitting the cytoplasm occurs during M phase. In many single-celled eukaryotes such as yeast, reproduction by budding is common, which results in asymmetrical portions of cytoplasm in the two daughter cells.

Molecular inheritance

The duplication and transmission of genetic material from one generation of cells to the next is the basis for molecular inheritance, and the link between the classical and molecular pictures of genes. Organisms inherit the characteristics of their parents because the cells of the offspring contain copies of the genes in their parents' cells. In asexually reproducing organisms, the offspring will be a genetic copy or clone of the parent organism. In sexually reproducing organisms, a specialized form of cell division called meiosis produces cells called gametes or germ cells that are haploid, or contain only one copy of each gene. The gametes produced by females are called eggs or ova, and those produced by males are called sperm. Two gametes fuse to form a fertilized egg, a single cell that once again has a diploid number of genes—each with one copy from the mother and one copy from the father.

During the process of meiotic cell division, an event called genetic recombination or crossing-over can sometimes occur, in which a length of DNA on one chromatid is swapped with a length of DNA on the corresponding sister chromatid. This has no effect if the alleles on the chromatids are the same, but results in reassortment of otherwise linked alleles if they are different. The Mendelian principle of independent assortment asserts that each of a parent's two genes for each trait will sort independently into gametes; which allele an organism inherits for one trait is unrelated to which allele it inherits for another trait. This is in fact only true for genes that do not reside on the same chromosome, or are located very far from one another on the same chromosome. The closer two genes lie on the same chromosome, the more closely they will be associated in gametes and the more often they will appear together; genes that are very close are essentially never separated because it is extremely unlikely that a crossover point will occur between them. This is known as genetic linkage.

Mutation

Main article: Mutation

DNA replication is for the most part extremely accurate, with an error rate per site of around 10⁻⁶ to 10⁻¹⁰ in eukaryotes.^[17] Rare, spontaneous alterations in the base sequence of a particular gene arise from a number of sources, such as errors in DNA replication and the aftermath of DNA damage. These errors are called mutations. The cell contains many DNA repair mechanisms for preventing mutations and maintaining the integrity of the genome; however, in some cases—such as breaks in both DNA strands of a chromosome — repairing the physical damage to the molecule is a higher priority than producing an exact copy. Due to the degeneracy of the genetic code, some mutations in protein-coding genes are silent, or produce no change in the amino acid sequence of the protein for which they code; for example, the codons UCU and UUC both code for serine, so the U↔C mutation has no effect on the protein. Mutations that do have phenotypic effects are most often neutral or deleterious to the organism, but sometimes they confer benefits to the organism's fitness.

Mutations propagated to the next generation lead to variations within a species' population. Variants of a single gene are known as alleles, and differences in alleles may give rise to differences in traits. Although it is rare for the variants in a single gene to have clearly distinguishable phenotypic effects, certain well-defined traits are in fact controlled by single genetic loci. A gene's most common allele is called the wild type allele, and rare alleles are called mutants. However, this does not imply that the wild-type allele is the ancestor from which the mutants are descended.

Genome

Chromosomal organization

The total complement of genes in an organism or cell is known as its genome. In prokaryotes, the vast majority of genes are located on a single chromosome of circular DNA, while eukaryotes usually possess multiple individual linear DNA helices packed into dense DNA-protein complexes called chromosomes. Genes that appear together on one chromosome of one species may appear on separate chromosomes in another species. Many species carry more than one copy of their genome within each of their somatic cells. Cells or organisms with only one copy of each chromosome are called haploid; those with two copies are called diploid; and those with more than two copies are called polyploid. The copies of genes on the chromosomes are not necessarily identical. In sexually reproducing organisms, one copy is normally inherited from each parent.

Number of genes

Early estimates of the number of human genes that used expressed sequence tag data put it at 50 000–100 000.^[18] Following the sequencing of the human genome and other genomes, it has been found that rather few genes (~20 000 in human, mouse and fly, ~13 000 in roundworm, >46 000 in rice) encode all the proteins in an organism.^[19] These protein-coding sequences make up 1–2% of the human genome.^[20] Most of the genome gives rise to RNA products however, but not much is known about the function of these non-coding RNAs.^[19][20]

Genetic and genomic nomenclature

Gene nomenclature has been established by the HUGO Gene Nomenclature Committee (HGNC) for each known human gene in the form of an approved gene name and symbol (short-form abbreviation). All approved symbols are stored in the HGNC Database. Each symbol is unique and each gene is only given one approved gene symbol. It is necessary to provide a unique symbol for each gene so that people can talk about them. This also facilitates electronic data retrieval from publications. In preference each symbol maintains parallel construction in different members of a gene family and can be used in other species, especially the mouse.

Evolutionary concept of a gene

George C. Williams first explicitly advocated the gene-centric view of evolution in his 1966 book Adaptation and Natural Selection. He proposed an evolutionary concept of gene to be used when we are talking about natural selection favoring some genes. The definition is: "that which segregates and recombines with appreciable frequency." According to this definition, even an asexual genome could be considered a gene, insofar that it have an appreciable permanency through many generations.

The difference is: the molecular gene transcribes as a unit, and the evolutionary gene inherits as a unit.

Richard Dawkins' books The Selfish Gene (1976) and The Extended Phenotype (1982) defended the idea that the gene is the only replicator in living systems. This means that only genes transmit their structure largely intact and are potentially immortal in the form of copies. So, genes should be the unit of selection. In The Selfish Gene Dawkins attempts to redefine the word 'gene' to mean "an inheritable unit" instead of the generally accepted definition of "a section of DNA coding for a particular protein". In River Out of Eden, Dawkins further refined the idea of gene-centric selection by describing life as a river of compatible genes flowing through geological time. Scoop up a bucket of genes from the river of genes, and we have an organism serving as temporary bodies or survival machines. A river of genes may fork into two branches representing two non-interbreeding species as a result of geographical separation.

Gene targeting and implications

Main article: Gene targeting

Gene targeting is commonly referred to techniques for altering or disrupting mouse genes and provides the mouse models for studying the roles of individual genes in embryonic development, human disorders, aging and diseases. The mouse models, where one or more of its genes are deactivated or made inoperable, are called knockout mice. Since the first reports in which homologous recombination in embryonic stem cells was used to generate gene-targeted mice,^[21] gene targeting has proven to be a powerful means of precisely manipulating the mammalian genome, producing at least ten thousand mutant mouse strains and it is now possible to introduce mutations that can be activated at specific time points, or in specific cells or organs, both during development and in the adult animal.^[22][23]

Gene targeting strategies have been expanded to all kinds of modifications, including point mutations, isoform deletions, mutant allele correction, large pieces of chromosomal DNA insertion and deletion, tissue specific disruption combined with spatial and temporal regulation and so on. It is predicted that the ability to generate mouse models with predictable phenotypes will have a major impact on studies of all phases of development, immunology, neurobiology, oncology, physiology, metabolism, and human diseases. Gene targeting is also in theory applicable to species from which totipotent embryonic stem cells can be established, and therefore may offer a potential to the improvement of domestic animals and plants.^[23][24]

Changing concept

The concept of the gene has changed considerably (see history section). From the original definition of a "unit of inheritance", the term evolved to mean a DNA-based unit that can exert its effects on the organism through RNA or protein products. It was also previously believed that one gene makes one protein; this concept was overthrown by the discovery of alternative splicing and trans-splicing.^[7]

The definition of a gene is still changing. The first cases of RNA-based inheritance have been discovered in mammals.^[12] Evidence is also accumulating that the control regions of a gene do not necessarily have to be close to the coding sequence on the linear molecule or even on the same chromosome. Spilianakis and colleagues discovered that the promoter region of the interferon-gamma gene on chromosome 10 and the regulatory regions of the T(H)2 cytokine locus on chromosome 11 come into close proximity in the nucleus possibly to be jointly regulated.^[25]

The concept that genes are clearly delimited is also being eroded. There is evidence for fused proteins stemming from two adjacent genes that can produce two separate protein products. While it is not clear whether these fusion proteins are functional, the phenomena is more frequent than previously thought.^[26] Even more ground-breaking than the discovery of fused genes is the observation that some proteins can be composed of exons from far away regions and even different chromosomes.^[2][27] This new data has led to an updated, and probably tentative, definition of a gene as "a union of genomic sequences encoding a coherent set of potentially overlapping functional products."^[7] This new definition categorizes genes by functional products, whether they be proteins or RNA, rather than specific DNA loci; all regulatory elements of DNA are therefore classified as gene-associated regions.^[7]

See also

• Copy number variation
• DNA
• Full genome sequencing
• Epigenetics
• Gene-centric view of evolution
• Gene dosage
• Gene expression
• Gene family
• Gene pool
• Gene redundancy
• Gene therapy
• Genetic algorithm
• Genetics
• Genome
• Genomics
• List of notable genes
• Meme
• Pseudogene
• Predictive Medicine

References

1. ^ ^{a b} Pearson H (2006). "Genetics: what is a gene?". Nature 441 (7092): 398–401. doi:10.1038/441398a. PMID 16724031. 
2. ^ ^{a b c} Elizabeth Pennisi (2007). "DNA Study Forces Rethink of What It Means to Be a Gene". Science 316 (5831): 1556–1557. doi:10.1126/science.316.5831.1556. PMID 17569836. 
3. ^ Noble, D. (Sep 2008). "Genes and causation" (Free full text). Philosophical transactions. Series A, Mathematical, physical, and engineering sciences 366 (1878): 3001–3015. doi:10.1098/rsta.2008.0086. ISSN 1364-503X. PMID 18559318. http://rsta.royalsocietypublishing.org/cgi/pmidlookup?view=long&pmid=18559318.  edit
4. ^ see eg Martin Nowak's Evolutionary Dynamics
5. ^ Gerstein MB, Bruce C, Rozowsky JS, Zheng D, Du J, Korbel JO, Emanuelsson O, Zhang ZD, Weissman S, Snyder M (2007). "What is a gene, post-ENCODE? History and updated definition". Genome Research 17 (6): 669–681. doi:10.1101/gr.6339607. PMID 17567988. 
6. ^ ^{a b} Vries, H. de (1889) Intracellular Pangenesis [1] ("pangen" definition on page 7 and 40 of this 1910 translation in English)
7. ^ ^{a b c d e} Mark B. Gerstein et al., "What is a gene, post-ENCODE? History and updated definition," Genome Research 17(6) (2007): 669-681
8. ^ Steinman RM, Moberg CL (February 1994). "A triple tribute to the experiment that transformed biology". J. Exp. Med. 179 (2): 379–84. doi:10.1084/jem.179.2.379. PMID 8294854. 
9. ^ Min Jou W, Haegeman G, Ysebaert M, Fiers W (1972). "Nucleotide sequence of the gene coding for the bacteriophage MS2 coat protein". Nature 237 (5350): 82–8. doi:10.1038/237082a0. PMID 4555447. 
10. ^ "The Human Genome Project Timeline". http://www.genome.gov/25019879. Retrieved 2006-09-13. 
11. ^ Darwin C. (1868). Animals and Plants under Domestication (1868).
12. ^ ^{a b} Rassoulzadegan M, Grandjean V, Gounon P, Vincent S, Gillot I, Cuzin F (2006). "RNA-mediated non-mendelian inheritance of an epigenetic change in the mouse". Nature 441 (7092): 469–74. doi:10.1038/nature04674. PMID 16724059. 
13. ^ Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B (May 2008). "Mapping and quantifying mammalian transcriptomes by RNA-Seq". Nat. Methods 5: 621. doi:10.1038/nmeth.1226. PMID 18516045. 
14. ^ Woodson SA (1998). "Ironing out the kinks: splicing and translation in bacteria". Genes Dev. 12 (9): 1243–7. doi:10.1101/gad.12.9.1243. PMID 9573040. http://genesdev.cshlp.org/content/12/9/1243.full. Retrieved 2009-08-07. 
15. ^ Braig M, Schmitt C (2006). "Oncogene-induced senescence: putting the brakes on tumor development". Cancer Res 66 (6): 2881–4. doi:10.1158/0008-5472.CAN-05-4006. PMID 16540631. 
16. ^ International Human Genome Sequencing Consortium (2004). "Finishing the euchromatic sequence of the human genome". Nature 431 (7011): 931–45. doi:10.1038/nature03001. PMID 15496913. http://www.nature.com/nature/journal/v431/n7011/full/nature03001.html. Retrieved 2009-08-07. 
17. ^ ^{a b} Watson JD, Baker TA, Bell SP, Gann A, Levine M, Losick R (2004). Molecular Biology of the Gene (5th ed.). Peason Benjamin Cummings (Cold Spring Harbor Laboratory Press). ISBN 080534635X. 
18. ^ Schuler GD, Boguski MS, Stewart EA, et al (October 1996). "A gene map of the human genome". Science 274 (5287): 540–6. doi:10.1126/science.274.5287.540. PMID 8849440. http://www.sciencemag.org/cgi/content/full/274/5287/540. 
19. ^ ^{a b} Carninci P, Hayashizaki Y (April 2007). "Noncoding RNA transcription beyond annotated genes". Curr. Opin. Genet. Dev. 17 (2): 139–44. doi:10.1016/j.gde.2007.02.008. PMID 17317145. 
20. ^ ^{a b} Claverie JM (September 2005). "Fewer genes, more noncoding RNA". Science 309 (5740): 1529–30. doi:10.1126/science.1116800. PMID 16141064. 
21. ^ Thomas KR, Capecchi MR. Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells. Cell. 1987;51:503-12
22. ^ The 2007 Nobel Prize in Physiology or Medicine - Press Release
23. ^ ^{a b} Deng C. In Celebration of Dr. Mario R. Capecchi's Nobel Prize. Int J Biol Sci 2007; 3:417-419. International Journal of Biological Sciences
24. ^ Mario R. Capecchi
25. ^ Spilianakis & colleagues (2005) Interchromosomal associations between alternatively expressed loci. PMID 15880101
26. ^ Parra & colleagues (2006) Tandem chimerism as a means to increase protein complexity in the human genome. PMID 16344564
27. ^ Kapranov & colleagues (2005) Examples of the complex architecture of the human transcriptome revealed by RACE and high-density tiling arrays. PMID 15998911

Further reading

• Dawkins, Richard (1990). The Selfish Gene. Oxford University Press. ISBN 0-19-286092-5.  Google Book Search; first published 1976.
• Dawkins, Richard (1995). River Out of Eden. Basic Books. ISBN 0-465-06990-8. 
• Ridley, Matt (1999). Genome: The Autobiography of a Species in 23 Chapters. Fourth Estate. ISBN 0-00-763573-7. 

External links

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• Comparative Toxicogenomics Database
• DNA From The Beginning - a primer on genes and DNA
• Entrez Gene - a searchable database of genes
• IDconverter - converts gene IDs between public databases
• iHOP - Information Hyperlinked over Proteins
• TranscriptomeBrowser - Gene expression profile analysis

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Dansk (Danish)
n. - gen, genanlæg

idioms:

• gene therapy    genterapi

Nederlands (Dutch)
gen

Français (French)
n. - (Biol) gène

idioms:

• gene therapy    thérapie génique

Deutsch (German)
n. - Gen, Erbträger

idioms:

• gene therapy    Gentherapie

Ελληνική (Greek)
n. - (βιολ.) γονίδιο

idioms:

• gene therapy    θεραπεία γονιδίου (για πρόληψη κληρονομικών ασθενειών)

Italiano (Italian)
gene

idioms:

• gene therapy    terapia genetica

Português (Portuguese)
n. - gene (m) (Biol.)

idioms:

• gene therapy    terapia (f) genética (Med.)

Русский (Russian)
ген

idioms:

• gene therapy    исправление генетических дефектов

Español (Spanish)
n. - gene, gen

idioms:

• gene therapy    terapia de genes

Svenska (Swedish)
n. - gen (biol.)

中文（简体）(Chinese (Simplified))
因子, 基因

idioms:

• gene therapy    基因治疗

中文（繁體）(Chinese (Traditional))
n. - 因數, 基因

idioms:

• gene therapy    基因治療

한국어 (Korean)
n. - 유전자

日本語 (Japanese)
n. - ジーン, 遺伝子

idioms:

• gene therapy    遺伝子治療, 遺伝子療法

العربيه (Arabic)
‏(الاسم) الجين, المورثه‏

עברית (Hebrew)
n. - ‮גן, גורם תורשתי‬

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