Gene

There are many different ways to use the term "gene" based on different aspects of their inheritance, selection, biological function, or molecular structure but most of these definitions fall into two categories, the Mendelian gene or the molecular gene. The Mendelian gene is the classical gene of genetics and it refers to any heritable trait. In The Selfish Gene, Richard Dawkins argues that it is the unit of evolution. More thorough discussions of this version of a gene can be found in the articles Genetics and Gene-centered view of evolution. The molecular gene definition is more commonly used across biochemistry, molecular biology, and most of genetics—the gene that is described in terms of DNA sequence. Very early work in the field that became molecular genetics suggested the concept that one gene makes one protein (originally 'one gene – one enzyme'). However, genes that produce repressor RNAs were proposed in the 1950s This idea of two kinds of genes is still part of the definition of a gene in most textbooks. For example, The important parts of such definitions are: (1) that a gene corresponds to a transcription unit; (2) that genes produce both mRNA and noncoding RNAs; and (3) regulatory sequences control gene expression but are not part of the gene itself. However, there is one other important part of the definition and it is emphasized in Kostas Kampourakis' book Making Sense of Genes. The emphasis on function is essential because there are stretches of DNA that produce non-functional transcripts and they do not qualify as genes. These include obvious examples such as transcribed pseudogenes as well as less obvious examples such as junk RNA produced as noise due to transcription errors. In order to qualify as a true gene, by this definition, one has to prove that the transcript has a biological function. In spite of the fact that both protein-coding genes and noncoding genes have been known for more than 50 years, there are still a number of textbooks, websites, and scientific publications that define a gene as a DNA sequence that specifies a protein. In other words, the definition is restricted to protein-coding genes. Here is an example from a 2021 article in American Scientist. This restricted definition is so common that it has spawned many recent articles that criticize this "standard definition" and call for a new expanded definition that includes noncoding genes. However, some modern writers still do not acknowledge noncoding genes although this so-called "new" definition has been recognised for more than half a century. Although some definitions can be more broadly applicable than others, the fundamental complexity of biology means that no definition of a gene can capture all aspects perfectly. Not all genomes are DNA (e.g. RNA viruses), bacterial operons are multiple protein-coding regions transcribed into single large mRNAs, alternative splicing enables a single genomic region to encode multiple distinct products and trans-splicing concatenates mRNAs from shorter coding sequence across the genome. Since molecular definitions exclude elements such as introns, promotors, and other regulatory regions, these are instead thought of as "associated" with the gene and affect its function. An even broader operational definition is sometimes used to encompass the complexity of these diverse phenomena, where a gene is defined as a union of genomic sequences encoding a coherent set of potentially overlapping functional products. This definition categorizes genes by their functional products (proteins or RNA) rather than their specific DNA loci, with regulatory elements classified as gene-associated regions. ==History==

Discovery of discrete inherited units The existence of discrete heritable units was discovered by Gregor Mendel. which suggested that each parent contributed fluids to the fertilization process and that the traits of the parents blended and mixed to produce the offspring. Charles Darwin developed a theory of inheritance he termed pangenesis, from Greek pan ("all, whole") and genesis ("birth") / genos ("origin"). Darwin used the term gemmule to describe hypothetical particles that would mix during reproduction. Mendel's work went largely unnoticed after its first publication in 1866, but was rediscovered in the late 19th century by Hugo de Vries, Carl Correns, and Erich von Tschermak, who (claimed to have) reached similar conclusions in their own research. In 1889, de Vries published Intracellular Pangenesis, in which he postulated that different characters have individual hereditary carriers and that inheritance of specific traits in organisms comes in particles. He called these units "pangenes" (Pangens in German), after Darwin's 1868 pangenesis theory. In 1906, William Bateson coined "genetics" (from Greek, γενετικός genetikos meaning "genitive"/"generative")." Eduard Strasburger, among others, still used the term "pangene" for the fundamental physical and functional unit of heredity. The structure of DNA was studied by Rosalind Franklin and Maurice Wilkins using X-ray crystallography, which led James D. Watson and Francis Crick to publish a model of the double-stranded DNA molecule whose paired nucleotide bases indicated a compelling hypothesis for the mechanism of genetic replication. In the early 1950s the prevailing view was that the genes in a chromosome acted as discrete entities arranged like beads on a string. The experiments of Seymour Benzer using mutants defective in the rII region of bacteriophage T4 (1955–1959) showed that individual genes have a simple linear structure and are likely to be equivalent to a linear section of DNA. In 1965, the lab of Max Birnstiel was the first to isolate single genes, the ribosomal RNA genes from Xenopus laevis. In 1972, Walter Fiers and his team were the first to determine the sequence of a gene: that of bacteriophage MS2 coat protein. The subsequent development of chain-termination DNA sequencing in 1977 by Frederick Sanger improved the efficiency of sequencing and turned it into a routine laboratory tool. An automated version of the Sanger method was used in early phases of the Human Genome Project. Modern synthesis and its successors R. A. Fisher, Sewall Wright and J.B.S. Haldane integrated Mendelian genetics with Darwinian evolution in the modern synthesis, a term introduced by Julian Huxley. W. D. Hamilton, George C. Williams and John Maynard Smith developed the gene-centric view of evolution, which argued that the Mendelian gene is a unit of natural selection. Williams defined the gene in this view: "that which segregates and recombines with appreciable frequency."Richard Dawkins popularized this view in several books, starting with The Selfish Gene. The development of the neutral theory of evolution by Motoo Kimura in the late 1960s led to the recognition that random genetic drift is a major player in evolution and that neutral theory should be the null hypothesis of molecular evolution. This led to the construction of phylogenetic trees and the development of the molecular clock, which is the basis of all dating techniques using DNA sequences. These techniques are not confined to molecular gene sequences but can be used on all DNA segments in the genome. ==Molecular basis==

double helix. The sugar-phosphate backbone chains run in opposite directions with the bases pointing inward, base-pairing A to T and C to G with hydrogen bonds. |alt=DNA chemical structure diagram showing how the double helix consists of two chains of sugar-phosphate backbone with bases pointing inward and specifically base pairing A to T and C to G with hydrogen bonds. DNA The vast majority of organisms encode their genes in long strands of DNA (deoxyribonucleic acid). DNA consists of a chain made from four types of nucleotide subunits, each composed of: a five-carbon sugar (2-deoxyribose), a phosphate group, and one of the four bases adenine, cytosine, guanine, and thymine. Two chains of DNA twist around each other to form a DNA double helix with the phosphate–sugar backbone spiralling around the outside, and the bases pointing inward with adenine base pairing to thymine and guanine to cytosine. The specificity of base pairing occurs because adenine and thymine align to form two hydrogen bonds, whereas cytosine and guanine form three hydrogen bonds. The two strands in a double helix must, therefore, be complementary, with their sequence of bases matching such that the adenines of one strand are paired with the thymines of the other strand, and so on. 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. of a human, with annotated bands and sub-bands. It shows dark and white regions on G banding. It shows 22 homologous chromosomes, both the male (XY) and female (XX) versions of the sex chromosome (bottom right), as well as the mitochondrial genome (at bottom left). The total complement of genes in an organism or cell is known as its genome, which may be stored on one or more chromosomes. A chromosome consists of a single, very long DNA helix on which thousands of genes are encoded. The centromere is required for binding spindle fibres to separate sister chromatids into daughter cells during cell division. Whereas the chromosomes of prokaryotes are relatively gene-dense, those of eukaryotes often contain 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. This DNA has often been referred to as "junk DNA". However, more recent analyses suggest that, although protein-coding DNA makes up barely 2% of the human genome, about 80% of the bases in the genome may be expressed, so the term "junk DNA" may be a misnomer. ==Structure and function== Structure The structure of a protein-coding gene consists of many elements of which the actual protein coding sequence is often only a small part. These include introns and untranslated regions of the mature mRNA. Noncoding genes can also contain introns that are removed during processing to produce the mature functional RNA. All genes are associated with regulatory sequences that are required for their expression. First, genes require a promoter sequence. The promoter is recognized and bound by transcription factors that recruit and help RNA polymerase bind to the region to initiate transcription. Highly transcribed genes have "strong" promoter sequences that form strong associations with transcription factors, thereby initiating transcription at a high rate. Others genes have "weak" promoters that form weak associations with transcription factors and initiate transcription less frequently. For example, enhancers increase transcription by binding an activator protein which then helps to recruit the RNA polymerase to the promoter; conversely silencers bind repressor proteins and make the DNA less available for RNA polymerase. The mature messenger RNA produced from protein-coding genes contains untranslated regions at both ends which contain binding sites for ribosomes, RNA-binding proteins, miRNA, as well as terminator, and start and stop codons. In addition, most eukaryotic open reading frames contain untranslated introns, which are removed and exons, which are connected together in a process known as RNA splicing. Finally, the ends of gene transcripts are defined by cleavage and polyadenylation (CPA) sites, where newly produced pre-mRNA gets cleaved and a string of ~200 adenosine monophosphates is added at the 3' end. The poly(A) tail protects mature mRNA from degradation and has other functions, affecting translation, localization, and transport of the transcript from the nucleus. Splicing, followed by CPA, generate the final mature mRNA, which encodes the protein or RNA product. Many noncoding genes in eukaryotes have different transcription termination mechanisms and they do not have poly(A) tails. Many prokaryotic genes are organized into operons, with multiple protein-coding sequences that are transcribed as a unit. The genes in an operon are transcribed as a continuous messenger RNA, referred to as a polycistronic mRNA. The term cistron in this context is equivalent to gene. The transcription of an operon's mRNA is often controlled by a repressor that can occur in an active or inactive state depending on the presence of specific metabolites. When active, the repressor binds to a DNA sequence at the beginning of the operon, called the operator region, and represses transcription of the operon; when the repressor is inactive transcription of the operon can occur (see e.g. Lac operon). The products of operon genes typically have related functions and are involved in the same regulatory network. and those introns can even have other genes nested inside them. Associated enhancers may be many kilobase away, or even on entirely different chromosomes operating via physical contact between two chromosomes. A single gene can encode multiple different functional products by alternative splicing, and conversely a gene may be split across chromosomes but those transcripts are concatenated back together into a functional sequence by trans-splicing. It is also possible for overlapping genes to share some of their DNA sequence, either on opposite strands or the same strand (in a different reading frame, or even the same reading frame). ==Gene expression==

In all organisms, two steps are required to read the information encoded in a gene's DNA and produce the protein it specifies. First, the gene's DNA is transcribed to messenger RNA (mRNA). (see Crick, Brenner et al. experiment). Additionally, a "start codon", and three "stop codons" indicate the beginning and end of the protein coding region. 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 universal among all species. Transcription Transcription produces a single-stranded RNA molecule known as messenger RNA, whose nucleotide sequence is complementary to the DNA from which it was transcribed. Translation intermediate, then translated to a functional protein. RNA-coding genes are transcribed to a functional non-coding RNA ().|alt=A protein-coding gene in DNA being transcribed and translated to a functional protein or a non-protein-coding gene being transcribed to a functional RNA Translation is the process by which a mature mRNA molecule is used as a template for synthesizing a new protein. RNA genes A typical protein-coding gene is first copied into RNA as an intermediate in the manufacture of the final protein product. 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. ==Inheritance==

s (blue and white). The gene is located on an autosomal chromosome. The white allele is recessive to the blue allele. The probability of each outcome in the children's generation is one quarter, or 25 percent.|alt=Illustration of autosomal recessive inheritance. Each parent has one blue allele and one white allele. Each of their 4 children inherit one allele from each parent such that one child ends up with two blue alleles, one child has two white alleles and two children have one of each allele. Only the child with both blue alleles shows the trait because the trait is recessive. Organisms inherit their genes from their parents. Asexual organisms simply inherit a complete copy of their parent's genome. Sexual organisms have two copies of each chromosome because they inherit one complete set from each parent. DNA replication and cell division The growth, development, and reproduction of organisms relies on cell division; 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. During the period of exponential DNA increase at 37 °C, the rate of elongation was 749 nucleotides per second. After DNA replication, the cell must physically separate the two genome copies and divide into two distinct membrane-bound cells. Genes that are very close are essentially never separated because it is extremely unlikely that a crossover point will occur between them. ==Genome==

The genome is the total genetic material of an organism and includes both the genes and non-coding sequences. Eukaryotic genes can be annotated using FINDER. Number of genes s (green), vertebrates (blue), invertebrates (orange), fungi (yellow), bacteria (purple), and viruses (grey). An inset on the right shows the smaller genomes expanded 100-fold area-wise. The genome size, and the number of genes it encodes varies widely between organisms. The smallest genomes occur in viruses, and viroids (which act as a single non-coding RNA gene). Conversely, plants can have extremely large genomes, with rice containing >46,000 protein-coding genes. The total number of protein-coding genes (the Earth's proteome) is estimated to be 5 million sequences. Although the number of base-pairs of DNA in the human genome has been known since the 1950s, the estimated number of genes has changed over time as definitions of genes, and methods of detecting them have been refined. Initial theoretical predictions of the number of human genes in the 1960s and 1970s were based on mutation load estimates and the numbers of mRNAs and these estimates tended to be about 30,000 protein-coding genes. During the 1990s there were guesstimates of up to 100,000 genes and early data on detection of mRNAs (expressed sequence tags) suggested more than the traditional value of 30,000 genes that had been reported in the textbooks during the 1980s. The initial draft sequences of the human genome confirmed the earlier predictions of about 30,000 protein-coding genes however that estimate has fallen to about 19,000 with the ongoing GENCODE annotation project. The number of noncoding genes is not known with certainty but the latest estimates from Ensembl suggest 26,000 noncoding genes. Essential genes of the synthetic organism, Syn 3 This definition assumes the abundant availability of all relevant nutrients and the absence of environmental stress. Only a small portion of an organism's genes are essential. In bacteria, an estimated 250–400 genes are essential for Escherichia coli and Bacillus subtilis, which is less than 10% of their genes. Half of these genes are orthologs in both organisms and are largely involved in protein synthesis. Although the number is more difficult to measure in higher eukaryotes, mice and humans are estimated to have around 2000 essential genes (~10% of their genes). The synthetic organism, Syn 3, has a minimal genome of 473 essential genes and quasi-essential genes (necessary for fast growth), although 149 have unknown function. Essential genes include housekeeping genes (critical for basic cell functions) as well as genes that are expressed at different times in the organisms development or life cycle. Housekeeping genes are used as experimental controls when analysing gene expression, since they are constitutively expressed at a relatively constant level. Genetic and genomic nomenclature Gene nomenclature was established by the HUGO Gene Nomenclature Committee (HGNC), a committee of the Human Genome Organisation, for each known human gene in the form of an approved gene name and symbol (short-form abbreviation), which can be accessed through a database maintained by HGNC. Symbols are chosen to be unique, and each gene has only one symbol (although approved symbols sometimes change). Symbols are preferably kept consistent with other members of a gene family and with homologs in other species, particularly the mouse due to its role as a common model organism. ==Genetic engineering==

Genetic engineering is the modification of an organism's genome through biotechnology. Since the 1970s, a variety of techniques have been developed to specifically add, remove and edit genes in an organism. Recently developed genome engineering techniques use engineered nuclease enzymes to create targeted DNA repair in a chromosome to either disrupt or edit a gene when the break is repaired. The related term synthetic biology is sometimes used to refer to extensive genetic engineering of an organism. Genetic engineering is now a routine research tool with model organisms. For example, genes are easily added to bacteria and lineages of knockout mice with a specific gene's function disrupted are used to investigate that gene's function. Many organisms have been genetically modified for applications in agriculture, industrial biotechnology, and medicine. For multicellular organisms, typically the embryo is engineered which grows into the adult genetically modified organism. However, the genomes of cells in an adult organism can be edited using gene therapy techniques to treat genetic diseases. ==See also==