Molecular biology is a branch of biology that concerns the molecular basis of biological activity between biomolecules in the various systems of a cell, including the interactions between DNA, RNA, proteins and their biosynthesis, as well as the regulation of these interactions. Writing in Nature in 1961, William Astbury described molecular biology as:...not so much a technique as an approach, an approach from the viewpoint of the so-called basic sciences with the leading idea of searching below the large-scale manifestations of classical biology for the corresponding molecular plan. It is concerned with the forms of biological molecules and is predominantly three-dimensional and structural – which does not mean, that it is a refinement of morphology, it must at the same time inquire into function. Researchers in molecular biology use specific techniques native to molecular biology but combine these with techniques and ideas from genetics and biochemistry. There is not a defined line between these disciplines.
This is shown in the following schematic that depicts one possible view of the relationships between the fields: Biochemistry is the study of the chemical substances and vital processes occurring in live organisms. Biochemists focus on the role and structure of biomolecules; the study of the chemistry behind biological processes and the synthesis of biologically active molecules are examples of biochemistry. Genetics is the study of the effect of genetic differences in organisms; this can be inferred by the absence of a normal component. The study of "mutants" – organisms which lack one or more functional components with respect to the so-called "wild type" or normal phenotype. Genetic interactions can confound simple interpretations of such "knockout" studies. Molecular biology is the study of molecular underpinnings of the processes of replication, transcription and cell function; the central dogma of molecular biology where genetic material is transcribed into RNA and translated into protein, despite being oversimplified, still provides a good starting point for understanding the field.
The picture has been revised in light of emerging novel roles for RNA. Much of molecular biology is quantitative, much work has been done at its interface with computer science in bioinformatics and computational biology. In the early 2000s, the study of gene structure and function, molecular genetics, has been among the most prominent sub-fields of molecular biology. Many other areas of biology focus on molecules, either directly studying interactions in their own right such as in cell biology and developmental biology, or indirectly, where molecular techniques are used to infer historical attributes of populations or species, as in fields in evolutionary biology such as population genetics and phylogenetics. There is a long tradition of studying biomolecules "from the ground up" in biophysics. One of the most basic techniques of molecular biology to study protein function is molecular cloning. In this technique, DNA coding for a protein of interest is cloned using polymerase chain reaction, and/or restriction enzymes into a plasmid.
A vector has 3 distinctive features: an origin of replication, a multiple cloning site, a selective marker antibiotic resistance. Located upstream of the multiple cloning site are the promoter regions and the transcription start site which regulate the expression of cloned gene; this plasmid can be inserted into either bacterial or animal cells. Introducing DNA into bacterial cells can be done by transformation via uptake of naked DNA, conjugation via cell-cell contact or by transduction via viral vector. Introducing DNA into eukaryotic cells, such as animal cells, by physical or chemical means is called transfection. Several different transfection techniques are available, such as calcium phosphate transfection, electroporation and liposome transfection; the plasmid may be integrated into the genome, resulting in a stable transfection, or may remain independent of the genome, called transient transfection. DNA coding for a protein of interest is now inside a cell, the protein can now be expressed.
A variety of systems, such as inducible promoters and specific cell-signaling factors, are available to help express the protein of interest at high levels. Large quantities of a protein can be extracted from the bacterial or eukaryotic cell; the protein can be tested for enzymatic activity under a variety of situations, the protein may be crystallized so its tertiary structure can be studied, or, in the pharmaceutical industry, the activity of new drugs against the protein can be studied. Polymerase chain reaction is an versatile technique for copying DNA. In brief, PCR allows a specific DNA sequence to be modified in predetermined ways; the reaction is powerful and under perfect conditions could amplify one DNA molecule to become 1.07 billion molecules in less than two hours. The PCR technique can be used to introduce restriction enzyme sites to ends of DNA molecules, or to mutate particular bases of DNA, the latter is a method referred to as site-directed mutagenesis. PCR can be used to determine whether a particular DNA fragment is found in a cDNA library.
PCR has many variations, like reverse transcription PCR for amplification of RNA, more quantitative PCR which allow for quantitative measurement of DNA or RNA molecules. Gel electrophoresis is one of the principal tools of molecular biology; the basic principle is that DNA, RNA, proteins can all be separated by means of an electric field and size. In agarose gel electrophoresis, DNA and RNA can be separated on th
Polymorphism in biology and zoology is the occurrence of two or more different morphs or forms referred to as alternative phenotypes, in the population of a species. To be classified as such, morphs must occupy the same habitat at the same time and belong to a panmictic population; the term polyphenism can be used to clarify. Genetic polymorphism is a term used somewhat differently by geneticists and molecular biologists to describe certain mutations in the genotype, such as single nucleotide polymorphisms that may not always correspond to a phenotype, but always corresponds to a branch in the genetic tree. See below. Polymorphism is common in nature. Polymorphism functions to retain variety of form in a population living in a varied environment; the most common example is sexual dimorphism. Other examples are mimetic forms of butterflies, human hemoglobin and blood types. According to the theory of evolution, polymorphism results from evolutionary processes, as does any aspect of a species, it is modified by natural selection.
In polyphenism, an individual's genetic makeup allows for different morphs, the switch mechanism that determines which morph is shown is environmental. In genetic polymorphism, the genetic makeup determines the morph; the term polymorphism refers to the occurrence of structurally and functionally more than two different types of individuals, called zooids, within the same organism. It is a characteristic feature of cnidarians. For example, Obelia has the gastrozooids. Although in general use, polymorphism is a broad term. In biology, polymorphism has been given a specific meaning. A more specific term, when only two forms occur, is dimorphism; the term omits characteristics showing continuous variation. Polymorphism deals with forms in which the variation is discrete or bimodal or polymodal. Morphs must occupy the same habitat at the same time; the use of the words "morph" or "polymorphism" for what is a visibly different geographical race or variant is common, but incorrect. The significance of geographical variation is in that it may lead to allopatric speciation, whereas true polymorphism takes place in panmictic populations.
The term was first used to describe visible forms, but nowadays it has been extended to include cryptic morphs, for instance blood types, which can be revealed by a test. Rare variations are not classified as polymorphisms, mutations by themselves do not constitute polymorphisms. To qualify as a polymorphism, some kind of balance must exist between morphs underpinned by inheritance; the criterion is that the frequency of the least common morph is too high to be the result of new mutations or, as a rough guide, that it is greater than 1%. Polymorphism crosses several discipline boundaries, including ecology and genetics, evolution theory, taxonomy and biochemistry. Different disciplines may give the same concept different names, different concepts may be given the same name. For example, there are the terms established in ecological genetics by E. B. Ford, for classical genetics by John Maynard Smith; the shorter term morphism may be more accurate than polymorphism, but is not used. It was the preferred term of the evolutionary biologist Julian Huxley.
Various synonymous terms exist for the various polymorphic forms of an organism. The most common are morpha, while a more formal term is morphotype. Form and phase are sometimes used, but are confused in zoology with "form" in a population of animals, "phase" as a color or other change in an organism due to environmental conditions. Phenotypic traits and characteristics are possible descriptions, though that would imply just a limited aspect of the body. In the taxonomic nomenclature of zoology, the word "morpha" plus a Latin name for the morph can be added to a binomial or trinomial name. However, this invites confusion with geographically variant ring species or subspecies if polytypic. Morphs have no formal standing in the ICZN. In botanical taxonomy, the concept of morphs is represented with the terms "variety", "subvariety" and "form", which are formally regulated by the ICN. Horticulturists sometimes confuse this usage of "variety" both with cultivar and with the legal concept "plant variety".
Three mechanisms may cause polymorphism: Genetic polymorphism – where the phenotype of each individual is genetically determined A conditional development strategy, where the phenotype of each individual is set by environmental cues A mixed development strategy, where the phenotype is randomly assigned during development Selection, whether natural or artificial, changes the frequency of morphs within a population. A genetic polymorphism persists over many generations, maintained by two or more opposed and powerful selection pressures. Diver found banding morphs in Cepaea nemoralis could be seen in prefossil shells going back to t
J. B. S. Haldane
John Burdon Sanderson Haldane was a British-Indian scientist known for his work in the study of physiology, evolutionary biology, mathematics. He made innovative contributions to the fields of biostatistics, his article on abiogenesis in 1929 introduced the "primordial soup theory", it became the foundation to build physical models for the chemical origin of life. Haldane established human gene maps for haemophilia and colour blindness on the X chromosome, codified Haldane's rule on sterility in the heterogametic sex of hybrids in species, he proposed that sickle-cell disease confers some immunity to malaria. He was the first to suggest the central idea of in vitro fertilisation, as well as concepts such as hydrogen economy and trans-acting regulation, coupling reaction, molecular repulsion, the darwin and organismal cloning. In 1957 he articulated Haldane's dilemma, a limit on the speed of beneficial evolution which subsequently proved incorrect, he willed his body for medical studies, as he wanted to remain useful in death.
He is remembered for coining the words "clone" and "cloning" in human biology, "ectogenesis". Haldane's first paper in 1915 demonstrated genetic linkage in mammals. Subsequent works established a unification of Mendelian genetics and Darwinian evolution by natural selection whilst laying the groundwork for modern evolutionary synthesis and thus helped to create population genetics. Haldane was a professed socialist, Marxist and humanist whose political dissent led him to leave England in 1956 and live in India, becoming a naturalised Indian citizen in 1961, he was the son of John Scott Haldane. Arthur C. Clarke credited him as "perhaps the most brilliant science populariser of his generation". Nobel laureate Peter Medawar called Haldane "the cleverest man I knew". According to Theodosius Dobzhansky, "Haldane was always recognized as a singular case". Haldane was born in Oxford to John Scott Haldane, a physiologist, scientist, a philosopher and a Liberal, Louisa Kathleen Trotter, a Conservative.
His younger sister, Naomi Mitchison, became a writer, his uncle was Viscount Haldane and his aunt the author Elizabeth Haldane. Descended from an aristocratic and secular family of the Clan Haldane, he would claim that his Y chromosome could be traced back to Robert the Bruce, he grew up at North Oxford. He learnt to read at the age of three, at four, after injuring his forehead he asked the doctor, "Is this oxyhaemoglobin or carboxyhaemoglobin?". From age eight he worked with his father in their home laboratory where he experienced his first self-experimentation, the method he would be famous for, he and his father became their own "human guinea pigs", such as in their investigation on the effects of poison gases. In 1899 his family moved to "Cherwell", a late Victorian house at the outskirts of Oxford with its own private laboratory, his formal education began in 1897 at Oxford Preparatory School, where he gained a First Scholarship in 1904 to Eton. In 1905 he joined Eton, where he experienced severe abuse from senior students for being arrogant.
The indifference of authority left him with a lasting hatred for the English education system. However, the ordeal did not stop him from becoming Captain of the school, he studied mathematics and classics at New College at the University of Oxford and obtained first-class honours in mathematical moderations in 1912 and first-class honours in Greats in 1914. He became engrossed in genetics and presented a paper on gene linkage in vertebrates in the summer of 1912, his first technical paper, a 30-page long article on haemoglobin function, was published that same year, as a co-author alongside his father. His education was interrupted by the First World War during which he fought in the British Army, being commissioned a temporary second lieutenant in the 3rd Battalion of the Black Watch on 15 August 1914, he was promoted to temporary captain on 18 October. He served in Iraq, where he was wounded, he relinquished his commission on 1 April 1920. For his ferocity and aggressiveness in battles, his commander called him the "bravest and dirtiest officer in my Army."Between 1919 and 1922 he was a Fellow of New College, where he researched physiology and genetics.
He moved to the University of Cambridge, where he accepted a readership in Biochemistry and taught until 1932. From 1927 until 1937 he was Head of Genetical Research at the John Innes Horticultural Institution. During his nine years at Cambridge, Haldane worked on enzymes and genetics the mathematical side of genetics, he was the Fullerian Professor of Physiology at the Royal Institution from 1930 to 1932 and in 1933 he became full Professor of Genetics at University College London, where he spent most of his academic career. Four years he became the first Weldon Professor of Biometry at University College London. In 1924, Haldane met Charlotte Franken. So that they could marry, Charlotte divorced Jack Burghes, causing some controversy. Haldane was dismissed from Cambridge for the way he handled his meeting with her, they married in 1926. Following their separation in 1942, the Haldanes divorced in 1945, he married Helen Spurway. Haldane, inspired by his father, would expose himself to danger to obtain data.
To test the effects of acidification of the blood he drank dilute hydrochloric acid, enclosed himself in an airtight room containing 7% carbon dioxide, found that it'gives one a rath
In biology, a mutation is the permanent alteration of the nucleotide sequence of the genome of an organism, virus, or extrachromosomal DNA or other genetic elements. Mutations result from errors during DNA replication or other types of damage to DNA, which may undergo error-prone repair, or cause an error during other forms of repair, or else may cause an error during replication. Mutations may result from insertion or deletion of segments of DNA due to mobile genetic elements. Mutations may or may not produce discernible changes in the observable characteristics of an organism. Mutations play a part in both normal and abnormal biological processes including: evolution and the development of the immune system, including junctional diversity; the genomes of RNA viruses are based on RNA rather than DNA. The RNA viral genome can be double single stranded. In some of these viruses replication occurs and there are no mechanisms to check the genome for accuracy; this error-prone process results in mutations.
Mutation can result in many different types of change in sequences. Mutations in genes can either have no effect, alter the product of a gene, or prevent the gene from functioning properly or completely. Mutations can occur in nongenic regions. One study on genetic variations between different species of Drosophila suggests that, if a mutation changes a protein produced by a gene, the result is to be harmful, with an estimated 70 percent of amino acid polymorphisms that have damaging effects, the remainder being either neutral or marginally beneficial. Due to the damaging effects that mutations can have on genes, organisms have mechanisms such as DNA repair to prevent or correct mutations by reverting the mutated sequence back to its original state. Mutations can involve the duplication of large sections of DNA through genetic recombination; these duplications are a major source of raw material for evolving new genes, with tens to hundreds of genes duplicated in animal genomes every million years.
Most genes belong to larger gene families of shared ancestry. Novel genes are produced by several methods through the duplication and mutation of an ancestral gene, or by recombining parts of different genes to form new combinations with new functions. Here, protein domains act as modules, each with a particular and independent function, that can be mixed together to produce genes encoding new proteins with novel properties. For example, the human eye uses four genes to make structures that sense light: three for cone cell or color vision and one for rod cell or night vision. Another advantage of duplicating a gene is. Other types of mutation create new genes from noncoding DNA. Changes in chromosome number may involve larger mutations, where segments of the DNA within chromosomes break and rearrange. For example, in the Homininae, two chromosomes fused to produce human chromosome 2. In evolution, the most important role of such chromosomal rearrangements may be to accelerate the divergence of a population into new species by making populations less to interbreed, thereby preserving genetic differences between these populations.
Sequences of DNA that can move about the genome, such as transposons, make up a major fraction of the genetic material of plants and animals, may have been important in the evolution of genomes. For example, more than a million copies of the Alu sequence are present in the human genome, these sequences have now been recruited to perform functions such as regulating gene expression. Another effect of these mobile DNA sequences is that when they move within a genome, they can mutate or delete existing genes and thereby produce genetic diversity. Nonlethal mutations increase the amount of genetic variation; the abundance of some genetic changes within the gene pool can be reduced by natural selection, while other "more favorable" mutations may accumulate and result in adaptive changes. For example, a butterfly may produce offspring with new mutations; the majority of these mutations will have no effect. If this color change is advantageous, the chances of this butterfly's surviving and producing its own offspring are a little better, over time the number of butterflies with this mutation may form a larger percentage of the population.
Neutral mutations are defined as mutations whose effects do not influence the fitness of an individual. These can increase in frequency over time due to genetic drift, it is believed that the overwhelming majority of mutations have no significant effect on an organism's fitness. DNA repair mechanisms are able to mend most changes before they become permanent mutations, many organisms have mechanisms for eliminating otherwise-permanently mutated somatic cells. Beneficial mutations can improve reproductive success. Mutationism is one of several alternatives to evolution by natural selection that have existed both before and after the publication of Charles Darwin's 1859 book, On the Origin of Species. In the theory, mutation was the source of novelty
Balancing selection refers to a number of selective processes by which multiple alleles are maintained in the gene pool of a population at frequencies larger than expected from genetic drift alone. This can happen by various mechanisms, in particular, when the heterozygotes for the alleles under consideration have a higher fitness than the homozygote. In this way genetic polymorphism is conserved. Evidence for balancing selection can be found in the number of alleles in a population which are maintained above mutation rate frequencies. All modern research has shown that this significant genetic variation is ubiquitous in panmictic populations. There are several mechanisms; the two major and most studied are frequency-dependent selection. In heterozygote advantage, or heterotic balancing selection, an individual, heterozygous at a particular gene locus has a greater fitness than a homozygous individual. Polymorphisms maintained by this mechanism are balanced polymorphisms. Due to unexpected high frequencies of heterozygotes, an elevated level of heterozygote fitness, heterozygotic advantage may be called "overdominance" in some literature.
A well-studied case is that of sickle cell anemia in humans, a hereditary disease that damages red blood cells. Sickle cell anemia is caused by the inheritance of an allele of the hemoglobin gene from both parents. In such individuals, the hemoglobin in red blood cells is sensitive to oxygen deprivation, which results in shorter life expectancy. A person who inherits the sickle cell gene from one parent and a normal hemoglobin allele from the other, has a normal life expectancy. However, these heterozygote individuals, known as carriers of the sickle cell trait, may suffer problems from time to time; the heterozygote is resistant to the malarial parasite which kills a large number of people each year. This is an example of balancing selection between the fierce selection against homozygous sickle-cell sufferers, the selection against the standard HgbA homozygotes by malaria; the heterozygote has a permanent advantage. Maintenance of the HgbS allele through positive selection is supported by significant evidence that heterozygotes have decreased fitness in regions where malaria is not prevalent.
In Surinam, for example, the allele is maintained in the gene pools of descendants of African slaves, as the Surinam suffers from perennial malaria outbreaks. Curacao, which has a significant population of individuals descending from African slaves, lacks the presence of widespread malaria, therefore lacks the selective pressure to maintain the HgbS allele. In Curacao, the HgbS allele has decreased in frequency over the past 300 years, will be lost from the gene pool due to heterozygote disadvantage. Frequency-dependent selection occurs when the fitness of a phenotype is dependent on its frequency relative to other phenotypes in a given population. In positive frequency-dependent selection the fitness of a phenotype increases as it becomes more common. In negative frequency-dependent selection the fitness of a phenotype increases as it becomes less common. For example, in prey switching, rare morphs of prey are fitter due to predators concentrating on the more frequent morphs; as predation drives the demographic frequencies of the common morph of prey down, the once rare morph of prey becomes the more common morph.
Thus, the morph of advantage now is the morph of disadvantage. This may lead to bust cycles of prey morphs. Host-parasite interactions may drive negative frequency-dependent selection, in alignment with the Red Queen hypothesis. For example, parasitism of freshwater New Zealand snail by the trematode Microphallus sp. results in decreasing frequencies of the most hosted genotypes across several generations. The more common a genotype became in a generation, the more vulnerable to parasitism by Microphallus sp. it became. Note that in these examples that no one phenotypic morph, nor one genotype is extinguished from a population, nor is one phenotypic morph nor genotype selected for fixation. Thus, polymorphism is maintained by negative frequency-dependent selection; the fitness of a genotype may vary between larval and adult stages, or between parts of a habitat range. Species in their natural habitat are far more complex than the typical textbook examples; the grove snail, Cepaea nemoralis, is famous for the rich polymorphism of its shell.
The system is controlled by a series of multiple alleles. Unbanded is the top dominant trait, the forms of banding are controlled by modifier genes. In England the snail is preyed upon by the song thrush Turdus philomelos, which breaks them open on thrush anvils. Here fragments accumulate; the thrushes hunt by sight, capture selectively those forms which match the habitat least well. Snail colonies are found in woodland and grassland, the predation determines the proportion of phenotypes found in each colony. A second kind of selection operates on the snail, whereby certain heterozygotes have a physiological advantage over the homozygotes. Thirdly, apostatic selection is with the birds preferentially taking the most common morph; this is the'search pattern' effect, where a predominantly visual predator persists in targeting the morph which gave a good result though other morphs are available. The polymorphism survives in all habitats, though the proportions of morphs varies considerably
Charles Robert Darwin, was an English naturalist and biologist, best known for his contributions to the science of evolution. His proposition that all species of life have descended over time from common ancestors is now accepted, considered a foundational concept in science. In a joint publication with Alfred Russel Wallace, he introduced his scientific theory that this branching pattern of evolution resulted from a process that he called natural selection, in which the struggle for existence has a similar effect to the artificial selection involved in selective breeding. Darwin published his theory of evolution with compelling evidence in his 1859 book On the Origin of Species, overcoming scientific rejection of earlier concepts of transmutation of species. By the 1870s, the scientific community and a majority of the educated public had accepted evolution as a fact. However, many favoured competing explanations, it was not until the emergence of the modern evolutionary synthesis from the 1930s to the 1950s that a broad consensus developed in which natural selection was the basic mechanism of evolution.
Darwin's scientific discovery is the unifying theory of the life sciences, explaining the diversity of life. Darwin's early interest in nature led him to neglect his medical education at the University of Edinburgh. Studies at the University of Cambridge encouraged his passion for natural science, his five-year voyage on HMS Beagle established him as an eminent geologist whose observations and theories supported Charles Lyell's uniformitarian ideas, publication of his journal of the voyage made him famous as a popular author. Puzzled by the geographical distribution of wildlife and fossils he collected on the voyage, Darwin began detailed investigations, in 1838 conceived his theory of natural selection. Although he discussed his ideas with several naturalists, he needed time for extensive research and his geological work had priority, he was writing up his theory in 1858 when Alfred Russel Wallace sent him an essay that described the same idea, prompting immediate joint publication of both of their theories.
Darwin's work established evolutionary descent with modification as the dominant scientific explanation of diversification in nature. In 1871 he examined human evolution and sexual selection in The Descent of Man, Selection in Relation to Sex, followed by The Expression of the Emotions in Man and Animals, his research on plants was published in a series of books, in his final book, The Formation of Vegetable Mould, through the Actions of Worms, he examined earthworms and their effect on soil. Darwin has been described as one of the most influential figures in human history, he was honoured by burial in Westminster Abbey. Since 2008, a statue of Charles Darwin occupies the place of honour at London's Natural History Museum. Charles Robert Darwin was born in Shrewsbury, Shropshire, on 12 February 1809, at his family's home, The Mount, he was the fifth of six children of wealthy society doctor and financier Robert Darwin and Susannah Darwin. His grandfathers Erasmus Darwin and Josiah Wedgwood were both prominent abolitionists.
Both families were Unitarian, though the Wedgwoods were adopting Anglicanism. Robert Darwin, himself a freethinker, had baby Charles baptised in November 1809 in the Anglican St Chad's Church, but Charles and his siblings attended the Unitarian chapel with their mother; the eight-year-old Charles had a taste for natural history and collecting when he joined the day school run by its preacher in 1817. That July, his mother died. From September 1818, he joined his older brother Erasmus attending the nearby Anglican Shrewsbury School as a boarder. Darwin spent the summer of 1825 as an apprentice doctor, helping his father treat the poor of Shropshire, before going to the University of Edinburgh Medical School with his brother Erasmus in October 1825. Darwin found lectures dull and surgery distressing, so he neglected his studies, he learned taxidermy in around 40 daily hour-long sessions from John Edmonstone, a freed black slave who had accompanied Charles Waterton in the South American rainforest.
In Darwin's second year at the university he joined the Plinian Society, a student natural-history group featuring lively debates in which radical democratic students with materialistic views challenged orthodox religious concepts of science. He assisted Robert Edmond Grant's investigations of the anatomy and life cycle of marine invertebrates in the Firth of Forth, on 27 March 1827 presented at the Plinian his own discovery that black spores found in oyster shells were the eggs of a skate leech. One day, Grant praised Lamarck's evolutionary ideas. Darwin was astonished by Grant's audacity, but had read similar ideas in his grandfather Erasmus' journals. Darwin was rather bored by Robert Jameson's natural-history course, which covered geology—including the debate between Neptunism and Plutonism, he learned the classification of plants, assisted with work on the collections of the University Museum, one of the largest museums in Europe at the time. Darwin's neglect of medical studies annoyed his father, who shrewdly sent him to Christ's College, Cambridge, to study for a Bachelor of Arts degree as the first step towards becoming an Anglican country parson.
As Darwin was unqualified for the Tripos, he joined the ordinary degree course in January 1828. He preferred shooting to studying, his cousin William Darwin Fox introduced him to the popular craze for beetle collecting.
Nearly neutral theory of molecular evolution
The nearly neutral theory of molecular evolution is a modification of the neutral theory of molecular evolution that accounts for the fact that not all mutations are either so deleterious such that they can be ignored, or else neutral. Deleterious mutations are reliably purged only when their selection coefficient are greater than one divided by the effective population size. In larger populations, a higher proportion of mutations exceed this threshold for which genetic drift cannot overpower selection, leading to fewer fixation events and so slower molecular evolution; the nearly neutral theory was proposed by Tomoko Ohta in 1973. The population-size-dependent threshold for purging mutations has been called the "drift barrier" by Michael Lynch, used to explain differences in genomic architecture among species. According to the neutral theory of molecular evolution, the rate at which molecular changes accumulate between species should be equal to the rate of neutral mutations and hence constant across species.
However, this is a per-generation rate. Since larger organisms have longer generation times, the neutral theory predicts that their rate of molecular evolution should be slower. However, molecular evolutionists found that rates of protein evolution were independent of generation time. Noting that population size is inversely proportional to generation time, Tomoko Ohta proposed that if most amino acid substitutions are deleterious, this would increase the rate of neutral mutation rate in small populations, which could offset the effect of long generation times. However, because noncoding DNA substitutions tend to be more neutral, independent of population size, their rate of evolution is predicted to depend on population size / generation time, unlike the rate of non-synonymous changes. In this case, the faster rate of neutral evolution in proteins expected in small populations is offset by longer generation times, but in large populations with short generation times, noncoding DNA evolves faster while protein evolution is retarded by selection In 1973, Ohta published a short letter in Nature suggesting that a wide variety of molecular evidence supported the theory that most mutation events at the molecular level are deleterious rather than neutral.
Between and the early 1990s, many studies of molecular evolution used a "shift model" in which the negative effect on the fitness of a population due to deleterious mutations shifts back to an original value when a mutation reaches fixation. In the early 1990s, Ohta developed a "fixed model" that included both beneficial and deleterious mutations, so that no artificial "shift" of overall population fitness was necessary. According to Ohta, the nearly neutral theory fell out of favor in the late 1980s, because the mathematically simpler neutral theory for the widespread molecular systematics research that flourished after the advent of rapid DNA sequencing; as more detailed systematics studies started to compare the evolution of genome regions subject to strong selection versus weaker selection in the 1990s, the nearly neutral theory and the interaction between selection and drift have once again become an important focus of research. The rate of substitution, ρ is ρ = u g N e P ¯ f i x,where u is the mutation rate, g is the generation time, N e is the effective population size.
The last term is the probability. Early models assumed that u is constant between species, that g increases with N e. Kimura’s equation for the probability of fixation in a haploid population gives: P f i x = 1 − e − s 1 − e − s N e,where s is the selection coefficient of a mutation; when | s | ≪ 1 N e, P f i x = 1 N e, when − s ≫ 1 N e, P f i x decreases exponentially with N e. Mutations with − s ≃ 1; these mutations can fix in small- N e populations through genetic drift. In large- N e populations, these mutations are purged by selection. If nearly neutral mutations are common the proportion for which P f